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Arredouani A. GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? Pharmacol Ther 2025; 269:108824. [PMID: 39983843 DOI: 10.1016/j.pharmthera.2025.108824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/07/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.
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Affiliation(s)
- Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Qatar.
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Yepes-Cortés CA, Cardenas-Moreno IC, Daza-Arnedo R, Feriz-Bonelo KM, Yama-Mosquera E, Ramirez-Rincón AH, Castillo-Barrios GA, Suarez-Rodriguez AF, Carreño-Jiménez J, Builes-Montaño CE. Combining GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Scoping Review and Expert Insights for Clinical Practice Utilizing the Nominal Group Technique. Diabetes Ther 2025; 16:813-849. [PMID: 40126829 PMCID: PMC12006584 DOI: 10.1007/s13300-025-01722-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 02/28/2025] [Indexed: 03/26/2025] Open
Abstract
INTRODUCTION Treating type 2 diabetes has shifted from a gluco-centric approach to broader cardio-renal-metabolic strategy, driven by the use of disease-modifying medications. Traditionally, diabetes management has relied on stepwise medication addition based on failures in glucose control. However, the benefits and risks of combining glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain inadequately understood. METHODS This study conducted a scoping review to examine the available clinical research on the benefits and risks of combining GLP1-RAs and SGLT2is. Additionally, the nominal group technique was used to gather insights from medical experts from different areas regarding the combined therapy's daily clinical use, concerns, and limitations. The review followed the guidelines outlined in the Joanna Briggs Institute Reviewer's Manual and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews). RESULTS The final report includes 50 studies. The most common designs are observational studies. The median (IQR) number of patients across studies was 355 (1295). Studies reporting metabolic outcomes were the most common. The follow-up time ranges from 1.5 to 60 months. Although limited, the available evidence seems to support the combined use of GLP1-RAs and SGLT2is. The experts agreed that the underlying mechanisms appear synergistic rather than antagonistic for most outcomes. CONCLUSIONS Combining medical therapy is common in diabetes treatment and may occur naturally in everyday practice. Limited evidence suggests that combined SGLT2is/GLP1-RAs therapy can potentially improve most but not all outcomes. Quality evidence and better-defined outcomes are paramount to guide the selection of patients for combined therapy.
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Affiliation(s)
- Carlos A Yepes-Cortés
- Hospital Universitario San Ignacio and Pontificia Universidad Javeriana, Bogotá, Colombia
| | | | | | | | | | | | | | | | | | - Carlos E Builes-Montaño
- The Department of Internal Medicine, Endocrinology Section, Hospital Pablo Tobón Uribe and Universidad de Antioquia, Medellin, Colombia.
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Mousavi A, Shojaei S, Soleimani H, Semirani-Nezhad D, Ebrahimi P, Zafari A, Ebrahimi R, Roozbehi K, Harrison A, Syed MA, Kuno T, Askari MK, Almandoz JP, Jun J, Hosseini K. Safety, efficacy, and cardiovascular benefits of combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists in patients with diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Diabetol Metab Syndr 2025; 17:68. [PMID: 39994802 PMCID: PMC11849334 DOI: 10.1186/s13098-025-01635-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND The potential benefits and risks of combination therapy with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus monotherapy remain a subject of debate to optimize metabolic and cardiovascular outcomes in patients with type 2 diabetes mellitus. This study aims to systematically review and meta-analyze the available evidence from randomized controlled trials. METHODS A comprehensive search identified relevant randomized controlled trials comparing combination therapy with SGLT-2i and GLP-1RA to monotherapy or treatment as usual (TAU). The main outcome was the incidence of hospitalization for heart failure. Other outcomes included major adverse cardiovascular events (MACE) (cardiovascular mortality, all-cause mortality, stroke, and myocardial infarction), changes in metabolic parameters, and adverse events. Random-effects meta-analysis estimated risk ratios (RRs), mean difference (MD), and 95% confidence intervals (CIs). We assessed the risk of bias in included studies using the Cochrane ROB 2.0 tool. RESULTS The meta-analysis included 10 randomized controlled trials with 42,651 participants, of which 2,820 were on combination therapy and the rest on SGLT-2i (37.1%), GLP-1RA (20.1%) monotherapies or TAU (42.8%). Combination therapy had a lower risk of hospitalization for heart failure versus GLP-1RA monotherapy (RR = 0.37, 95% CI 0.22; 0.65), SGLT-2i monotherapy (RR = 0.37, 95% CI 0.19; 0.75), and TAU (RR = 0.43, 95% CI 0.24; 0.75), respectively. Combination therapy also had a significantly lower risk of MACE versus TAU (RR = 0.73, 95% CI 0.61; 0.88). Combination therapy showed greater weight loss and hemoglobin A1c reduction versus SGLT-2i monotherapy (MD = -2.20, 95% CI -3.09; -1.31 and MD = -0.74, 95% CI -1.21; -0.27), respectively, while no difference was noted versus GLP-1RA monotherapy. The incidence of nausea and diarrhea was higher with combination therapy versus SGLT-2i monotherapy (MD = 3.34, 95% CI 1.74; 6.43 and MD = 1.75, 95% CI 1.10; 2.77), respectively. CONCLUSION Combination therapy with SGLT-2i and GLP-1RA may provide superior cardiovascular, weight, and Hemoglobin A1c outcomes versus monotherapy despite higher gastrointestinal adverse events. These results may impact the management of patients with metabolic and cardiovascular diseases and highlight the need for further research on combination therapy to optimize outcomes.
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Affiliation(s)
- Asma Mousavi
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave, Tehran, Iran
| | - Shayan Shojaei
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave, Tehran, Iran
| | - Hamidreza Soleimani
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave, Tehran, Iran
| | | | - Pouya Ebrahimi
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave, Tehran, Iran
| | - Ali Zafari
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khatere Roozbehi
- School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Anil Harrison
- Internal Medicine, Midwestern University, Arizona, USA
| | | | - Toshiki Kuno
- Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Jaime P Almandoz
- Department of Internal Medicine, Division of Endocrinology, UT Southwestern Medical Center, Dallas, TX, USA
| | - John Jun
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Ohio, USA
| | - Kaveh Hosseini
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, North Kargar Ave, Tehran, Iran.
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Vale C, Lourenço IM, Jordan G, Golovaty I, Torres H, Moin T, Buysschaert M, Neves JS, Bergman M. Early combination therapy with SGLT2i and GLP-1 RA or dual GIP/GLP-1 RA in type 2 diabetes. Diabetes Obes Metab 2025; 27:468-481. [PMID: 39604324 DOI: 10.1111/dom.16077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/31/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.
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Affiliation(s)
- Catarina Vale
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Internal Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Inês Mariana Lourenço
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | - Ilya Golovaty
- General Medicine Service, VA Puget Sound Health Care System, Seattle, Washington, USA
- Division of General Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Hugo Torres
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Tannaz Moin
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
- HSR&D Center for the Study of Healthcare Innovation, Implementation & Policy, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - João Sérgio Neves
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Michael Bergman
- Holman Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Population Health, VA New York Harbor Healthcare System, New York University Grossman School of Medicine, New York, New York, USA
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Martha S, Jangam PH, Bhansali SG. Influence of Dapagliflozin Dosing on Low-Density Lipoprotein Cholesterol in Type 2 Diabetes Mellitus: A Systematic Literature Review and Meta-Analysis. J Clin Pharmacol 2024; 64:1528-1540. [PMID: 39087862 DOI: 10.1002/jcph.6105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
A systematic literature review and meta-analysis was performed to evaluate the effects of dapagliflozin on low-density lipoprotein (LDL) cholesterol in type 2 diabetes mellitus. Data on changes in LDL cholesterol, adverse cardiac events (ACEs), glycated hemoglobin (HbA1c), and fasting blood glucose (FBG) were pooled in a meta-analysis. Data from dose comparison trials were separately pooled, and meta-analysis was conducted by using RevMan (5.4.1) and R (4.1.2). Dapagliflozin increased LDL cholesterol by 2.33 mg/dL (95% CI, 1.46 to 3.19; I2 = 0%; P < .00001), increased risk of ACEs by 1.56 (95% CI, 1.02 to 2.39; I2 = 0%; P < .04), decreased HbA1c by -0.41% (95% CI, -0.44 to -0.39; I2 = 85%; P < .00001), and decreased FBG by -13.51 mg/dL (95% CI, -14.43 to -12.59; I2 = 92%; P < .00001) versus any placebo or active comparator. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 1.71 mg/dL (95% CI, -1.20 to 4.62; I2 = 53%; P = .25) versus a 5 mg dose and by 1.04 mg/dL (95% CI, -1.17 to 3.26; I2 = 62%; P = .36) versus a 2.5 mg dose. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 3.13 mg/dL (95% CI, 1.31 to 4.95; I2 = 0%; P = .0008), increased the risk of ACEs by 1.26 (95% CI, 0.56 to 2.87; I2 = 0%; P = .58), decreased HbA1c by -0.4% (95% CI, -0.45 to -0.35; I2 = 89%; P < .00001), and decreased FBG by -8.39 mg/dL (95% CI, -10 to -6.77; I2 = 96%; P < .00001) versus a placebo or active comparator. Dapagliflozin monotherapy resulted in a minimal but statistically significantly (P = .0002) increase in LDL cholesterol. However, this minor change does not increase the risk of ACEs (P = .17) when compared with placebo or active comparator.
