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Lagunas-Rangel FA, Liao S, Williams MJ, Trukhan V, Fredriksson R, Schiöth HB. Drosophila as a Rapid Screening Model to Evaluate the Hypoglycemic Effects of Dipeptidyl Peptidase 4 (DPP4) Inhibitors: High Evolutionary Conservation of DPP4. Biomedicines 2023; 11:3032. [PMID: 38002032 PMCID: PMC10669173 DOI: 10.3390/biomedicines11113032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, have been an integral part of the treatment of type 2 diabetes mellitus (T2DM) for several years. Despite their remarkable efficacy in lowering glucose levels and their compatibility with other hypoglycemic drugs, recent studies have revealed adverse effects, prompting the search for improved drugs within this category, which has required the use of animal models to verify the hypoglycemic effects of these compounds. Currently, in many countries the use of mammals is being significantly restricted, as well as cost prohibitive, and alternative in vivo approaches have been encouraged. In this sense, Drosophila has emerged as a promising alternative for several compelling reasons: it is cost-effective, offers high experimental throughput, is genetically manipulable, and allows the assessment of multigenerational effects, among other advantages. In this study, we present evidence that diprotin A, a DPP4 inhibitor, effectively reduces glucose levels in Drosophila hemolymph. This discovery underscores the potential of Drosophila as an initial screening tool for novel compounds directed against DPP4 enzymatic activity.
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Affiliation(s)
- Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | - Sifang Liao
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | - Michael J. Williams
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | | | - Robert Fredriksson
- Department of Pharmaceutical Biosciences, Uppsala University, 751 24 Uppsala, Sweden;
| | - Helgi B. Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
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Gidda H, Singh I, Mohamed A, Nashed B. Mild Pancreatitis Induced by Linagliptin Revealed by a Medication Review. Cureus 2023; 15:e36455. [PMID: 37090411 PMCID: PMC10116583 DOI: 10.7759/cureus.36455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
As dipeptidyl peptidase-4 inhibitors are becoming more utilized in the treatment of diabetes, it is important to recognize their side effects and become more familiar with them. As these side effects arise, physicians are more prepared to recognize and discontinue these medications. This case report describes a 34-year-old male who initially presented with a hemoglobin A1c greater than 16%. After titration of his diabetic medications, he presented with pancreatitis diagnosed by symptoms and imaging. Common causes of pancreatitis were ruled out, including biliary pathology, alcohol use, tobacco use, elevated calcium levels, and hypertriglyceridemia. The patient followed up in the clinic with persistent symptoms. A review of his medication list revealed pancreatitis as a side effect of linagliptin. After holding this medication, his symptoms improved over the course of a month.
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Affiliation(s)
- Harish Gidda
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Inderpal Singh
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Ayman Mohamed
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
| | - Bola Nashed
- Internal Medicine, Ascension St. John Hospital, Detroit, USA
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Comparison of Adverse Events Occurred During Administration of Dipeptidyl Peptidase-4 Inhibitor in Patients with Diabetes Using FDA Adverse Event Reporting System. Clin Drug Investig 2023; 43:129-140. [PMID: 36637688 DOI: 10.1007/s40261-022-01242-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND OBJECTIVE Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of diabetes. The frequencies of known serious side effects might differ among DPP-4 inhibitors, therefore a large sample size is needed to study them in prospective clinical trials. We examined the adverse events that occurred during the administration of a DPP-4 inhibitor in patients with diabetes using FDA Adverse Event Reporting System (FAERS) data. METHODS We used FAERS data reported between January 2013 and March 2022 in patients with diabetes who received a DPP-4 inhibitor. Statistical analyses were conducted to calculate reporting odds ratio (ROR) and adjusted ROR (aROR) controlling for differences in patient background. RESULTS The 9 target DPP-4 inhibitors were sitagliptin (N = 26,843), vildagliptin (N = 4767), alogliptin (N = 2085), linagliptin (N = 7969), saxagliptin (N = 3334), teneligliptin (N = 461), anagliptin (N = 102), trelagliptin (N = 17), and omarigliptin (N = 12). Compared with sitagliptin, aROR of acute kidney injury was significantly < 1.000 for alogliptin (0.247 [95% confidence interval (CI) 0.150-0.408], p < 0.001) but aROR of pemphigoid was significantly > 1.000 for alogliptin (3.082 [95% CI 2.156-4.406], p < 0.001). Similar statistical analyses were conducted for other adverse events and the types of adverse events with aROR of significantly < 1.000 or > 1.000 differed depending on the type of DPP-4 inhibitor. CONCLUSIONS Although it is impossible to select a DPP-4 inhibitor with aROR of < 1.000 of all occurrences of adverse events, these results may be used for drug selection when the patient has adverse events that need to be avoided. We provided the sample code of software R that can reproduce the results.
