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Yu PL, Yu Y, Li S, Mu BC, Nan MH, Pang M. Dapagliflozin in heart failure and type 2 diabetes: Efficacy, cardiac and renal effects, safety. World J Diabetes 2024; 15:1518-1530. [PMID: 39099807 PMCID: PMC11292345 DOI: 10.4239/wjd.v15.i7.1518] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/12/2024] [Accepted: 05/14/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Heart failure (HF), especially HF with reduced ejection fraction (HFrEF), presents complex challenges, particularly in the aging population where it often coexists with type 2 diabetes mellitus (T2DM). AIM To analyze the effect of dapagliflozin treatment on cardiac, renal function, and safety in patients with HFrEF combined with T2DM. METHODS Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study. The propensity score matching method was used, and a total of 102 eligible samples were scaled. The clinical efficacy of the two groups was evaluated at the end of the treatment, comparing the results of blood glucose, insulin, cardiac function, markers of myocardial injury, renal function indexes, and 6-min walk test (6MWT) before and after the treatment. We compared the occurrence of adverse effects on the treatment process of the two groups of patients. The incidence of adverse outcomes in patients within six months of treatment was counted. RESULTS The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group (P = 0.013). After treatment, the pancreatic beta-cell function index, left ventricular ejection fraction, and glomerular filtration rate of patients in the study group were significantly higher than control group (P < 0.001), while their fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin, insulin resistance index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, cardiac troponin I, creatine kinase-MB, N-terminal pro b-type natriuretic peptide, serum creatinine, and blood urea nitrogen were significantly lower than those of the control group. After treatment, patients in the study group had a significantly higher 6MWT than those in the control group (P < 0.001). Hypoglycemic reaction (P = 0.647), urinary tract infection (P = 0.558), gastrointestinal adverse effect (P = 0.307), respiratory disturbance (P = 0.558), and angioedema (P = 0.647) were not statistically different. There was no significant difference between the incidence of adverse outcomes between the two groups (P = 0.250). CONCLUSION Dapagliflozin significantly enhances clinical efficacy, cardiac and renal function, and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.
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Affiliation(s)
- Pei-Ling Yu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - You Yu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Shuang Li
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Bai-Chen Mu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Ming-Hua Nan
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Min Pang
- Department of Outpatient, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
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Tang H, Xu C, Zhang P, Luo T, Huang Y, Yang X. A profile of SGLT-2 inhibitors in hyponatremia: The evidence to date. Eur J Pharm Sci 2023; 184:106415. [PMID: 36870579 DOI: 10.1016/j.ejps.2023.106415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/14/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
Hyponatremia is the most common electrolyte disorder in clinical practice, which may lead to life-threatening complications. Several lines of evidence suggest that hyponatremia is associated not only with significant increases in length of stay, cost, and financial burden, but also with increased morbidity and mortality. Hyponatremia is also considered to be a negative prognostic factor in patients with heart failure and cancer. Although multiple therapeutic methods are available for treating hyponatremia, most have some limitations, such as poor compliance, rapid correction of serum Na+, other negative side effects and high cost. Given these limitations, identifying novel therapies for hyponatremia is essential. Recent clinical studies have shown that SGLT-2 inhibitors (SGLT 2i) significantly increased serum Na+ levels and were well tolerated by patients who underwent this treatment. Therefore, oral administration of SGLT 2i appears to be an effective treatment for hyponatremia. This article will briefly review the etiology of hyponatremia and integrated control of sodium within the kidney, current therapies for hyponatremia, potential mechanisms and efficacy of SGLT 2i for hyponatremia, and the benefits in cardiovascular, cancer, and kidney disease by regulating sodium and water balance.
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Affiliation(s)
- Hui Tang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Changjing Xu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Piao Zhang
- Department of Pharmacy, Ya 'an People's Hospital, Ya 'an, Sichuan 646000, China
| | - Taimin Luo
- Department of pharmacy, Chengdu Seventh People's Hospital, Chengdu, Sichuan 610000, China
| | - Yilan Huang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
| | - Xuping Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
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Adam CA, Anghel R, Marcu DTM, Mitu O, Roca M, Mitu F. Impact of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors on Arterial Stiffness and Vascular Aging-What Do We Know So Far? (A Narrative Review). Life (Basel) 2022; 12:803. [PMID: 35743834 PMCID: PMC9224553 DOI: 10.3390/life12060803] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
Vascular aging, early vascular aging or supernormal vascular aging are concepts used for estimating the cardiovascular risk at a certain age. From the famous line of Thomas Sydenham that "a man is as old as his arteries" to the present day, clinical studies in the field of molecular biology of the vasculature have demonstrated the active role of vascular endothelium in the onset of cardiovascular diseases. Arterial stiffness is an important cardiovascular risk factor associated with the occurrence of cardiovascular events and a high risk of morbidity and mortality, especially in the presence of diabetes. Sodium-glucose cotransporter 2 inhibitors decrease arterial stiffness and vascular resistance by decreasing endothelial cell activation, stimulating direct vasorelaxation and ameliorating endothelial dysfunction or expression of pro-atherogenic cells and molecules.