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Affiliation(s)
- Srinivas Martha
- Excelra Knowledge Solutions, NSL SEZ ARENA, IDA Uppal, Hyderabad, Telangana, India
| | | | - Suraj G Bhansali
- Excelra Knowledge Solutions, NSL SEZ ARENA, IDA Uppal, Hyderabad, Telangana, India
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Tuersun A, Hou G, Cheng G. Efficacy and safety of the combination or monotherapy with GLP-1 receptor agonists and SGLT-2 inhibitors in Type 2 diabetes mellitus: An update systematic review and meta-analysis. Am J Med Sci 2024; 368:579-588. [PMID: 38977245 DOI: 10.1016/j.amjms.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024]
Abstract
PURPOSE To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter2(SGLT-2) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM). METHODS To construct an exhaustive database of randomized controlled trials (RCTs) concerning SGLT-2 inhibitors and GLP-1 agonists, a methodical search was undertaken across a range of databases, such as Embase, PubMed, and the Cochrane Central Register of Controlled Trials, from their inception to January 2023. Following this, a meta-analysis was executed to amalgamate the collected data, which allowed for the calculation of standardized mean differences (SMDs), odds ratios (ORs), and 95 % confidence intervals (CIs) for a spectrum of outcomes. This analytical approach was designed to yield a quantitative evaluation of the therapeutic efficacy and safety profile of SGLT-2 inhibitors and GLP-1 agonists for the treatment of diabetes mellitus. RESULTS When compared to GLP-1 agonist therapy alone, the combination therapy did not significantly reduce fasting plasma glucose (FPG) levels (95 % confidence interval [CI]: -0.27, 0.10; p = 0.35), body weight (95 % CI: -0.18, 0.18; p = 1.00), Glycosylated Hemoglobin, Type A1C (HbA1c) (95 % CI: -0.29, 0.07; p = 0.22), or systolic blood pressure (SBP) values (95 % CI: -0.29, 0.06; p = 0.21). In contrast, when compared to SGLT-2 inhibitor therapy alone, combination therapy significantly decreased FPG by 0.24 mmol/L (95 % CI: -0.43, -0.05; p = 0.01), HbA1c by 0.45 % (95 % CI: -0.72, -0.18; p = 0.001), and SBP by 0.12 mmHg (95 % CI: -0.24, 0.00; p = 0.05). However, the combination therapy failed to demonstrate a significant reduction in body weight when compared with either SGLT-2 inhibitor therapy (95 % CI: -0.20, 0.05; p = 0.24) or GLP-1 agonist therapy (95 % CI: -0.18, 0.18; p = 1.00). Additionally, the combination therapy did not increase the incidence of hypoglycemia. It should be noted that data regarding mortality and cardiovascular outcomes were limited. CONCLUSIONS The combination treatment of SGLT-2 inhibitors and GLP-1 receptor agonists effectively reduces HbA1c, FPG, and SBP without elevating the risk of hypoglycemia when compared to monotherapy with SGLT-2 inhibitors. However, these beneficial effects were not observed when the combination therapy was compared with GLP-1 receptor agonist treatment alone.
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Affiliation(s)
- Adili Tuersun
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Guanxin Hou
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Gang Cheng
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
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Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab 2024; 26:5376-5389. [PMID: 39267269 DOI: 10.1111/dom.15901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 09/17/2024]
Abstract
AIM Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.
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Affiliation(s)
- Li Geng
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bing Sun
- Department of Neurology, Changchun Central Hospital, Changchun, China
| | - Yan Chen
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
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Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G, Zhang Y, Shen S, Tong N. Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduct Target Ther 2024; 9:262. [PMID: 39353925 PMCID: PMC11445387 DOI: 10.1038/s41392-024-01951-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/21/2024] [Accepted: 08/06/2024] [Indexed: 10/03/2024] Open
Abstract
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".
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Affiliation(s)
- Xi Lu
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ruining Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ge Peng
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sumin Shen
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China.
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Drake T, Landsteiner A, Langsetmo L, MacDonald R, Anthony M, Kalinowski C, Ullman K, Billington CJ, Kaka A, Sultan S, Wilt TJ. Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med 2024; 177:618-632. [PMID: 38639549 DOI: 10.7326/m23-1490] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE American College of Physicians. (PROSPERO: CRD42022322129).
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Affiliation(s)
- Tyler Drake
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Adrienne Landsteiner
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Lisa Langsetmo
- Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Roderick MacDonald
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Maylen Anthony
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Caleb Kalinowski
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Kristen Ullman
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Charles J Billington
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Anjum Kaka
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Shahnaz Sultan
- Department of Medicine, University of Minnesota, and Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (S.S.)
| | - Timothy J Wilt
- Department of Medicine, VA Health Care System; Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Health Policy & Management, School of Public Health, University of Minnesota, Minneapolis, Minnesota (T.J.W.)
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10
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Terenzi DC, Bakbak E, Teoh H, Krishnaraj A, Puar P, Rotstein OD, Cosentino F, Goldenberg RM, Verma S, Hess DA. Restoration of blood vessel regeneration in the era of combination SGLT2i and GLP-1RA therapy for diabetes and obesity. Cardiovasc Res 2024; 119:2858-2874. [PMID: 38367275 DOI: 10.1093/cvr/cvae016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/20/2022] [Accepted: 01/05/2023] [Indexed: 02/19/2024] Open
Abstract
Ischaemic cardiovascular diseases, including peripheral and coronary artery disease, myocardial infarction, and stroke, remain major comorbidities for individuals with type 2 diabetes (T2D) and obesity. During cardiometabolic chronic disease (CMCD), hyperglycaemia and excess adiposity elevate oxidative stress and promote endothelial damage, alongside an imbalance in circulating pro-vascular progenitor cells that mediate vascular repair. Individuals with CMCD demonstrate pro-vascular 'regenerative cell exhaustion' (RCE) characterized by excess pro-inflammatory granulocyte precursor mobilization into the circulation, monocyte polarization towards pro-inflammatory vs. anti-inflammatory phenotype, and decreased pro-vascular progenitor cell content, impairing the capacity for vessel repair. Remarkably, targeted treatment with the sodium-glucose cotransporter-2 inhibitor (SGLT2i) empagliflozin in subjects with T2D and coronary artery disease, and gastric bypass surgery in subjects with severe obesity, has been shown to partially reverse these RCE phenotypes. SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the management of individuals with T2D and comorbid obesity. In addition to glucose-lowering action, both drug classes have been shown to induce weight loss and reduce mortality and adverse cardiovascular outcomes in landmark clinical trials. Furthermore, both drug families also act to reduce systemic oxidative stress through altered activity of overlapping oxidase and antioxidant pathways, providing a putative mechanism to augment circulating pro-vascular progenitor cell content. As SGLT2i and GLP-1RA combination therapies are emerging as a novel therapeutic opportunity for individuals with poorly controlled hyperglycaemia, potential additive effects in the reduction of oxidative stress may also enhance vascular repair and further reduce the ischaemic cardiovascular comorbidities associated with T2D and obesity.
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Affiliation(s)
- Daniella C Terenzi
- UCD School of Medicine, University College Dublin, Belfield, Dublin 4 D04 V1W8, Ireland
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
| | - Ehab Bakbak
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3J3, Canada
| | - Hwee Teoh
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
- Division of Endocrinology and Metabolism, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
| | - Aishwarya Krishnaraj
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3J3, Canada
| | - Pankaj Puar
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
| | - Ori D Rotstein
- Division of General Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
- Department of Surgery, University of Toronto, Stewart Building, 149 College Street, 5th floor, Toronto, ON M5T 1P5, Canada
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Solnavagen 1, 171 77 Solna, Sweden
| | | | - Subodh Verma
- Division of Cardiovascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3J3, Canada
- Department of Surgery, University of Toronto, Stewart Building, 149 College Street, 5th floor, Toronto, ON M5T 1P5, Canada
| | - David A Hess
- Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3J3, Canada
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cells Biology, Robarts Research Institute, University of Western Ontario, 1151 Richmond Street North, London, ON N6H 0E8, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street North, London, ON N6H 0E8, Canada
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11
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Liaghatdar A, Mazaheri-Tehrani S, Fakhrolmobasheri M. Management of Hypertension in Patients With Polycystic Ovarian Syndrome: A Mini-Review. Cardiol Rev 2024:00045415-990000000-00199. [PMID: 38305409 DOI: 10.1097/crd.0000000000000635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Polycystic ovarian syndrome (PCOS) is a common problem among young women. It is characterized mainly by hyperandrogenism features, such as hirsutism, menstrual problems, and anovulation. Diagnosis is based on the existence of 2 items out of, oligo-ovulation, hyperandrogenism features, and ultrasounds findings. Cardiovascular complications such as hypertension are a prevalent serious condition in these patients which is mainly predisposed by the high levels of androgens, and insulin resistance. High blood pressure should be controlled well to prevent the progression of other serious conditions. Various antihypertensive drugs could be prescribed. However, in selecting an antihypertensive medication, other therapeutic properties of the drug should also be considered. Up to now, many clinicians do not differ between PCOS patients with hypertension and other hypertensive patients. However, being aware of the potential effects of each hypertension drug could help to choose better options for the patient. Here is a brief review of how each antihypertensive drug could affect PCOS women and if they cause any improvement in the disorder progression.
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Affiliation(s)
- Amin Liaghatdar
- From the Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sadegh Mazaheri-Tehrani
- From the Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Fakhrolmobasheri
- From the Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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12
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Lunati ME, Cimino V, Bernasconi D, Gandolfi A, Morpurgo PS, Tinari C, Lazzaroni E, Baruffaldi L, Muratori M, Montefusco L, Pastore I, Rossi A, Franzetti IG, Muratori F, Manfrini R, Disoteo OE, Terranova R, Desenzani P, Girelli A, Ghelardi R, D'Addio F, Ben Nasr M, Berra C, Folli F, Bucciarelli L, Fiorina P. Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide. Pharmacol Res 2024; 199:107040. [PMID: 38128857 DOI: 10.1016/j.phrs.2023.107040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/10/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023]
Abstract
Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.