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 234] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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Model JFA, Rocha DS, Fagundes ADC, Vinagre AS. Physiological and pharmacological actions of glucagon like peptide-1 (GLP-1) in domestic animals. Vet Anim Sci 2022; 16:100245. [PMID: 35372707 PMCID: PMC8966211 DOI: 10.1016/j.vas.2022.100245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/25/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
GLP-1 improves peripheral glucose uptake in healthy dogs and cats. GLP-1 analogues administration in diabetic cats reduces exogenous insulin requirement. Dogs cardiomyocytes apoptosis is reduced by GLP-1-derived molecules action. Analogues of glucagon like peptide-1 (GLP-1) and other drugs that increase this peptide half-life are used worldwide in human medicine to treat type 2 diabetes mellitus (DM) and obesity. These molecules can increase insulin release and satiety, interesting effects that could also be useful in the treatment of domestic animals pathologies, however their use in veterinary medicine are still limited. Considering the increasing incidence of DM and obesity in cats and dogs, the aim of this review is to summarize the available information about the physiological and pharmacological actions of GLP-1 in domestic animals and discuss about its potential applications in veterinary medicine. In diabetic dogs, the use of drugs based on GLP-1 actions reduced blood glucose and increased glucose uptake, while in diabetic cats they reduced glycemic variability and exogenous insulin administration. Thus, available evidence indicates that GLP-1 based drugs could become alternatives to DM treatment in domestic animals. Nevertheless, current data do not provide enough elements to recommend these drugs widespread clinical use.
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Li Z, Tian J, Cheng Z, Teng W, Zhang W, Bao Y, Wang Y, Song B, Chen Y, Li B. Hypoglycemic bioactivity of anthocyanins: A review on proposed targets and potential signaling pathways. Crit Rev Food Sci Nutr 2022; 63:7878-7895. [PMID: 35333674 DOI: 10.1080/10408398.2022.2055526] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated interrelationships responsible for initiating its pathogenesis. Novel strategies for the treatment of this devastating disease have attracted increasing attention worldwide. Anthocyanins are bioactive compounds that are widely distributed in the plant kingdom, and multiple studies have elucidated their beneficial role in preventing and managing T2DM. This review summarizes and comments on the hypoglycemic actions of anthocyanins from the perspective of molecular mechanisms and different target-related signaling pathways in vitro, in vivo, and clinical trials. Anthocyanins can ameliorate T2DM by functioning as carbohydrate digestive enzyme inhibitors, facilitating glucose transporter 4 (GLUT4) translocation, suppressing the effectiveness of dipeptidyl peptidase IV (DPP-IV), promoting glucagon-like peptide-1 (GLP-1) secretion, inhibiting protein tyrosine phosphatase 1B (PTP1B) overexpression, and interacting with sodium-glucose co-transporter (SGLT) to delay glucose absorption in various organs and tissues. In summary, anthocyanin is a promising and practical small molecule that can hyperglycemic symptoms and accompanying complications suffered by patients with diabetes. However, rational and potent doses for daily intake and clinical studies are required in the future.
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Affiliation(s)
- Zhiying Li
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Jinlong Tian
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Zhen Cheng
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Wei Teng
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Weijia Zhang
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Yiwen Bao
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Yidi Wang
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Baoge Song
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
| | - Yi Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Bin Li
- College of Food Science, Shenyang Agricultural University, Shenyang, Liaoning, China
- Key Laboratory of Healthy Food Nutrition and Innovative Manufacturing, Shenyang, Liaoning, China
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Kanasaki K, Qu S, Yamamoto F, Schepers C, Sani Simões R, Yabe D, Ji L. Safety and tolerability of linagliptin in Asians with type 2 diabetes: a pooled analysis of 4457 patients from 21 randomized, double-blind, placebo-controlled clinical trials. Expert Opin Drug Saf 2022; 21:425-434. [PMID: 34711126 DOI: 10.1080/14740338.2022.1999409] [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: 08/05/2021] [Accepted: 10/25/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D. RESEARCH DESIGN AND METHODS This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup. RESULTS This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians. CONCLUSIONS Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.