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Affiliation(s)
- Cristina Andreea Adam
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
| | - Razvan Anghel
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Dragos Traian Marius Marcu
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Ovidiu Mitu
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
- Sf. Spiridon Clinical Emergency Hospital, Independence Boulevard nr. 1, 700111 Iasi, Romania
| | - Mihai Roca
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Florin Mitu
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
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Estrada AK, Delgado-Maldonado T, Lara-Ramírez EE, Martínez-Vázquez AV, Ortiz-Lopez E, Paz-González AD, Bandyopadhyay D, Rivera G. Recent Advances in the Development of Type 2 Sodium-Glucose Cotransporter Inhibitors for the Treatment of Type 2 Diabetes Mellitus. Mini Rev Med Chem 2021; 22:586-599. [PMID: 34353256 DOI: 10.2174/1389557521666210805112416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is one of the most serious and prevalent diseases worldwide. In the last decade, type 2 sodium-glucose cotransporter inhibitors (iSGLT2) were approved as alternative drugs for the pharmacological treatment of T2DM. The anti-hyperglycemic mechanism of action of these drugs involves glycosuria. In addition, SGLT2 inhibitors cause beneficial effects such as weight loss, a decrease in blood pressure, and others. OBJECTIVE This review aimed to describe the origin of SGLT2 inhibitors and analyze their recent development in preclinical and clinical trials. RESULTS In 2013, the FDA approved SGLT2 inhibitors as a new alternative for the treatment of T2DM. These drugs have shown good tolerance with few adverse effects in clinical trials. Additionally, new potential anti-T2DM agents based on iSGLT2 (O-, C-, and N-glucosides) have exhibited a favorable profile in preclinical evaluations, making them candidates for advanced clinical trials. CONCLUSION The clinical results of SGLT2 inhibitors show the importance of this drug class as new anti-T2DM agents with a potential dual effect. Additionally, the preclinical results of SGLT2 inhibitors favor the design and development of more selective new agents. However, several adverse effects could be a potential risk for patients.
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Affiliation(s)
- Ana Karen Estrada
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
| | - Timoteo Delgado-Maldonado
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
| | - Edgar E Lara-Ramírez
- Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social (IMSS), 98000 Zacatecas. Mexico
| | - Ana Verónica Martínez-Vázquez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
| | - Eyra Ortiz-Lopez
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
| | - Alma D Paz-González
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
| | | | - Gildardo Rivera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710 Reynosa. Mexico
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Baruah MP, Makkar BM, Ghatnatti VB, Mandal K. Sodium Glucose Co-transporter-2 Inhibitor: Benefits beyond Glycemic Control. Indian J Endocrinol Metab 2019; 23:140-149. [PMID: 31016169 PMCID: PMC6446679 DOI: 10.4103/ijem.ijem_160_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a family of metabolic disorders characterized by hyperglycemia as a consequence of abnormalities in insulin secretion and insulin sensitivity. It affects hundreds of millions of people worldwide and leads to increased morbidity, compromised quality of life, higher mortality sodium glucose co-transporter 2 (SGLT2) inhibitors, a new class of oral antidiabetic drugs, have garnered considerable attention in the recent past and are considered potential first-line candidates for the management of T2DM. This review outlines the evidence-based therapeutic efficacy, safety, limitations, and advantages of SGLT2 inhibitors in the management of T2DM. SGLT2 inhibitors work by preventing the kidneys from reabsorbing glucose back into the blood, leading to increase in excretion of glucose through urine, thereby lowering hyperglycemia. Treatment with SGLT2 inhibitors improves A1C levels, reduces blood pressure and body weight, and is overall well tolerated by patients with T2DM. However, additional data on long-term cardiovascular safety are still needed. Characteristic adverse events include mild genital - urinary tract infection more commonly seen in women than in men, but serious infection is uncommon. Their use should be exercised with extra caution in patients suffering from renal impairment. Further, advancing to dual/triple combinational therapies with SGLT2 inhibitors and existing oral antidiabetic options may prove to be a breakthrough in the management of T2DM.