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Affiliation(s)
| | - Vincenzo Cimino
- Department of Biomedical and Clinical Sciences L. Sacco Endocrinology and Diabetology, Milan, Italy
| | | | | | | | - Camilla Tinari
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Elisa Lazzaroni
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Baruffaldi
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Milena Muratori
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Antonio Rossi
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Fabrizio Muratori
- Division of Endocrinology and Diabetology, Sant'Anna Hospital, Como, Italy
| | - Roberto Manfrini
- Endocrinology and Metabolism, Department of Health Science, Università di Milano, ASST Santi Paolo e Carlo, Milan, Italy
| | | | - Rosa Terranova
- Division of Diabetology, Niguarda Hospital, Milan, Italy
| | | | | | | | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Italy
| | - Cesare Berra
- IRCCS MultiMedica Sesto San Giovanni, Milano, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, Università di Milano, ASST Santi Paolo e Carlo, Milan, Italy
| | | | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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13
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Berra C, Manfrini R, Mirani M, Bucciarelli L, Zakaria AS, Piccini S, Ghelardi R, Lunati ME, Rodovalho S, Bifari F, Fiorina P, Folli F. AWARE A novel web application to rapidly assess cardiovascular risk in type 2 diabetes mellitus. Acta Diabetol 2023; 60:1257-1266. [PMID: 37270748 PMCID: PMC10359387 DOI: 10.1007/s00592-023-02115-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/07/2023] [Indexed: 06/05/2023]
Abstract
AIM To describe the development of the AWARE App, a novel web application for the rapid assessment of cardiovascular risk in Type 2 Diabetes Mellitus (T2DM) patients. We also tested the feasibility of using this App in clinical practice. METHODS Based on 2019 European Society of Cardiology/European Association for the Study of Diabetes criteria for cardiovascular risk stratification in T2DM, the AWARE App classifies patients into very high (VHCVR), high (HCVR) and moderate (MCVR) cardiovascular risk categories. In this retrospective clinical study, we employed the App to assess the cardiovascular risk of T2DM patients, while also collecting data about current glycaemic control and pharmacological treatment. RESULTS 2243 T2DM consecutive patients were evaluated. 72.2% of the patients were VHCVR, 8.9% were HCVR, 0.8% were MCVR while 18.2% did not fit into any of the risk categories and were classified as "moderate-to-high" (MHCVR). Compared with the other groups, patients with VHCVD were more frequently ≥ 65 years old (68.9%), with a longer disease duration (≥ 10 years [56.8%]), a history of cardiovascular disease (41.4%), organ damage (35.5%) and a higher numbers of cardiovascular risk factors. Patients with MHCVD generally had disease duration < 10 years (96%), younger age (50-60 years [55%]), no history of cardiovascular disease, no organ damage, and 1-2 cardiovascular risk factors (89%). Novel drugs such as Glucagon Like Peptyde 1 Receptor Agonists or Sodium-Glucose Linked Transporter 2 inhibitors were prescribed only to 26.3% of the patients with VHCVR and to 24.7% of those with HCVR. Glycaemic control was unsatisfactory in this patients population (HbA1c 7.5 ± 3.4% [58.7 ± 13.4 mmol/mol]). CONCLUSIONS The AWARE App proved to be a practical tool for cardiovascular risk stratification of T2DM patients in real-world clinical practice.
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Affiliation(s)
- Cesare Berra
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS Multimedica, Milan, Italy.
| | - Roberto Manfrini
- Departmental Unit of Diabetes and Metabolism, San Paolo Hospital, ASST Santi Paolo E Carlo, Milan, Italy
- Endocrinology and Metabolism, Department of Health Science, Università Degli Studi Di Milano, Milan, Italy
| | - Marco Mirani
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Loredana Bucciarelli
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS Multimedica, Milan, Italy
| | - Ahmed S Zakaria
- Departmental Unit of Diabetes and Metabolism, San Paolo Hospital, ASST Santi Paolo E Carlo, Milan, Italy
| | - Sara Piccini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Renata Ghelardi
- UOC Coordinamento E Integrazione Rete ASST Melegnano E Della Martesana, Melegnano, Milan, Italy
| | | | - Sylka Rodovalho
- Endocrinology and Metabolism, Pontificia Università de Campinas, Campinas, Sao Paulo State, Brazil
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, Italy
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
- International Center for T1D, Pediatric Clinical Research Center Romeo Ed Enrica Invernizzi, DIBIC, Università Di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Franco Folli
- Departmental Unit of Diabetes and Metabolism, San Paolo Hospital, ASST Santi Paolo E Carlo, Milan, Italy.
- Endocrinology and Metabolism, Department of Health Science, Università Degli Studi Di Milano, Milan, Italy.
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14
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Castro Conde A, Marzal Martín D, Campuzano Ruiz R, Fernández Olmo MR, Morillas Ariño C, Gómez Doblas JJ, Gorriz Teruel JL, Mazón Ramos P, García-Moll Marimon X, Soler Romeo MJ, León Jiménez D, Arrarte Esteban V, Obaya Rebollar JC, Escobar Cervantes C, Gorgojo Martínez JJ. Comprehensive Cardiovascular and Renal Protection in Patients with Type 2 Diabetes. J Clin Med 2023; 12:3925. [PMID: 37373620 PMCID: PMC10299569 DOI: 10.3390/jcm12123925] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/19/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Type 2 diabetes (T2DM) is one of the main public health care problems worldwide. It is associated with a marked increased risk of developing atherosclerotic vascular disease, heart failure, chronic kidney disease and death. It is essential to act during the early phases of the disease, through the intensification of lifestyle changes and the prescription of those drugs that have been shown to reduce these complications, with the aim not only of achieving an adequate metabolic control, but also a comprehensive vascular risk control. In this consensus document, developed by the different specialists that treat these patients (endocrinologists, primary care physicians, internists, nephrologists and cardiologists), a more appropriate approach in the management of patients with T2DM or its complications is provided. A particular focus is given to the global control of cardiovascular risk factors, the inclusion of weight within the therapeutic objectives, the education of patients, the deprescription of those drugs without cardiovascular benefit, and the inclusion of GLP-1 receptor agonists and SGLT2 inhibitors as cardiovascular protective drugs, at the same level as statins, acetylsalicylic acid, or renin angiotensin system inhibitors.
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Affiliation(s)
| | | | | | | | | | | | | | - Pilar Mazón Ramos
- Cardiology Department, Complejo Hospitalario Universitario Santiago de Compostela, 15706 A Coruña, Spain;
| | | | | | - David León Jiménez
- Internal Medicine Department, University Hospital Virgen del Rocío, 41013 Sevilla, Spain;
| | | | | | | | - Juan J. Gorgojo Martínez
- Department of Endocrinology and Nutrition, University Hospital Fundación Alcorcón, 28922 Madrid, Spain;
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15
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Sabouret P, Manzo-Silberman S, Alasnag M, Fysekidis M, Gulati M, Galati G, Spadafora L, Banach M, Biondi-Zoccai G, Bhatt DL. New approaches to reduce recurrent PCI: to angioplasty and beyond! EUROPEAN HEART JOURNAL OPEN 2023; 3:oead049. [PMID: 37273260 PMCID: PMC10233093 DOI: 10.1093/ehjopen/oead049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 05/02/2023] [Accepted: 05/15/2023] [Indexed: 06/06/2023]
Affiliation(s)
- Pierre Sabouret
- Heart Institute, ACTION Study Group-CHU Pitié-Salpétrière Paris, 47-83 Boulevard de l'Hôpital, 75005 Paris, France
- Collège National des Cardiologues Français (CNCF), 13 rue Niepce, 75014 Paris, France
| | - Stéphane Manzo-Silberman
- Heart Institute, ACTION Study Group-CHU Pitié-Salpétrière Paris, 47-83 Boulevard de l'Hôpital, 75005 Paris, France
| | - Mirvat Alasnag
- Cardiac Center, King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Marinos Fysekidis
- Department of endocrinology, Avicenne Hospital, AP-HP, 125, rue de Stalingrad, 93000 Bobigny, France
| | - Martha Gulati
- Barbra Streisand Women’s Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Giuseppe Galati
- Heart Failure Unit, Division of Cardiology, Department of Cardiothoracic and Vascular, San Raffaele Hospital, Scientific Institute (IRCCS), Via Olgettina 60, 20132 Milan, Italy
| | - Luigi Spadafora
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz and Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Deepak L Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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16
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Koufakis T, Liberopoulos EN, Kokkinos A, Zebekakis P, Kotsa K. Weight Loss Versus Glycemic Control as the Primary Treatment Target in Newly Diagnosed Type 2 Diabetes: Why Choose When You Can Have Both? Drugs 2023; 83:469-477. [PMID: 36941489 DOI: 10.1007/s40265-023-01852-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2023] [Indexed: 03/23/2023]
Abstract
Weight loss has been associated with significant improvements in glycemic control, quality of life, and comorbidities in people with type 2 diabetes. Furthermore, achieving diabetes remission can reduce the risk of microvascular complications and mitigate the burden of diabetes on healthcare systems. However, preventing weight regain is challenging in the long term. Strict glycemic control, particularly in the early stages of the disease, can reduce the subsequent risk of microvascular complications and specific macrovascular endpoints in the long run; however, its impact on cardiovascular and all-cause mortality remains controversial. New classes of antidiabetic agents, namely glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, have been shown to reduce cardiorenal risk and induce weight loss, in addition to effectively lowering blood glucose with a minimal risk of hypoglycemia. Recently, it has been debated whether weight loss or glycemic control should be the first priority in people with a recent diagnosis of type 2 diabetes. This article aims to discuss the debate from a clinical perspective, evaluate the advantages and disadvantages of each therapeutic strategy, and assess the impact of both approaches on the future risk of diabetic complications, based on the latest evidence. Given that both goals are equally important, the authors suggest that merging the two strategies, with the early and aggressive use of combination therapies consisting of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, will confer maximum benefits in terms of weight loss and glycemic control, and will reduce the future risk of complications from diabetes. A personalized approach that takes into account specific patient characteristics, including age, sex, race, frailty, and cognitive status, among others, can lead to more effective diabetes care.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - Evangelos N Liberopoulos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
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Elsaeed EM, Hamad AGA, Erfan OS, El-Shahat MA, Ebrahim FAE. Exenatide promotes the autophagic function in the diabetic hippocampus: a review. EGYPTIAN JOURNAL OF BASIC AND APPLIED SCIENCES 2022; 9:229-238. [DOI: 10.1080/2314808x.2022.2067388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/14/2022] [Indexed: 09/02/2023]
Affiliation(s)
| | | | - Omnia S. Erfan
- Human Anatomy and Embryology, Mansoura University, Al Mansurah, Egypt
| | - Mona A. El-Shahat
- Human Anatomy and Embryology, Mansoura University, Al Mansurah, Egypt
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18
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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19
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Janez A, Muzurovic E, Stoian AP, Haluzik M, Guja C, Czupryniak L, Duvnjak L, Lalic N, Tankova T, Bogdanski P, Papanas N, Nunes JS, Kempler P, Fras Z, Rizzo M. Translating results from the cardiovascular outcomes trials with glucagon-like peptide-1 receptor agonists into clinical practice: Recommendations from a Eastern and Southern Europe diabetes expert group. Int J Cardiol 2022; 365:8-18. [PMID: 35905827 DOI: 10.1016/j.ijcard.2022.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/05/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.