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Affiliation(s)
- Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fumiko Yamamoto
- Medicine Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan
| | - Cornelia Schepers
- Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Rafael Sani Simões
- Global Patient Safety & Pharmacovigilance, Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
- Center for Healthcare Information Technology (C-HIT), Tokai National Higher Education and Research System, Nagoya, Japan
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Marzoog BA, Vlasova TI. Beta-cell autophagy under the scope of hypoglycemic drugs; possible mechanism as a novel therapeutic target. OBESITY AND METABOLISM 2022; 18:465-470. [DOI: 10.14341/omet12778] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Physiologically, autophagy is a major protective mechanism of β-cells from apoptosis, through can reserve normal β- cell mass and inhibit the progression of β-cells destruction. Beta-cell mass can be affected by differentiation from progenitors and de-differentiation as well as self-renewal and apoptosis. Shred evidence indicated that hypoglycemic drugs can induce β-cell proliferation capacity and neogenesis via autophagy stimulation. However, prolonged use of selective hypoglycemic drugs has induced pancreatitis besides several other factors that contribute to β-cell destruction and apoptosis initiation. Interestingly, some nonhypoglycemic medications possess the same effects on β-cells but depending on the combination of these drugs and the duration of exposure to β-cells. The paper comprehensively illustrates the role of the hypoglycemic drugs on the insulin-producing cells and the pathogeneses of β-cell destruction in type 2 diabetes mellitus, in addition to the regulation mechanisms of β-cells division in norm and pathology. The grasping of the hypoglycemic drug’s role in beta-cell is clinically crucial to evaluate novel therapeutic targets such as new signaling pathways. The present paper addresses a new strategy for diabetes mellitus management via targeting specific autophagy inducer factors (transcription factors, genes, lipid molecules, etc.).
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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Thiruvengadam S, Peter PR. Management of type 2 diabetes without insulin: An update for the PCP. Dis Mon 2021; 68:101290. [PMID: 34563347 DOI: 10.1016/j.disamonth.2021.101290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Sudha Thiruvengadam
- Department of Medicine, Trinity Health of New England, 166 Waterbury Rd, Ste 300, Prospect, Waterbury, CT 06712, USA.
| | - Patricia R Peter
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Inzucchi SE, Peixoto AJ, Testani JM. Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes. N Engl J Med 2021; 385:671-672. [PMID: 34379938 DOI: 10.1056/nejmc2107340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Kashyap S, Bala R, Madaan R, Behl T. Uncurtaining the effect of COVID-19 in diabetes mellitus: a complex clinical management approach. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:35429-35436. [PMID: 34021454 PMCID: PMC8139544 DOI: 10.1007/s11356-021-14480-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/14/2021] [Indexed: 04/12/2023]
Abstract
The aim of the present review is to overview the common properties of corona virus and hence proofs well beginning of corona virus in persons with diabetes, and its treatment. Globally, it has been observed that according to the statistics, India has the second largest number of people with diabetes. Literature review has been implemented within the databases using suitable keywords. For persons suffering from diabetic disorder, the COVID-19 infection becomes a dual challenge. Diabetes is a severe metabolic situation which causes the sugar levels in the blood to increase than the normal level. Normally, communicable disease like COVID-19 is more prevailing in patients with diabetes. Diabetic patient has poor immune response to infections. The different bacterial, viral, parasitic, and mycotic infections showed increased probability in diabetic patients as compared to non-diabetic patient. All these conclusions clear out the intention that the diabetic patients are more susceptible to enhanced inflammatory response that may lead to rapid spreading of COVID-19 infection with high rate of mortality. In the present situation of pandemic, managing diabetes seems to be quite challenging and diabetic patient having COVID-19 infection should follow normal course of antihypertensive and antidiabetic drugs prescribed with the exception of sodium glucose co-transpoters-2 inhibitors which would increase the risk of dehydration and ketoacidosis. In view of above discussion, this article highlights the proposed mechanism of COVID-19 infection linking it with diabetes, antidiabetic drugs to be used in COVID-19 infection along with their advantages, and disadvantages and management of COVID-19 infection diabetic patient.
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Affiliation(s)
- Shilpi Kashyap
- Pharmaceutics, Himachal Institute of Pharmacy, Paonta Sahib, India
| | - Rajni Bala
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Reecha Madaan
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea. JAMA Dermatol 2021; 156:1107-1114. [PMID: 32697283 DOI: 10.1001/jamadermatol.2020.2158] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Importance Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. Objective To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. Design, Setting, and Participants This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included. Main Outcomes and Measures The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. Results A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). Conclusions and Relevance This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.