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Affiliation(s)
- Andrej Janez
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Slovenia.
| | - Emir Muzurovic
- Faculty of Medicine, University of Montenegro, Department of Internal Medicine, Endocrinology Section, Clinical Centre of Montenegro, Podgorica, Montenegro
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Martin Haluzik
- Diabetes Centre and Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic
| | - Cristian Guja
- Department of Diabetes, Nutrition and Metabolic Diseases, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Leszek Czupryniak
- Department of Diabetology and Internal Medicine, Medical University of Warsaw, Poland
| | - Lea Duvnjak
- School of Medicine University of Zagreb, Vuk Vrhovac University Clinic, Zagreb, Croatia
| | - Nebojsa Lalic
- Faculty of Medicine University of Belgrade, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia
| | | | - Pawel Bogdanski
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, University of Medical Sciences, Poznan, Poland
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Josè Silva Nunes
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal
| | - Peter Kempler
- First Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Zlatko Fras
- Preventive Cardiology Unit, Division of Medicine, University Medical Centre Ljubljana and Chair of Internal Medicine, Medical Faculty, University of Ljubljana, Slovenia
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), School of Medicine, University of Palermo, Italy
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20
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Kroopnick JM, Davis SN. The role of Recent Pharmacotherapeutic Options on the Management of Treatment Resistant Type 2 Diabetes. Expert Opin Pharmacother 2022; 23:1259-1271. [PMID: 35765193 DOI: 10.1080/14656566.2022.2089021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Type 2 diabetes mellitus is a complex progressive disease leading to chronic hyperglycemia due to insulin resistance and pancreatic beta-cell failure. Intensification of treatment regimens is often necessary due to the overall decline in insulin secretion. Unfortunately, many patients are unable to achieve optimal glycemic control despite the standard of care and thus may be classified as 'treatment resistant'. AREAS COVERED Newer pharmacotherapeutic agents, either injectable or oral, such as Glucagon-like-peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose Cotransporter-2 (SGLT2) inhibitors are, herein, described. These agents can be used as single agents or fixed combinations that reduce glycemia while lessening the risk for hypoglycemia and renal and cardiovascular diseases. EXPERT OPINION If individualized target HbA1c is not obtained despite diet, lifestyle, and metformin therapy, then additional oral and injectable therapies should be considered. This may include newer agents such as GLP-1RA and SGLT2 inhibitors alone or in combination that provide renal protection and reduce cardiovascular and hypoglycemic risks. These newer agents have substantial potential for lowering HbA1c through differing but complementary mechanisms. Use of new insulin analogs with GLP-1RA preparations either alone or in fixed-ratio combinations, such as glargine/lixisenatide and degludec/liraglutide, can also reduce the multiple drug adherence burden while improving glycemic control.
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Affiliation(s)
- Jeffrey M Kroopnick
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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21
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Singh AK, Singh R. Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. World J Cardiol 2022; 14:329-342. [PMID: 35979179 PMCID: PMC9258221 DOI: 10.4330/wjc.v14.i6.329] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/17/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Diabetes and Endocrinology, G.D Hospital and Diabetes Institute, Kolkata 700013, India.
| | - Ritu Singh
- Department of Reproductive Endocrinology, G.D Hospital and Diabetes Institute, Kolkata 700013, India
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22
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Sabouret P, Angoulvant D, Pathak A, Fysekidis M, Laterra G, Costa F, Angelini F, Bocchino PP, Montalescot G, Biondi-Zoccai G. How to fill the GAPS-I in secondary prevention: application of a strategy based on GLP1 analogues, antithrombotic agents, PCSK9 inhibitors, SGLT2 inhibitors and immunomodulators. Panminerva Med 2022; 64:265-273. [PMID: 34060278 DOI: 10.23736/s0031-0808.21.04284-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The continuous progress in cardiovascular risk prevention strategies has led to an impressive reduction in mortality and recurrent ischemic events in patients with coronary artery disease (CAD). However, the control of several cardiovascular risk factors remains suboptimal in many CAD patients, with a high rate of recurrent events, underlying the need for more new prevention strategies. The GAPS-I (glucagon-like peptide 1 analogues, antithrombotic agents, proprotein convertase subtilisin/kexin type 9 inhibitors, sodium glucose cotransporter type 2 inhibitors and immunomodulators) strategy offers a promising potential in patients with a high-residual cardiovascular risk, who are frequently encountered in daily practice, by offering an individualized and structured approach to addressing their individual risk factors. The current review summarizes the evidence to date on each of its components, with respect to clinical outcomes and economic feasibility. The current evidence points to an efficacy of GAPS-I in reducing major adverse cardiovascular events and mortality, without a compromise on safety, albeit with the need for longer follow-up data.
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Affiliation(s)
- Pierre Sabouret
- INSERM UMRS_1166, Institute of Cardiology, Pitié Salpêtrière Hospital (AP-HP), Sorbonne University, Paris, France -
| | - Denis Angoulvant
- Department of Cardiology, Loire Valley Cardiovascular Collaboration and EA4245, Centre Hospitalier Régional Universitaire de TOURS (CHRU), University of Tours, Tours, France
| | - Atul Pathak
- Department of Diabetology, Avicenne Hospital, Bobigny, France
| | - Marinos Fysekidis
- Department of Cardiovascular Medicine, INSERM 1048, Clinique Pasteur, Toulouse, France
| | - Giulia Laterra
- Department of Cardiology, University of Messina, Messina, Italy
| | - Francesco Costa
- Department of Cardiology, University of Messina, Messina, Italy
| | - Filippo Angelini
- Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Pier P Bocchino
- Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Gilles Montalescot
- INSERM UMRS_1166, Institute of Cardiology, Pitié Salpêtrière Hospital (AP-HP), Sorbonne University, Paris, France
| | - Giuseppe Biondi-Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
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23
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Exenatide and Dapagliflozin Combination Enhances Sertoli Cell Secretion of Key Metabolites for Spermatogenesis. Biomedicines 2022; 10:biomedicines10051115. [PMID: 35625851 PMCID: PMC9139030 DOI: 10.3390/biomedicines10051115] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 01/14/2023] Open
Abstract
The incidence of metabolic diseases such as type 2 diabetes mellitus (DM) and obesity has been increasing dramatically. Both diseases are closely linked and new approaches for type 2 DM treatment aim to enable weight loss. A combined therapy of dapagliflozin and exenatide has been used against type 2 DM, influencing allbody glucose dynamics. Spermatogenesis is highly dependent on the metabolic cooperation established between Sertoli cells (SCs) and developing germ cells. To study the effects of dapagliflozin and exenatide on SC metabolism, mouse SCs were treated in the presence of sub-pharmacologic, pharmacologic, and supra-pharmacologic concentrations of dapagliflozin (50, 500, 5000 nM, respectively) and/or exenatide (2.5, 25, 250 pM, respectively). Cytotoxicity of these compounds was evaluated and the glycolytic profile, glycogen content assay, and lipid accumulation of SCs were determined. Dapagliflozin treatment decreased fat cellular deposits, demonstrating its anti-obesity properties at the cellular level. Polytherapy of exenatide plus dapagliflozin increased lactate production by SCs, which has been reported to improve sperm production and quality. Thus, the results herein suggest that the use of these two pharmacological agents can protect male fertility, while improving their glucose homeostasis and inducing weight loss.
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24
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Lau KTK, Wong CKH, Au ICH, Lau WCY, Man KKC, Chui CSL, Wong ICK. Switching to Versus Addition of Incretin-Based Drugs Among Patients With Type 2 Diabetes Taking Sodium-Glucose Cotransporter-2 Inhibitors. J Am Heart Assoc 2022; 11:e023489. [PMID: 35322676 PMCID: PMC9075422 DOI: 10.1161/jaha.121.023489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Background Evidence is limited in comparing treatment modification by substitution or add‐on of glucose‐lowering medications in patients with type 2 diabetes. This observational study aims to compare switching versus add‐on of incretin‐based drugs among patients with type 2 diabetes on background sodium‐glucose cotransporter‐2 inhibitors (SGLT2i). Methods and Results This population‐based, retrospective cohort study was conducted using the IQVIA Medical Research Data, including adults with type 2 diabetes on background SGLT2i from 2005 to 2020. New users of incretin‐based drugs were allocated into the “Switch” group if they had discontinued SGLT2i treatment, or the “Add‐on” group if their background SGLT2i was continued. Baseline characteristics of patients were balanced between groups. Study outcomes were all‐cause mortality, cardiovascular diseases, kidney diseases, hypoglycemia, and ketoacidosis. Patients were observed from the index date of initiating incretin‐based drugs until the earliest of an outcome event, death, or data cut‐off date. Changes in anthropometric and metabolic parameters were also compared between groups from baseline to 12‐month follow‐up. A total of 2888 patients were included, classified into “Switch” (n=1461) or “Add‐on” group (n=1427). Median follow‐up was 18 months with 5183 person‐years. Overall, no significant differences in the risks of study outcomes were observed between groups; however, patients in the “Add‐on” group achieved significantly greater reductions in glycated hemoglobin, weight, percentage weight loss, and systolic blood pressure than their “Switch” counterparts. Conclusions Initiating incretin‐based drugs as add‐on among patients with type 2 diabetes on background SGLT2i was associated with risks of clinical end points comparable to switching treatments, in addition to better glycemic and weight control observed with the combination approach.
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Affiliation(s)
- Kristy T K Lau
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China
| | - Carlos K H Wong
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,Department of Family Medicine and Primary Care School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,Laboratory of Data Discovery for Health (D24H) Hong Kong Science Park, New Territories Hong Kong SAR China
| | - Ivan C H Au
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China
| | - Wallis C Y Lau
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,Research Department of Policy and Practice University College London School of Pharmacy London UK
| | - Kenneth K C Man
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,Research Department of Policy and Practice University College London School of Pharmacy London UK
| | - Celine S L Chui
- Laboratory of Data Discovery for Health (D24H) Hong Kong Science Park, New Territories Hong Kong SAR China.,School of Nursing Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,School of Public Health Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China
| | - Ian C K Wong
- Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China.,Laboratory of Data Discovery for Health (D24H) Hong Kong Science Park, New Territories Hong Kong SAR China.,Research Department of Policy and Practice University College London School of Pharmacy London UK
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25
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López-Cano C, Santos MD, Sánchez E, Martí R, Bueno M, Gutiérrez-Carrasquilla L, Lecube A. Dapagliflozin plus exenatide on patients with type 2 diabetes awaiting bariatric surgery in the DEXBASU study. Sci Rep 2022; 12:3236. [PMID: 35217772 PMCID: PMC8881618 DOI: 10.1038/s41598-022-07250-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 01/25/2022] [Indexed: 11/09/2022] Open
Abstract
The glucagon-like peptide-1 receptor agonist family together with the renal sodium/glucose cotransporter-2 inhibitors have garnered interest as potential therapeutic agents for subjects with type 2 diabetes and obesity. In these patients, bariatric surgery is indicated based in a BMI ≥ 35 kg/m2. A 24-week non-blinded, randomized pilot study to assess the efficacy of subcutaneous exenatide 2.0 mg once weekly plus oral dapagliflozin 10 mg once daily (Group A) compared to a control group (Group B) in 56 patients with type 2 diabetes awaiting bariatric surgery was conducted (EudraCTid.: 2017-001,454-33). Both groups received an energy-deficit low-fat diet. The primary endpoint was the proportion of patients running off the criteria for bariatric surgery at the end of the follow-up period (BMI ≤ 35.0 kg/m2 or a BMI ≤ 40.0 kg/m2 plus an HbA1c ≤ 6.0%). Changes in the BMI were also of interest. The proportion of patients who ran off the criteria for bariatric surgery was larger in Group A than in the control group (45.8% vs. 12.0%, p = 0.010). Participants in Group A exhibited an absolute decrease in body weight and BMI of 8.1 kg (95%IC: - 11.0 to - 5.2) and 3.3 kg/m2 (95%IC: - 4.5 to - 2.2), respectively (p < 0.001 for both in comparison with Group B). A higher percentage of participants in Group A reached a BMI < 35 kg/m2 (45.8 vs 12.0%) and lost > 10% of their initial body weight (20.8 vs 0%) compared to Group B. The combination of exenatide plus dapagliflozin appears as a strategic option to reduce the waiting list for bariatric surgery, especially in those patients with type 2 diabetes.