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Affiliation(s)
- Hemin Lee
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Hye Jin Chung
- Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ajinkya Pawar
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Dae Hyun Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.,Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.,Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts
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14
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Sharko A, Samuel S, Jain N. Acute Pancreatitis Induced by Linagliptin: A Rare but Dangerous Side Effect. Cureus 2021; 13:e14104. [PMID: 33927920 PMCID: PMC8075763 DOI: 10.7759/cureus.14104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Diabetes mellitus type 2 (DMT2) is a highly prevalent disease both in the United States and worldwide. Multiple treatment options are currently available, and several new groups of medications have been introduced over the last couple of decades. One of these groups is dipeptidyl peptidase-4 (DPP-4) inhibitors. These medications have side effects, some of which are severe and potentially life-threatening; however, some of their side effects have been underreported since they are relatively new. When prescribing these medications, it is essential to be cautious, especially with patients at an increased risk of developing an adverse effect. We present the case of a 57-year-old male who developed DPP-4 inhibitor-induced acute pancreatitis after the initiation of linagliptin. The patient did not have any apparent risk factors for pancreatitis as he did not drink alcohol or smoke cigarettes, his lipid panel was within normal limits, and he had a cholecystectomy five years prior. His linagliptin was held in the hospital and discontinued post-discharge, which led to the resolution of his symptoms.
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Affiliation(s)
- Artem Sharko
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
| | - Shirly Samuel
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
| | - Nikita Jain
- Internal Medicine, Northwestern Medicine McHenry Hospital, McHenry, USA
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15
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Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:642-653. [PMID: 32929230 DOI: 10.1038/s41574-020-0399-8] [Citation(s) in RCA: 207] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2020] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.
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Affiliation(s)
- Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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16
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Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19. JAMA Dermatol 2020; 156:1-3. [PMID: 32756881 PMCID: PMC7376463 DOI: 10.1001/jamadermatol.2020.2800] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/30/2020] [Indexed: 01/22/2023]
Abstract
Question What is the absolute risk of bullous pemphigoid in patients who initiate use of dipeptidyl peptidase–4 inhibitors and its comparative risk against sulfonylurea use? Findings In this cohort study of 1 664 880 patients with type 2 diabetes, the incidence rate of bullous pemphigoid per 1000 person-years among patients who initiated dipeptidyl peptidase–4 inhibitor therapy was 0.42 compared with 0.31 for sulfonylurea. The risk was 42% higher with dipeptidyl peptidase–4 inhibitors than with sulfonylurea and 62% to 70% higher in subgroups of patients who were 65 years or older, white, and linagliptin users. Meaning These findings suggest that use of dipeptidyl peptidase–4 inhibitors is associated with higher risk of bullous pemphigoid compared with sulfonylurea, and that clinicians should be aware of this rare adverse effect in subgroups with higher risk. Importance Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase–4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. Objective To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. Design, Setting, and Participants This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included. Main Outcomes and Measures The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. Results A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). Conclusions and Relevance This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.
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Affiliation(s)
- Hemin Lee
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Hye Jin Chung
- Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ajinkya Pawar
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Dae Hyun Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts
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17
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Anderson S, Cotiguala L, Tischer S, Park JM, McMurry K. Review of Newer Antidiabetic Agents for Diabetes Management in Kidney Transplant Recipients. Ann Pharmacother 2020; 55:496-508. [PMID: 32795145 DOI: 10.1177/1060028020951955] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE This systematic review describes the efficacy, safety, and drug interactions of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose transport protein 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs). DATA SOURCES Articles were identified by English-language MEDLINE search, published prior to May 2020, using the terms kidney transplant, OR PTDM, OR NODAT, AND metformin, OR DPP4, OR GLP1, OR SGLT2. STUDY SELECTION AND DATA EXTRACTION All selected studies were included if the study population was composed of adult KTRs who were diagnosed with either impaired glucose tolerance, diabetes mellitus (DM), new-onset diabetes after transplant (NODAT), or posttransplantation diabetes mellitus (PTDM). DATA SYNTHESIS In KTRs, there is evidence for safety with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors. However, urinary tract infections and a slight initial decrease in renal function may limit use of SGLT2 inhibitors. As compared with the nontransplant type 2 DM population, SGLT2 inhibitors are not as efficacious in KTRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE This review provides an overview of the current literature on newer antidiabetic agents, addressing efficacy, safety, and drug interactions to help guide clinical decision-making for their use in KTRs. CONCLUSION Newer antidiabetic agents have been recommended by the American Diabetes Association for potential cardiovascular, renal, and hypoglycemic benefits. Particular agents, such as DPP-4 inhibitors and GLP-1 RAs may play a role in correcting PTDM-related defects. Clinicians need to take into account both patient-specific and drug-specific characteristics when initiating these agents in KTRs.
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18
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Mirabelli M, Chiefari E, Puccio L, Foti DP, Brunetti A. Potential Benefits and Harms of Novel Antidiabetic Drugs During COVID-19 Crisis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E3664. [PMID: 32456064 PMCID: PMC7277613 DOI: 10.3390/ijerph17103664] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 02/07/2023]
Abstract
Patients with diabetes have been reported to have enhanced susceptibility to severe or fatal COVID-19 infections, including a high risk of being admitted to intensive care units with respiratory failure and septic complications. Given the global prevalence of diabetes, affecting over 450 million people worldwide and still on the rise, the emerging COVID-19 crisis poses a serious threat to an extremely large vulnerable population. However, the broad heterogeneity and complexity of this dysmetabolic condition, with reference to etiologic mechanisms, degree of glycemic derangement and comorbid associations, along with the extensive sexual dimorphism in immune responses, can hamper any patient generalization. Even more relevant, and irrespective of glucose-lowering activities, DPP4 inhibitors and GLP1 receptor agonists may have a favorable impact on the modulation of viral entry and overproduction of inflammatory cytokines during COVID-19 infection, although current evidence is limited and not univocal. Conversely, SGLT2 inhibitors may increase the likelihood of COVID-19-related ketoacidosis decompensation among patients with severe insulin deficiency. Mindful of their widespread popularity in the management of diabetes, addressing potential benefits and harms of novel antidiabetic drugs to clinical prognosis at the time of a COVID-19 pandemic deserves careful consideration.
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Affiliation(s)
- Maria Mirabelli
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (M.M.); (E.C.); (D.P.F.)
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (M.M.); (E.C.); (D.P.F.)
| | - Luigi Puccio
- Complex Operative Unit of Endocrinology and Diabetes, Hospital Pugliese-Ciaccio, 88100 Catanzaro, Italy;
| | - Daniela Patrizia Foti
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (M.M.); (E.C.); (D.P.F.)
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (M.M.); (E.C.); (D.P.F.)
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19
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Abstract
PURPOSE OF REVIEW Our goal is to discuss how to personalize the management of patients with type 2 diabetes by adjusting glycemic targets and tailoring medical therapy to account for unique patient characteristics. RECENT FINDINGS We review the pharmacotherapeutic options for the management of type 2 diabetes, focusing on potential advantages and disadvantages of each class of agents. We also discuss how to approach specific patient subpopulations and propose a conceptual framework for incorporating these factors into clinical practice. As the diabetes treatment landscape rapidly expands, physicians have the exciting opportunity to offer patients increasingly individualized care.
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Affiliation(s)
- Patricia R Peter
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, FMP 106, P.O. Box 208020, New Haven, CT, 06520, USA.
| | - Beatrice C Lupsa
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, FMP 106, P.O. Box 208020, New Haven, CT, 06520, USA
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20
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Mishra A, Cross M, Hofmann A, Coster MJ, Karim A, Sattar A. Identification of a Novel Scaffold for Inhibition of Dipeptidyl Peptidase-4. J Comput Biol 2019; 26:1470-1486. [PMID: 31390221 DOI: 10.1089/cmb.2019.0201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) is considered a major drug target for type 2 diabetes mellitus (T2DM). In addition to T2DM, a regulatory role of DPP-4 was also found in cardiovascular diseases. Existing DPP-4 inhibitors have been reported to have several adverse effects. In this study, a computer-aided drug design approach and its use to detect a novel class of inhibitor for DPP-4 are reported. Through structure and pharmacophore-based screening, we identified 13 hit compounds from an ∼4-million-compound library. Physical interactions of these hits with DPP-4 were studied using docking and explicit solvent molecular dynamics (MD) simulations. Later, MMPBSA binding energy was calculated for the ligand/protein simulation trajectories to determine the stability of compounds in the binding cavity. These compounds have a novel scaffold and exhibited a stable binding mode. "Best-in-screen" compounds (or their closest available analogs) were resourced and their inhibition of DPP-4 activity was experimentally validated using an in vitro enzyme activity assay in the presence of 100 and 10 μM compounds. These assays identified a compound with a spirochromanone center with 53% inhibition activity at a 100 μM concentration. A further five spirochromanone compounds were synthesized and examined in silico and in vitro; again, one compound showed 53% inhibitory activity action at 100 μM. Overall, this study identified two novel "spirochromanone" compounds that lowered DPP-4 activity by more than ∼50% at 100 μM. This study also showed the impact of fast in silico drug design techniques utilizing virtual screening and MD to identify novel scaffolds to bind and inhibit DPP-4. Spirochromanone motif identified here may be used to design molecules to achieve drug-like inhibitory action against DPP-4.