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Affiliation(s)
- Carolina López-Cano
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Maria Dolores Santos
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Enric Sánchez
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Raquel Martí
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Marta Bueno
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Liliana Gutiérrez-Carrasquilla
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain
| | - Albert Lecube
- Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova de Lleida, Obesity, Diabetes and Metabolism Research Group (ODIM), Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, Avda. Rovira Roure 80, 25198, Lleida, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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26
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Sinha B, Ghosal S. A Meta-Analysis of the Effect of Sodium Glucose Cotransporter-2 Inhibitors on Metabolic Parameters in Patients With Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2022; 13:830401. [PMID: 35265039 PMCID: PMC8900375 DOI: 10.3389/fendo.2022.830401] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/17/2022] [Indexed: 11/28/2022] Open
Abstract
Objective Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of childbearing age and is associated with multiple morbidities. However, treatment for this condition is mainly applied for symptomatic relief and does not address the complex pathophysiology of this condition. This meta-analysis was conducted on the usage of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) in PCOS because this group of drugs presents an attractive strategy to address the metabolic and hormonal defects by managing the pathophysiological defects observed in this syndrome. Methods We included prospective trials that enrolled patients with established PCOS and compared an SGLT-2i group versus a control group with at least 2 weeks of follow-up. The standardized mean difference (SMD) was used for effect size estimation from individual studies and was pooled using the fixed effect model. Results We included four trials with a pooled population of 158 patients with documented PCOS who received either an SGLT-2i or standard management. From a metabolic perspective, significant improvements were observed in the reduction in body weight (SMD: -0.68, 95% CI -1.16 to -0.19, <0.01), fasting plasma glucose (FPG) (SMD: -0.59, 95% CI -0.99 to -0.19, P<0.01), and insulin resistance as assessed with the HOMA-IR (SMD: -0.39, 95% CI -0.76 to -0.03, P=0.03). In addition, a significant improvement was noted in dehydroepiandrosterone sulphate (DHEAS) levels (SMD: -0.55, 95% CI -0.94 to -0.16, P<0.01). Conclusion SGLT-2i use is associated with salutary outcomes of metabolic and anthropometric markers of PCOS and likely favourable hormonal effects. Clinical Trial Registration [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021268564], PROSPERO 2021 CRD42021268564.
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Affiliation(s)
- Binayak Sinha
- Department of Endocrinology, AMRI Hospitals, Kolkata, India
| | - Samit Ghosal
- Department of Endocrinology, Nightingale Hospital, Kolkata, India
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27
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Li C, Luo J, Jiang M, Wang K. The Efficacy and Safety of the Combination Therapy With GLP-1 Receptor Agonists and SGLT-2 Inhibitors in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. Front Pharmacol 2022; 13:838277. [PMID: 35185588 PMCID: PMC8854770 DOI: 10.3389/fphar.2022.838277] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 01/18/2022] [Indexed: 12/19/2022] Open
Abstract
Aims: Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors play a key role in the treatment of type 2 diabetes mellitus. This meta-analysis aims to evaluate the efficacy and safety of their combination, emphatically focusing on the effects of treatment duration and add-on drugs. Methods: Seven databases were searched until June 2021 for randomized controlled trials with a duration of at least 12 weeks, evaluating the effects of combination therapy with glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors. Results: A total of eight eligible articles were included, pooling data retrieved from 1895 patients with type 2 diabetes mellitus. Compared to monotherapy, combination therapy resulted in a greater reduction in glycated haemoglobin (HbA1c), body weight, fasting plasma glucose (FPG), 2 h postprandial glucose (2 h PG), systolic blood pressure (SBP), body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C). The decrease in HbA1c, body weight and FPG was maintained for more than 1 year, but these effects gradually regressed over time. The risk for hypoglycaemia was significantly increased with combination therapy. In addition, drug discontinuation, diarrhoea, injection-site-related events, nausea, vomiting and genital infections were more likely to occur in combination therapy. Conclusion: Glucagon-like peptide-1 receptor agonist and sodium-glucose co-transporter-2 inhibitor combination therapy showed superior effects on reducing HbA1c, body weight, FPG, 2 h PG, SBP, BMI and LDL-C, without major safety issues, when compared with monotherapy in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Chen Li
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China
- School of Pharmacy, China Medical University, Shenyang, China
| | - Jie Luo
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China
- School of Pharmacy, China Medical University, Shenyang, China
| | - Mingyan Jiang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China
- School of Pharmacy, China Medical University, Shenyang, China
| | - Keke Wang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, China
- School of Pharmacy, China Medical University, Shenyang, China
- *Correspondence: Keke Wang,
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Jiang Y, Yang P, Fu L, Sun L, Shen W, Wu Q. Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:802992. [PMID: 35370961 PMCID: PMC8967154 DOI: 10.3389/fendo.2022.802992] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND A network meta-analysis of randomized controlled trials (RCTs) was conducted to explore the cardiovascular outcomes of all the kind and dosages of sodium-glucose cotransport-2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients. METHOD AND RESULT The Cochrane Library, PubMed, and Embase databases were systematically searched for studies to compare the therapeutic effects of different SGLT2 inhibitors in T2DM patients. The effect measurements estimate chosen were odds ratios (ORs) and their corresponding 95% confidence interval (CI). Forty-seven RCTs involving a total of 70574 participants were eligible for direct and indirect comparisons. In direct comparison, treatment with dapagliflozin 5mg showed significantly lower risk of all-cause mortality compared with treatment with dapagliflozin 2.5mg (OR 0.09, 95% CI 0.01-0.70). According to NMA, interestingly, empagliflozin 10mg/25mg, and canagliflozin 100mg was associated with significantly lower risks of all-cause mortality compared with placebo (OR of 0.70, 95% CI 0.58-0.85; 0.69, 95% CI 0.57-0.84; and 0.83, 95% CI 0.73-0.95, respectively). Compared with placebo, dapagliflozin 10mg, empagliflozin 10mg and 25mg displayed the lower risks for cardiovascular events (OR 0.78, 95% CI 0.44-1.00; OR 0.47, 95% CI 0.22-0.93; and 0.43, 95% CI 0.24-0.74, respectively) by direct comparison. Moreover, canagliflozin 100/300mg showed significantly higher risks of cardiovascular events compared with empagliflozin 10mg (OR of 4.83, 95% CI 1.14-20.46 and 5.31, 95% CI 1.26-22.34, respectively) and empagliflozin 25mg (4.23, 95% CI 1.13-15.83 and 4.65, 95% CI 1.25-17.27, respectively) according to NMA. There were non-significant differences among all interventions in volume depletion in traditional pairwise meta-analysis. While in NMA, canagliflozin 100/300mg were associated with significantly increased risks of volume depletion compared with placebo (OR of 1.47, 95% CI 1.08-1.99 and 2.19, 95% CI 1.66-2.90, respectively). CONCLUSION In the limitations of the NMA, this study showed that empagliflozin might be better than other SGLT2 inhibitors with low risks of all-cause mortality and cardiovascular events in patients with T2DM suggesting the need for ad hoc RCTs.
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Affiliation(s)
- Yu Jiang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pingping Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linghua Fu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lizhe Sun
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wen Shen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Chua MWJ. High-Dose Liraglutide and SGLT2 Inhibitor: A Promising Combination. Clin Pract 2021; 12:1-7. [PMID: 35076486 PMCID: PMC8788265 DOI: 10.3390/clinpract12010001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists are important drugs in our armamentarium of treatment for Type 2 diabetes mellitus (DM). In addition to their glucose-lowering effects, they have effects on weight, other metabolic diseases and perhaps most importantly, a cardioprotective and reno-protective effect. Liraglutide is a long-acting GLP-1 agonist which was originally used at 1.8 mg daily for the treatment of DM. However, high-dose liraglutide-liraglutide 3 mg daily, has been demonstrated to be a safe and effective treatment for obesity, with or without DM. In this manuscript, I present two patients who had unusual responses to combination therapy with high-dose liraglutide and SGLT2 inhibitor-marked and/or rapid improvement in glycemic control and weight loss. Drawing from the observations in both cases, I discuss the complementary mechanisms of actions of both drugs, review the clinical effects of combination therapy and distil them into clinical pearls of practical utility for the physician. Given the "clash of the two pandemics" of obesity and COVID-19 and the burgeoning rates of obesity which loom in the near horizon, this is most timely.