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Affiliation(s)
- Avinash Mishra
- Institute for Integrated and Intelligent Systems, Griffith University, Nathan, Australia.,Novo Informatics Pvt. Ltd., New Delhi, India
| | - Megan Cross
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Australia
| | - Andreas Hofmann
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Australia.,Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Australia
| | - Mark J Coster
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Australia
| | - Abdul Karim
- Institute for Integrated and Intelligent Systems, Griffith University, Nathan, Australia
| | - Abdul Sattar
- Institute for Integrated and Intelligent Systems, Griffith University, Nathan, Australia
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21
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Hupfeld C, Mudaliar S. Navigating the "MACE" in Cardiovascular Outcomes Trials and decoding the relevance of Atherosclerotic Cardiovascular Disease benefits versus Heart Failure benefits. Diabetes Obes Metab 2019; 21:1780-1789. [PMID: 30957945 DOI: 10.1111/dom.13740] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 03/29/2019] [Accepted: 04/03/2019] [Indexed: 12/31/2022]
Abstract
The publication of results from recent cardiovascular outcome trials (CVOTs) has transformed the landscape of diabetes treatment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 (SGLT2) inhibitors have demonstrated CV benefits in large, well-conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are US Food and Drug Administration-approved not only for glucose-lowering, but also to reduce the risk of cardiovascular (CV) events/CV mortality in people with type 2 diabetes (T2DM) and established CV disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the diabetes community, but the replication of the CV benefits with different compounds in the same class alleviated concerns about the CV benefits being chance findings. However, many questions remain. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1RA class and the SGLT2 inhibitor class appear to be more complex. An analysis of major adverse cardiovascular events (MACE) in the CVOTs shows that the CV benefits of GLP-1RAs are predominantly specific to atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). By contrast, the SGLT2 inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function ("the pump"), and not on the "pipes" (coronary arteries). In the present review, we discuss the rationale for the conduct of CVOTs, highlight the inability of the classic three-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially HF in T2DM, and discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus HF, which develops in a sizeable proportion of people with diabetes and without prior ASCVD.
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Affiliation(s)
- Christopher Hupfeld
- Endocrinology/Diabetes Section, Veterans Affairs Medical Centre, San Diego, California
- Endocrinology Division, Department of Medicine, University of California, San Diego School of Medicine, San Diego, California
| | - Sunder Mudaliar
- Endocrinology/Diabetes Section, Veterans Affairs Medical Centre, San Diego, California
- Endocrinology Division, Department of Medicine, University of California, San Diego School of Medicine, San Diego, California
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22
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Hanssen NMJ, Jandeleit-Dahm KAM. Dipeptidyl peptidase-4 inhibitors and cardiovascular and renal disease in type 2 diabetes: What have we learned from the CARMELINA trial? Diab Vasc Dis Res 2019; 16:303-309. [PMID: 31018682 PMCID: PMC6613297 DOI: 10.1177/1479164119842339] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Dipeptidyl peptidase-4 inhibitors are a relatively new class of oral anti-hyperglycaemic drugs to treat type 2 diabetes through prevention of degradation of incretins by the dipeptidyl peptidase-4 enzyme. The large trials evaluating the dipeptidyl peptidase-4 inhibitors sitagliptin, alogliptin and saxagliptin demonstrated safety for cardiovascular disease. Post hoc analyses on renal endpoints yielded similar findings. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor evaluated in the CARMELINA trial. CARMELINA included individuals with type 2 diabetes and high cardiovascular and renal risk. Even in this setting, linagliptin displayed cardiovascular safety. CARMELINA also removed initial concerns for heart failure as a class-specific side-effect of dipeptidyl peptidase-4 inhibitors, as no signal for heart failure was found. Although numerically low, CARMELINA did confirm increased rates of pancreatitis in the linagliptin group, suggesting that pancreatitis is a class-specific side-effect of dipeptidyl peptidase-4 inhibitors. Linagliptin reduced progression of albuminuria, but had no effect on other hard renal endpoints. Overall, dipeptidyl peptidase-4 inhibitors are safe but do not confer significant reductions in complications observed for some of the other new glucose-lowering drugs. However, linagliptin is a safe alternative in renal impairment, without dose adjustment. Furthermore, dipeptidyl peptidase-4 inhibitors may hold value as alternatives to sulfonyl-urea derivatives or as an add-on therapy to delay insulin prescription given their favourable safety profile.