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Affiliation(s)
- Marvin Wei Jie Chua
- Endocrinology Service, Department of General Medicine, Sengkang General Hospital, 110 Sengkang East Way, Singapore 544886, Singapore
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Joaqui VB, Gómez NB, Ortiz RC, Toro LMO, Lombo JPM, Cifuentes CAS, García MAM, Lomba AA. Effectiveness of triple therapy with dapagliflozin add-on to dual therapy over 52 weeks in patients with uncontrolled type 2 diabetes mellitus in a centre of high complexity, Cali-Colombia. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:49-59. [PMID: 33444492 PMCID: PMC10528692 DOI: 10.20945/2359-3997000000319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 10/27/2020] [Indexed: 06/12/2023]
Abstract
OBJECTIVE To evaluate the effectiveness of adding dapagliflozin as an intensification strategy for the treatment of patients with uncontrolled type 2 diabetes mellitus (T2DM). METHODS A historical cohort study was conducted in 123 adult patients over 18 years old who were diagnosed with uncontrolled T2DM, who received dapagliflozin add-on to their dual base treatment: metformin plus glibenclamide (n = 32), metformin plus saxagliptin (n = 29), metformin plus exenatide (n = 28), or metformin plus insulin (n = 34). The endpoints were evaluated using analysis of variance. RESULTS All the patients completed a 52-week follow-up. Overall, 52.85% of patients were female, the Hispanic population represented the largest proportion of patients in all groups (60.98%), and the mean ± SD patient age and body weight were 55.05 ± 7.58 years and 83.55 ± 9.65 kg, respectively. The mean ± SD duration of T2DM, glycated hemoglobin (HbA1c), and fasting plasma glucose (FPG) were 5.93 ± 2.98 years, 8.1 ± 0.53%, and 166.03 ± 26.80 mg/dL, respectively. The grand mean changes of HbA1c, FPG, body weight and blood pressure showed a decreasing trend during the study period and it was statistically significant in all groups (p-value = <0.001). The proportion of patients achieving HbA1c target (<7%) was highest in the group that used a dapagliflozin add-on to metformin plus saxagliptin. CONCLUSION The addition of dapagliflozin as an alternative for intensification of dual therapy consistently improved, not only FPG and HbA1c, but also body weight and blood pressure, with statistically significant results.
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Affiliation(s)
- Vanessa Bedoya Joaqui
- Departamento de Medicina Interna, GIMI1 (Grupo Interinstitucional de Medicina Interna 1), Universidad Libre, Cali, Colombia
| | - Nathalia Buitrago Gómez
- Departamento de Medicina Interna, GIMI1 (Grupo Interinstitucional de Medicina Interna 1), Universidad Libre, Cali, Colombia
| | - Reinaldo Carvajal Ortiz
- Centro Médico Imbanaco S.A., Cali, Colombia; Departamento de Medicina Interna, GIMI1 (Grupo Interinstitucional de Medicina Interna 1), Universidad Libre, Cali, Colombia
| | | | - Jenny Patricia Muñoz Lombo
- Departamento de Medicina Interna, GIMI1 (Grupo Interinstitucional de Medicina Interna 1), Universidad Libre, Cali, Colombia
| | | | | | - Alín Abreu Lomba
- Centro Médico Imbanaco S.A., Cali, Colombia; Departamento de Medicina Interna, GIMI1 (Grupo Interinstitucional de Medicina Interna 1), Universidad Libre, Cali, Colombia,
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Täger T, Atar D, Agewall S, Katus HA, Grundtvig M, Cleland JGF, Clark AL, Fröhlich H, Frankenstein L. Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Heart Fail Rev 2021; 26:1421-1435. [PMID: 32314085 PMCID: PMC8510986 DOI: 10.1007/s10741-020-09954-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.
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Affiliation(s)
- Tobias Täger
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Dan Atar
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Stefan Agewall
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Hugo A Katus
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Morten Grundtvig
- Medical Department, Innlandet Hospital Trust Division Lillehammer, Lillehammer, Norway
| | - John G F Cleland
- National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, and Robertson Centre for Biostatistics & Clinical Trials, Glasgow, UK
| | - Andrew L Clark
- Castle Hill Hospital of the University of Hull, Cottingham, UK
| | - Hanna Fröhlich
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Lutz Frankenstein
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
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Natali A, Nesti L, Tricò D, Ferrannini E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence. Cardiovasc Diabetol 2021; 20:196. [PMID: 34583699 PMCID: PMC8479881 DOI: 10.1186/s12933-021-01385-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023] Open
Abstract
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.
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Affiliation(s)
- Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy.
| | - Lorenzo Nesti
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
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Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function. Handb Exp Pharmacol 2021; 274:439-465. [PMID: 34114119 DOI: 10.1007/164_2021_474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Beta-cell dysfunction and beta-cell death are critical events in the development of type 2 diabetes mellitus (T2DM). Therefore, the goals of modern T2DM management have shifted from merely restoring normoglycemia to maintaining or regenerating beta-cell mass and function. In this review we summarize current and novel approaches to achieve these goals, ranging from lifestyle interventions to N-methyl-D-aspartate receptor (NMDAR) antagonism, and discuss the mechanisms underlying their effects on beta-cell physiology and glycemic control. Notably, timely intervention seems critical, but not always strictly required, to maximize the effect of any approach on beta-cell recovery and disease progression. Conventional antidiabetic medications are not disease-modifying in the sense that the disease does not progress or reoccur while on treatment or thereafter. More invasive approaches, such as bariatric surgery, are highly effective in restoring normoglycemia, but are reserved for a rather small proportion of obese individuals and sometimes associated with serious adverse events. Finally, we recapitulate the broad range of effects mediated by peripheral NMDARs and discuss recent evidence on the potential of NMDAR antagonists to be developed as a novel class of antidiabetic drugs. In the future, a more refined assessment of disease risk or disease subtype might enable more targeted therapies to prevent or treat diabetes.
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Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab 2021; 46:101102. [PMID: 33068776 PMCID: PMC8085572 DOI: 10.1016/j.molmet.2020.101102] [Citation(s) in RCA: 780] [Impact Index Per Article: 195.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). SCOPE OF REVIEW To summarize current knowledge about GLP-1 receptor agonist. MAJOR CONCLUSIONS At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
| | - Daniel R Quast
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
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Tang H, Yang K, Li X, Song Y, Han J. Pancreatic safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2021; 29:161-172. [PMID: 32017292 DOI: 10.1002/pds.4943] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/07/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE This study aimed to systematically evaluate the association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and pancreatic safety in patients with type 2 diabetes mellitus (T2DM). METHODS Electronic databases were searched before September 2019 to include randomized controlled trials (RCTs) of SGLT2 inhibitors that reported any event on pancreatitis or pancreatic cancer among patients with T2DM. Peto odds ratio (OR) with 95% confidence interval (CI) was used to pool the data. The GRADE framework was introduced to assess the quality of evidence. RESULTS Of the 35 trials involving 44 912 patients with T2DM included, 41 events of acute pancreatitis (19 trials; 32 932 patients), 72 events of overall pancreatitis (including acute pancreatitis, chronic pancreatitis, or nonspecific pancreatitis; 26 trials; 36 688 patients), and 40 events of pancreatic cancer (18 trials; 27 806 patients) were reported during a median follow-up of 52 weeks. SGLT2 inhibitors were not associated with an increased risk of acute pancreatitis compared to controls (placebo or other active drugs; Peto OR, 1.13; 95% CI, 0.60-2.13; moderate quality evidence). A similar result was found for risk of overall pancreatitis (Peto OR, 1.08; 95% CI, 0.67-1.75; moderate quality evidence) and pancreatic cancer (Peto OR, 1.34; 95% CI, 0.71-2.54; very low-quality evidence). CONCLUSIONS Moderate quality evidence from RCTs shows no significantly increased risk of acute pancreatitis associated with SGLT2 inhibitors, while there is very low-quality evidence suggesting no significant association between SGLT2 inhibitors and pancreatic cancer among patients with T2DM.
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Affiliation(s)
- Huilin Tang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Keming Yang
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Xin Li
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Yiqing Song
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana
| | - Jiali Han
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indiana.,Melvin and Bren Simon Cancer Center, Indiana University, Indiana
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Gardner H, Hamdy O. Oral GLP1 Analog: Where Does the Tide Go? Clin Med Insights Endocrinol Diabetes 2020; 13:1179551420984130. [PMID: 33447122 PMCID: PMC7780176 DOI: 10.1177/1179551420984130] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
T2D is a potentially preventable disease that has been ranked the seventh leading cause of mortality in the United States. There is strong evidence demonstrating that preventing type 2 diabetes is, in many cases, attainable through lifestyle intervention. Unfortunately, prediabetes is mostly overlooked and awareness with diabetes prevention tools is lacking among primary care physicians. Nationally, efforts were not successful in reversing this epidemic even with an array of diabetes medications. Among the most effective medications for T2D are glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have been shown to reduce both A1C and body weight. Dulaglutide, liraglutide and injectable semaglutide also reduced cardiovascular events and cardiovascular mortality in patients with established cardiovascular disease or multiple cardiovascular risk factors. In this review, we will examine the first FDA approved oral GLP-1 RA; semaglutide. Moreover, this review will discuss the potential impact oral semaglutide may have on glycemic control, weight loss and cardiovascular comorbidities. It also examines the factors that may impact patient compliance, including cost, side effects and clinical issues. Finally, it deliberates the optimism surrounding the development of oral semaglutide in the treatment of diabetes as well as related conditions, such as obesity and non-alcoholic fatty liver disease (NAFLD).
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Berkovic MC, Bilic-Curcic I, Bozek T, Mahecic DH, Majanovic SK, Canecki-Varzic S, Andric J, Marusic S, Mrzljak A. Glucagon-like-1 receptor agonists and sodium/glucose cotransporter-2 inhibitors combination-are we exploiting their full potential in a real life setting? World J Diabetes 2020; 11:540-552. [PMID: 33269065 PMCID: PMC7672794 DOI: 10.4239/wjd.v11.i11.540] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/29/2020] [Accepted: 10/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The sodium/glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like-1 receptor agonists (GLP-1RA) are antidiabetic agents effective both in hemoglobin A1c (HbA1c) reduction (with a low risk of hypoglycemia) and cardiovascular event prevention. In patients with type 2 diabetes, the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising. AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up. METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with (1) GLP-1RA on top of SGLT-2i, (2) SGLT-2i on top of GLP-1RA compared to (3) simultaneous addition of both agents. The primary study endpoint was the proportion of participants with HbA1c < 7.0% and/or 5% bodyweight reduction. Secondary outcomes included changes in fasting plasma glucose (FPG), prandial plasma glucose, low-density lipoprotein cholesterol, estimated glomerular filtration rate (eGFR), and cardiovascular (CV) incidents assessment over a follow-up period of 12 mo. RESULTS The majority of patients were over 65-years-old, had diabetes duration for more than 10 years. The initial body mass index was 39.41 ± 5.49 kg/m2 and HbA1c 8.32 ± 1.26%. Around half of the patients in all three groups achieved target HbA1c below 7%. A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy. The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group (P = 0.021), and 5% weight loss was dominantly achieved in the simultaneous therapy group (P = 0.044). A composite outcome (reduction of HbA1c below 7% (53 mmol/mol) with 5% weight loss) was achieved in 32.3% of total patients included in the study. Only 18.2% of patients attained composite outcome defined as HbA1c below 7% (53 mmol/mol) with 5% weight loss and low-density lipoprotein cholesterol < 2.5 mmol/L. There were no significant differences between treatment groups. No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period. CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control, although it remains to be determined whether simultaneous or sequential intensification is better.
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Affiliation(s)
- Maja Cigrovski Berkovic
- Faculty of Medicine, J. J. Strossmayer University Osijek, Osijek 31000, Croatia
- Department for Endocrinology, Diabetes and Clinical Pharmacology, Clinical Hospital Dubrava, Zagreb 10000, Croatia
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb, Zagreb 10000, Croatia
| | - Ines Bilic-Curcic
- Faculty of Medicine, J. J. Strossmayer University Osijek, Osijek 31000, Croatia
- Department of Endocrinology and Metabolism Disorders, Clinical Hospital Center, Osijek 31000, Croatia
| | - Tomislav Bozek
- University Clinic for Diabetes “Vuk Vrhovac”, Merkur University Hospital, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Davorka Herman Mahecic
- Department for Endocrinology, Diabetes and Metabolism, University Hospital Centre “Sestre milosrdnice”, Zagreb 10000, Croatia
| | - Sanja Klobucar Majanovic
- Department for Endocrinology, Diabetes and Metabolism, University Hospital Centre Rijeka, School of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Silvija Canecki-Varzic
- Faculty of Medicine, J. J. Strossmayer University Osijek, Osijek 31000, Croatia
- Department of Endocrinology and Metabolism Disorders, Clinical Hospital Center, Osijek 31000, Croatia
| | - Jelena Andric
- Department for Endocrinology, Diabetes and Clinical Pharmacology, Clinical Hospital Dubrava, Zagreb 10000, Croatia
| | - Srecko Marusic
- Department for Endocrinology, Diabetes and Clinical Pharmacology, Clinical Hospital Dubrava, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Medicine, Merkur University Hospital, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:556-577. [PMID: 32855502 DOI: 10.1038/s41574-020-0392-2] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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Mantsiou C, Karagiannis T, Kakotrichi P, Malandris K, Avgerinos I, Liakos A, Tsapas A, Bekiari E. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2020; 22:1857-1868. [PMID: 32476254 DOI: 10.1111/dom.14108] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/13/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
AIM To assess the efficacy and safety of combination therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose co-transporter-2 inhibitor (SGLT2i) in patients with type 2 diabetes. METHODS We searched Medline, Embase, the Cochrane Library and grey literature sources up to 2 December 2019 for randomized controlled trials in adults with type 2 diabetes assessing the combination of GLP-1RA and SGLT2i, either as co-initiation therapy or as add-on to each other, against placebo or an active comparator. The primary outcome was change in HbA1c . Secondary outcomes included change in body weight, blood pressure and estimated glomerular filtration rate, and incidence of severe hypoglycaemia, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and hospitalization for heart failure. We pooled data using random effects meta-analyses. RESULTS Seven trials (1913 patients) were eligible. Compared with GLP-1RA, GLP-1RA/SGLT2i combination therapy was associated with a greater reduction in HbA1c (weighted mean difference -0.61%, 95% CI -1.09% to -0.14%, four studies), body weight (-2.59 kg, -3.68 to -1.51 kg, three studies) and systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, four studies). Compared with SGLT2i, GLP-1RA/SGLT2i combination therapy reduced HbA1c (-0.85%, -1.19% to -0.52%, six studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, six studies), but not body weight (-1.46 kg, -2.94 to 0.03 kg, five studies). After excluding data for one trial that had a considerably longer duration than the remaining studies, body weight was also reduced versus SGLT2i (-1.79 kg, -2.99 to -0.59 kg, five studies). Combination therapy did not increase the incidence of severe hypoglycaemia. Data for mortality and cardiovascular outcomes were scarce. CONCLUSIONS GLP-1RA/SGLT2i combination therapy seems to reduce HbA1c , body weight and systolic blood pressure without increasing the risk of severe hypoglycaemia compared with either GLP-1RA or SGLT2i. No conclusions can be made regarding long-term effectiveness or the effect on cardiovascular outcomes.
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Affiliation(s)
- Chrysanthi Mantsiou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panagiota Kakotrichi
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Avgerinos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Harris Manchester College, University of Oxford, Oxford, UK
| | - Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Jabbour SA, Frías JP, Ahmed A, Hardy E, Choi J, Sjöström CD, Guja C. Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial. Diabetes Care 2020; 43:2528-2536. [PMID: 32816874 PMCID: PMC7510043 DOI: 10.2337/dc19-1350] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 07/17/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-h postprandial glucose [2-h PPG]), weight, and systolic blood pressure (SBP) than exenatide QW or dapagliflozin alone after 28 weeks of treatment in DURATION-8. Following a 24-week extension period, improvements were sustained at 52 weeks. In this study, we investigated efficacy and safety at 104 weeks after randomization. RESEARCH DESIGN AND METHODS DURATION-8 was a 104-week, multicenter, double-blind, randomized, active-controlled, phase 3 trial. In total, 695 adults (aged ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA1c 8.0-12.0% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1,500 mg/day) were randomly assigned (1:1:1) to receive exenatide 2 mg QW plus once-daily dapagliflozin 10 mg, exenatide QW plus placebo, or dapagliflozin plus placebo. All 104-week evaluations were exploratory. RESULTS At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean change (SE) from baseline to week 104 in HbA1c was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) versus exenatide QW plus placebo (-1.29% [0.12]; P = 0.007) and dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001). Clinically relevant changes in FPG, 2-h PPG, weight, and SBP were also observed with exenatide QW plus dapagliflozin. There were no unexpected safety findings, and exenatide QW plus dapagliflozin was well tolerated, with no episodes of major hypoglycemia. CONCLUSIONS In this exploratory analysis, among those individuals who completed the trial without rescue therapy, there was clinically relevant efficacy over 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.
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Affiliation(s)
| | | | | | | | | | | | - Cristian Guja
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Practical Considerations and Rationale for Glucagon-Like Peptide-1 Receptor Agonist Plus Sodium-Dependent Glucose Cotransporter-2 Inhibitor Combination Therapy in Type 2 Diabetes. Can J Diabetes 2020; 45:291-302. [PMID: 33189580 DOI: 10.1016/j.jcjd.2020.09.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
Glucagon-like peptide-1 receptor agonists and sodium-dependent glucose cotransporter-2 inhibitors have demonstrated clinically significant benefits on glycated hemoglobin, weight, blood pressure and cardiorenal outcomes. The emerging evidence from clinical trials and meta-analyses that assessed the combination of these 2 classes of drugs has been promising. An expert forum that included individuals with expertise in endocrine, cardiology and nephrology issues was held in May 2020 to review the literature on the metabolic and cardiorenal benefits of these 2 classes, independently and in combination, in adults with type 2 diabetes mellitus. Although hard outcome data are not available, the group concluded that the combination of glucagon-like peptide-1 receptor agonists with sodium-dependent glucose cotransporter-2 inhibitors is an emerging option for managing adults with type 2 diabetes as long as cost is not a barrier. Ongoing research may offer further insights on hard cardiorenal outcomes for this therapeutic combination as well as provide direction on the potential of this approach in obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and populations without diabetes.
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Górriz JL, Navarro-González JF, Ortiz A, Vergara A, Nuñez J, Jacobs-Cachá C, Martínez-Castelao A, Soler MJ. Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease. Nephrol Dial Transplant 2020; 35:i13-i23. [PMID: 32003834 PMCID: PMC6993197 DOI: 10.1093/ndt/gfz237] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Indexed: 12/19/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin–angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin–angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.
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Affiliation(s)
- Jose Luis Górriz
- Hospital Clínico Universitario de Valencia, Universitat de València, INCLIVA, GEENDIAB, Valencia, Spain.,REDINREN, Madrid, Spain
| | - Juan F Navarro-González
- REDINREN, Madrid, Spain.,Unidad de Investigación y Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,Instituto de Tecnologías Biomédicas, Universidad de La Laguna, GEENDIAB, Santa Cruz de Tenerife, Spain
| | - Alberto Ortiz
- REDINREN, Madrid, Spain.,IIS-Fundación Jimenez Diaz UAM and School of Medicine, UAM, GEENDIAB, Madrid, Spain
| | - Ander Vergara
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
| | - Julio Nuñez
- Department of Cardiology, Hospital Clínico Universitario de Valencia, Universitat de Valencia, INCLIVA, Valencia, Spain.,CIBER Cardiovascular
| | - Conxita Jacobs-Cachá
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
| | | | - Maria Jose Soler
- REDINREN, Madrid, Spain.,Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Nephrology Research Group, Vall d'Hebron Research Institute (VHIR), GEENDIAB, Barcelona, Spain
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Gan S, Dawed AY, Donnelly LA, Nair ATN, Palmer CNA, Mohan V, Pearson ER. Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care 2020; 43:1948-1957. [PMID: 33534728 PMCID: PMC7372059 DOI: 10.2337/dc19-2419] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The pathophysiology of type 2 diabetes differs markedly by ethnicity. PURPOSE A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs). DATA SOURCES A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords. STUDY SELECTION A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis. DATA EXTRACTION Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study. DATA SYNTHESIS Change in HbA1c was evaluated by computing mean differences and 95% CIs between treatment and placebo arms. LIMITATIONS The study is based on summarized data and could not be separated based on East Asians and South Asians. CONCLUSIONS The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.
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Affiliation(s)
| | | | | | | | | | - Viswanathan Mohan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Chennai, India
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Berra C, Manfrini R, Regazzoli D, Radaelli MG, Disoteo O, Sommese C, Fiorina P, Ambrosio G, Folli F. Blood pressure control in type 2 diabetes mellitus with arterial hypertension. The important ancillary role of SGLT2-inhibitors and GLP1-receptor agonists. Pharmacol Res 2020; 160:105052. [PMID: 32650058 DOI: 10.1016/j.phrs.2020.105052] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus and arterial hypertension are major cardiovascular risks factors which shares metabolic and haemodynamic abnormalities as well as pathophysiological mechanisms. The simultaneous presence of diabetes and arterial hypertension increases the risk of left ventricular hypertrophy, congestive heart failure, and stroke, as compared to either condition alone. A number of guidelines recommend lifestyle measures such as salt restriction, weight reduction and ideal body weight mainteinance, regular physical activity and smoking cessation, together with moderation of alcohol consumption and high intake of vegetables and fruits, as the basis for reduction of blood pressure and prevention of CV diseases. Despite the availability of multiple drugs effective for hypertension, BP targets are reached in only 50 % of patients, with even fewer individuals with T2DM-achieving goals. It is established that new emerging classes of type 2 diabetes mellitus treatment, SGLT2 inhibitors and GLP1-receptor agonists, are efficacious on glucose control, and safe in reducing HbA1c significantly, without increasing hypoglycemic episodes. Furthermore, in recent years, many CVOT trials have demonstrated, using GLP1-RA or SGLT2-inihibitors compared to placebo (in combination with the usual diabetes medications) important benefits on reducing MACE (cardio-cerebral vascular events) in the diabetic population. In this hypothesis-driven review, we have examined the anti-hypertensive effects of these novel molecules of the two different classes, in the diabetic population, and suggest that they could have an interesting ancillary role in controlling blood pressure in type 2 diabetic patients.