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Affiliation(s)
- Nordin MJ Hanssen
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands
- Nordin MJ Hanssen, Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Debeyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Karin AM Jandeleit-Dahm
- Department of Diabetes, Monash University, Melbourne, VIC, Australia
- German Diabetes Centre, Leibniz Centre for Diabetes Research, Institute for Clinical Diabetology, Research Group Diabetic Nephropathy, Germany
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23
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Nishimura R, Kato H, Kisanuki K, Oh A, Hiroi S, Onishi Y, Guelfucci F, Shimasaki Y. Treatment patterns, persistence and adherence rates in patients with type 2 diabetes mellitus in Japan: a claims-based cohort study. BMJ Open 2019; 9:e025806. [PMID: 30826768 PMCID: PMC6429930 DOI: 10.1136/bmjopen-2018-025806] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE To determine real-world trends in antidiabetic drug use, and persistence and adherence, in Japanese patients with type 2 diabetes mellitus (T2DM). DESIGN Retrospective evaluation of administrative claims data (2011-2015) using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. SETTING Analysis of two administrative claims databases for Japanese patients with T2DM. PARTICIPANTS Adults (aged ≥18 years) with an International Classification of Diseases, 10th Revision code of T2DM and at least one antidiabetic drug prescription. MAIN OUTCOME MEASURES Treatment patterns in untreated (UT) or previously treated (PT) patients receiving antidiabetic therapy; persistence with treatment at 12 months; adherence to treatment at 12 months. RESULTS 40 908 and 90 421 patients were included from the JMDC and MDV databases, respectively. The most frequently prescribed therapy at the index (first prescription) date was dipeptidyl peptidase-4 inhibitor (DPP-4i) in UT patients (JMDC: 44.0%, MDV: 54.8%) and combination therapy in PT patients (74.6%, 81.1%). Most common combinations were DPP-4i plus: biguanide (BG; 11.4%, 10.9%), sulfonylurea (SU; 8.4%, 11.0%) or BG+SU (7.8%, 9.1%). In UT or PT patients from either database whose index prescription was for any antidiabetic drug class(es) other than DPP-4i, the most frequent add-on or switch was to DPP-4i. 12-month persistence with index monotherapy was highest with DPP-4i and BG. Adherence was high (≥80%) for all monotherapy schedules, except insulin and glucagon-like peptide-1 agonist, and for the five most frequent two-drug and three-drug combinations. Persistence was greater in elderly UT patients and in those receiving ≤5 medications, but comparatively worse in UT patients with ≥3 index antidiabetic drug classes. CONCLUSIONS The findings indicate that DPP-4i is the most commonly used antidiabetic drug class in Japanese patients with T2DM, and persistence and adherence to this antidiabetic drug class are high.
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Affiliation(s)
| | - Haruka Kato
- Japan Medical Affairs, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Koichi Kisanuki
- Japan Medical Affairs, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Akinori Oh
- Japan Medical Affairs, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Shinzo Hiroi
- Japan Medical Affairs, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | | | | | - Yukio Shimasaki
- Japan Medical Affairs, Takeda Pharmaceutical Company Limited, Tokyo, Japan
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24
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Sato A, Takei M, Hiramatsu K, Takeda T, Miyamoto T, Yamazaki M, Sato Y, Komatsu M. Effects of Sitagliptin on Pancreatic Beta-Cells in Type 2 Diabetes With Sulfonylurea Treatment: A Prospective Randomized Study. J Clin Med Res 2019; 11:15-20. [PMID: 30627273 PMCID: PMC6306137 DOI: 10.14740/jocmr3632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 10/20/2018] [Indexed: 11/22/2022] Open
Abstract
Background This prospective randomized, multicenter, open-label, comparative study was performed to analyze the effects of sitagliptin on glycemic control and maintenance of beta-cell function in patients with poorly controlled type 2 diabetes treated with low-dose glimepiride. Methods Forty-one patients with type 2 diabetes mellitus treated with low-dose glimepiride (≤ 2 mg/day) were prospectively enrolled in this study (age: 20 - 75 years; hemoglobin A1c (HbA1c): 7.4- 9.4%). The patients were randomized into two groups: the glimepiride (G) group, in which glimepiride dose was increased gradually to 6 mg/day, and the sitagliptin (S) group, in which sitagliptin was added at a dose of 50 mg/day. Results HbA1c level was significantly decreased after 24 weeks, but not 12 weeks, in the G group, while a significant decrease was seen after 12 weeks in the S group. Although there were no significant differences in HbA1c level at 24 weeks between the two groups (P = 0.057). The overall trend of changes in HbA1c level suggested that the glucose-lowering effects were superior in the S group. Furthermore, a significant change in fasting glucose was seen in the S group, but not in the G group. Glycemic control target was achieved in 36.7% and 16.7% patients in the S group and the G group, respectively. The proinsulin/insulin (P/I) ratio was significantly increased in the G group, whereas it tended to decrease in the S group. After 24 weeks of treatment, no significant difference was observed in the P/I ratio between the two groups, whereas a significant difference was noted in the ΔP/I (amount of change). Albuminuria tended to increase in the G group compared with the S group. Conclusion The results of the present study suggested that sitagliptin effectively lowered hyperglycemia and that it may have a protective effect on pancreatic beta-cells when combined with a low dose of glimepiride. Therefore, sitagliptin may represent a useful combination therapy with low-dose sulfonylurea, not only for achieving glycemic control but also for protection of pancreatic beta-cells.