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Affiliation(s)
- C Berra
- Department of Endocrine and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy.
| | - R Manfrini
- Departmental Unit of Diabetes and Metabolic Disease, ASST Santi Paolo e Carlo, Milan, Italy
| | - D Regazzoli
- Department of Cardiovascular Disease, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - M G Radaelli
- Department of Endocrine and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - O Disoteo
- Endocrinology and Diabetology Service, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - C Sommese
- IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - P Fiorina
- University of Milano, Milan, Italy; TID International Center, Invernizzi Research Center, Milan, Italy; Endocrinology and Diabetology Unit, ASST Fatebenefratelli-Sacco, Luigi Sacco Hospital, Milan, Italy
| | - G Ambrosio
- University of Perugia School of Medicine, Perugia, Italy
| | - F Folli
- Departmental Unit of Diabetes and Metabolic Disease, ASST Santi Paolo e Carlo, Milan, Italy; University of Milano, Milan, Italy; Endocrinology and Metabolism, Department of Health Science University of Milano, Italy
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Hussein H, Zaccardi F, Khunti K, Davies MJ, Patsko E, Dhalwani NN, Kloecker DE, Ioannidou E, Gray LJ. Efficacy and tolerability of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A systematic review and network meta-analysis. Diabetes Obes Metab 2020; 22:1035-1046. [PMID: 32077218 DOI: 10.1111/dom.14008] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/07/2020] [Accepted: 02/17/2020] [Indexed: 12/13/2022]
Abstract
AIM To compare the efficacy and tolerability of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes. MATERIALS AND METHODS Electronic databases were searched from inception to 24 April 2019 for randomized controlled trials reporting change in glycated haemoglobin (HbA1c) at approximately 24 and/or 52 weeks for SGLT-2is and/or GLP-1RAs (classified as short- and long-acting). Bayesian network meta-analyses were conducted to compare within and between SGLT-2i and GLP-1RA classes for cardiometabolic efficacy and adverse events (PROSPERO registration number: CRD42018091306). RESULTS Sixty-four trials (53 trials of 24 weeks; seven trials of 52 weeks; four trials of both 24 and 52 weeks), comprising 31 384 participants were identified. Compared with placebo, all treatments improved HbA1c. Long-acting GLP-1RAs reduced HbA1c compared with short-acting GLP-1RAs and SGLT-2is, with semaglutide showing greater reduction compared with placebo [24 weeks: -1.49% (95% credible interval: -1.76, -1.22); 52 weeks: -1.38% (-2.05, -0.71)] and all other treatments. Long-acting GLP-1RAs showed benefits in body weight and waist circumference reduction, while SGLT-2is reduced blood pressure. SGLT-2is showed increased risk of genital infection in comparison with long-acting GLP-1RAs [odds ratio (95% credible interval): 5.26 (1.45, 25.00)], while GLP-1RAs showed increased risk of diarrhoea in comparison with SGLT-2is [short-acting GLP-1RAs: 1.65 (1.09, 2.49); long-acting GLP-1RAs: 2.23 (1.51, 3.28)]. No other differences were found between SGLT-2is and GLP-1RAs in adverse events. CONCLUSION Long-acting GLP-1RAs showed superiority in reducing HbA1c levels, body weight and waist circumference. SGLT-2is showed reductions in blood pressure levels. This review provides essential evidence to guide treatment recommendations in the management of type 2 diabetes.
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Affiliation(s)
- Humaira Hussein
- Department of Health Sciences, University of Leicester, Leicester, UK
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | | | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Emily Patsko
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | | | - David E Kloecker
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | | | - Laura J Gray
- Department of Health Sciences, University of Leicester, Leicester, UK
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Zhang X, Zhong Z, Li Y, Li W. Long-term renal outcomes associated with sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Metab Res Rev 2020; 36:e3303. [PMID: 32134558 DOI: 10.1002/dmrr.3303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 10/08/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022]
Abstract
AIMS The long-term impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on renal functions remains undefined. This study was undertaken to investigate the renal outcomes associated with SGLT2 inhibitors in patients with type 2 diabetes (T2DM) in the long term. METHODS A systematic literature search of PubMed and ClinicalTrials.gov was conducted. Randomized controlled trials which reported renal outcomes at the study endpoint in patients with T2DM receiving treatments of SGLT2 inhibitors were included. Renal adverse events were determined using prespecified lists from the Medical Dictionary for Regulatory Activities or laboratory values. Odds ratio with 95% confidence interval (CI) was used for assessment of dichotomous data. The mean difference or standardized mean difference with 95% CI was used for assessment of continuous data. Random effects models were adopted to measure the pooled outcomes. RESULTS Thirty-nine studies involving 35 trials were identified. Compared with placebo or other anti-diabetic medications, SGLT2 inhibitors were associated with significant lower incidence of composite renal outcome and acute renal failure or injury in patients with T2DM. The risk of progression of albuminuria also appeared to be decreased. No significant changes of estimated glomerular filtration rate levels or urine albumin-creatinine ratios were found in patients receiving SGLT2 inhibitors. CONCLUSIONS Overall renal safety and beneficial effects are indicated for SGLT2 inhibitors. Further confirmative data from large trials and real-world studies are needed.
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Affiliation(s)
- Xiaodan Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhen Zhong
- Department of Endocrinology, The First People's Hospital of Nankang District, Ganzhou, China
| | - Yanli Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wangen Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Davies MJ, Bianchi C, Del Prato S. Use of incretin-based medications: what do current international recommendations suggest with respect to GLP-1 receptor agonists and DPP-4 inhibitors? Metabolism 2020; 107:154242. [PMID: 32315698 DOI: 10.1016/j.metabol.2020.154242] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/25/2022]
Abstract
In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.
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Affiliation(s)
- Melanie J Davies
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK; Diabetes Research Centre, University of Leicester, UK
| | - Cristina Bianchi
- Department of Clinical & Experimental Medicine, Section of Diabetes & Metabolic Diseases, University of Pisa, Pisa, Italy
| | - Stefano Del Prato
- Department of Clinical & Experimental Medicine, Section of Diabetes & Metabolic Diseases, University of Pisa, Pisa, Italy.
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Cai Y, Liu X, Xu G. Combination therapy with SGLT2 inhibitors for diabetic kidney disease. Biomed Pharmacother 2020; 127:110192. [PMID: 32559844 DOI: 10.1016/j.biopha.2020.110192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/25/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents developed in recent years. They could block most glucose reabsorption in renal proximal tubules, thereby exerting glucose lowering effects through glycosuric ways. The renal and cardiovascular protection effects of SGLT2 inhibitors have also been demonstrated both in preclinical studies and clinical trials. However, SGLT2 inhibitors alone could induce an increase in endogenous/hepatic glucose production as well as in fasting plasma glucose levels; a sharp decrease of blood glucose concentration induced by SGLT2 inhibitors could also promote the secretion of counter-regulatory hormones such as glucagon, which has been reported to be associated with the occurrence of glycemic ketoacidosis. Therefore, coadministration of SGLT2 inhibitors and other antihyperglycemic agents should be considered when the therapeutic effect of SGLT2 inhibitors alone was unsatisfactory.
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Affiliation(s)
- Yuwen Cai
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Jiangxi, China; Grade 2016, The Second Clinical Medical College of Nanchang University, Jiangxi, China
| | - Xin Liu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Jiangxi, China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Jiangxi, China.
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Patoulias D, Katsimardou A, Kalogirou MS, Zografou I, Toumpourleka M, Imprialos K, Stavropoulos K, Stergiou I, Papadopoulos C, Doumas M. Glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors as add-on therapy for patients with type 2 diabetes? A systematic review and meta-analysis of surrogate metabolic endpoints. DIABETES & METABOLISM 2020; 46:272-279. [PMID: 32437914 DOI: 10.1016/j.diabet.2020.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/04/2020] [Accepted: 04/19/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE As sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are second-line treatment options in type 2 diabetes mellitus (T2DM), our study sought to provide precise effect estimates regarding the role of GLP-1RAs vs SGLT-2is as add-on treatments in patients uncontrolled by metformin monotherapy. RESEARCH DESIGN AND METHODS PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and 'grey literature' were searched from their inception up to December 2019 for randomized controlled trials (RCTs) with durations≥12weeks to evaluate the safety and efficacy of adding a GLP-1RA vs an SGLT-2i in patients with T2DM. RESULTS Three eligible RCTs were identified. Administration of GLP-1RAs vs SGLT-2is resulted in significant decreases in HbA1c with no significant impact on either body weight or fasting plasma glucose. GLP-1RA treatment led to a significant increase in odds for achieving an HbA1c<7% compared with SGLT-2is, whereas no difference was detected in body weight reductions of>5%. Significantly greater risk for any hypoglycaemia, nausea and diarrhoea, and lower risk for genital infections, was also observed with GLP-1RAs, while no differences regarding severe hypoglycaemia, treatment discontinuation and impact on blood pressure levels were identified. No other major safety issues arose. CONCLUSION Our meta-analysis suggests that GLP-1RAs provide better glycaemic effects than SGLT-2is in patients with T2DM uncontrolled by metformin, albeit while increasing risk for hypoglycaemia and gastrointestinal adverse events.
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Affiliation(s)
- D Patoulias
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece.
| | - A Katsimardou
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - M-S Kalogirou
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - I Zografou
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - M Toumpourleka
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - K Imprialos
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - K Stavropoulos
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece
| | - I Stergiou
- Diabetes Outpatient Department, General Hospital G. Gennimatas, Thessaloniki, Greece
| | - C Papadopoulos
- Third Department of Cardiology, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - M Doumas
- Second Propaedeutic Department of Internal Medicine, General Hospital Ippokrateio, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; VAMC and George Washington University, Washington, DC, USA
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