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Affiliation(s)
- Ai Sato
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.,AS and MT equally contributed to this study
| | - Masahiro Takei
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.,AS and MT equally contributed to this study
| | | | | | | | - Masanori Yamazaki
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoshihiko Sato
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mitsuhisa Komatsu
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Gallego-Colon E, Wojakowski W, Francuz T. Incretin drugs as modulators of atherosclerosis. Atherosclerosis 2018; 278:29-38. [DOI: 10.1016/j.atherosclerosis.2018.09.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 07/06/2018] [Accepted: 09/13/2018] [Indexed: 02/06/2023]
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26
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Jonnalagadda VG, Char HP, Ankana PK. Effect of Anagliptin and Sitagliptin in Type 2 Diabetic Patients with Dyslipidemia and Cardiovascular Risk: What Is the Real REASON Behind It? Cardiovasc Drugs Ther 2018. [PMID: 29516206 DOI: 10.1007/s10557-018-6779-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Venu Gopal Jonnalagadda
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research, C/O NETES Institute of Technology & Science, NH-37, Shantipur, Parli Part, Mirza, Assam, 781125, India.
| | - Harish Prabhanna Char
- National Institute of Management Studies, 201 Nirman Estate, Link Road, Malad West, Mumbai, Maharashtra, 400064, India
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27
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Abstract
INTRODUCTION Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes. AREAS COVERED An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed. EXPERT OPINION The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.
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Affiliation(s)
- André Jacques Scheen
- a Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Sart Tilman, University of Liège , Liège , Belgium.,b Division of Clinical Pharmacology , Center for Interdisciplinary Research on Medicines (CIRM) , Liège , Belgium
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28
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Rizos CV, Filippatos TD, Elisaf MS. Pharmacokinetic drug evaluation of empagliflozin plus linagliptin for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol 2017; 14:117-125. [PMID: 29241374 DOI: 10.1080/17425255.2018.1418325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion. Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination. Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients.
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Affiliation(s)
- Christos V Rizos
- a Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece
| | - Theodosios D Filippatos
- a Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece
| | - Moses S Elisaf
- a Department of Internal Medicine, School of Medicine , University of Ioannina , Ioannina , Greece
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Hwang TJ, Franklin JM, Kesselheim AS. Effect of US Food and Drug Administration's Cardiovascular Safety Guidance on Diabetes Drug Development. Clin Pharmacol Ther 2017; 102:290-296. [PMID: 28390139 DOI: 10.1002/cpt.705] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/03/2017] [Accepted: 04/03/2017] [Indexed: 12/15/2022]
Abstract
In 2008, the US Food and Drug Administration (FDA) issued guidance on the need for cardiovascular outcome trials to assess the safety of new diabetes medications. Using two large commercial databases, we evaluated the effect of the FDA's cardiovascular safety guidance on drug development for type 2 diabetes as well as a comparison group of drugs intended to treat other alimentary and metabolic conditions. The FDA's guidance was associated with a 31% differential decrease in the rate of diabetes drugs entering phase II trials, but the remaining drugs were significantly more likely to target novel biological pathways (72% of drugs had novel mechanisms after the guidance vs. 49% before the guidance). No differential changes were observed for phase I and phase III trials. There was no measurable improvement during the study period in glycemic efficacy among investigational products entering phase III trials. This research highlights how regulatory actions can impact pharmaceutical innovation.
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Affiliation(s)
- T J Hwang
- Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - J M Franklin
- Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - A S Kesselheim
- Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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