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Affiliation(s)
| | - B. M. Makkar
- Dr. Makkar's Diabetes and Obesity Centre, New Delhi, India
| | - Vikrant B. Ghatnatti
- Department of Endocrinology, Kles Dr. Prabhakar Kore Hospital and MRC, Belgaum, Karnataka, India
| | - Kaushik Mandal
- Department of Medical Affairs, AstraZeneca Pharma India Limited, Bengaluru, Karnataka, India
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Chen L, LaRocque LM, Efe O, Wang J, Sands JM, Klein JD. Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats. Am J Med Sci 2016; 352:517-523. [PMID: 27865300 PMCID: PMC5119919 DOI: 10.1016/j.amjms.2016.08.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/19/2016] [Accepted: 08/19/2016] [Indexed: 01/14/2023]
Abstract
AIM This study evaluates the effect of dapagliflozin, a SGLT2 inhibitor, on fluid or electrolyte balance and its effect on urea transporter-A1 (UT-A1), aquaporin-2 (AQP2) and Na-K-2Cl cotransporter (NKCC2) protein abundance in diabetic rats. METHODS Diabetes mellitus (DM) was induced by injection of streptozotocin into the tail vein. Serum Na+, K+, Cl- concentration, urine Na+, K+, Cl- excretion, blood glucose, urine glucose excretion, urine volume, urine osmolality and urine urea excretion were analyzed after the administration of dapagliflozin. UT-A1, AQP2 and NKCC2 proteins were detected by western blot. RESULTS Dapagliflozin treatment decreased blood glucose concentration by 38% at day 7 and by 47% at day 14 and increased the urinary glucose excretion rate compared with the untreated diabetic animals. Increased 24-hour urine volume, decreased urine osmolality and hyponatremia, hypokalemia and hypochloremia observed in diabetic rats were attenuated by dapagliflozin treatment. Western blot analysis showed that UT-A1, AQP2 and NKCC2 proteins are upregulated in DM rats over control rats; dapagliflozin treatment results in a further increase in inner medulla tip UT-A1 protein abundance by 42% at day 7 and by 46% at day 14, but it did not affect the DM-induced upregulation of AQP2 and NKCC2 proteins. CONCLUSION Dapagliflozin treatment augmented the compensatory changes in medullary transport proteins in DM. These changes would tend to conserve solute and water even with persistent glycosuria. Therefore, diabetic rats treated with dapagliflozin have a mild osmotic diuresis compared to nondiabetic animals, but this does not result in an electrolyte disorder or significant volume depletion.
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Affiliation(s)
- Ling Chen
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Internal Medicine & Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lauren M LaRocque
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Orhan Efe
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Juan Wang
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Jeff M Sands
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Physiology, Emory University School of Medicine, Atlanta, Georgia.
| | - Janet D Klein
- Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
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Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, Ahn YB, Kim ES, Moon SD, Kim MJ, Ko SH. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes. PLoS One 2016; 11:e0165703. [PMID: 27802313 PMCID: PMC5089752 DOI: 10.1371/journal.pone.0165703] [Citation(s) in RCA: 140] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022] Open
Abstract
Background Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Methods Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. Results After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05). Conclusion Dapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.
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Affiliation(s)
- Seok Joon Shin
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sungjin Chung
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soo Jung Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eun-Mi Lee
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Hye Yoo
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji-Won Kim
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu-Bae Ahn
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eun-Sook Kim
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Dae Moon
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myung-Jun Kim
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Hyun Ko
- Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- * E-mail:
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Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care 2015; 38:1730-5. [PMID: 26180105 PMCID: PMC4542276 DOI: 10.2337/dc15-0355] [Citation(s) in RCA: 274] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 06/12/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Sodium-glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively. RESEARCH DESIGN AND METHODS Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min(-1) ⋅ 1.73 m(-2)) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes. RESULTS At week 90, weight loss averaged -3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of -11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = -0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01). CONCLUSIONS Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.
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Affiliation(s)
| | - Thomas Hach
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Susanne Crowe
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Arjun Sanghvi
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Kevin D Hall
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Alsahli M, Gerich JE. Hypoglycemia in Patients with Diabetes and Renal Disease. J Clin Med 2015; 4:948-64. [PMID: 26239457 PMCID: PMC4470208 DOI: 10.3390/jcm4050948] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 04/19/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022] Open
Abstract
This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.
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Affiliation(s)
- Mazen Alsahli
- Department of Medicine, Southlake Health Center and University of Toronto Faculty of Medicine, 531 Davis Dr, Newmarket, Ontario L3Y 6P5, Canada.
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA.
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Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo Clin Proc 2014; 89:1564-71. [PMID: 25305751 DOI: 10.1016/j.mayocp.2014.07.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 07/12/2014] [Accepted: 07/25/2014] [Indexed: 12/21/2022]
Abstract
Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.
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MESH Headings
- Albuminuria/etiology
- Biomarkers/urine
- Databases, Bibliographic
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Glomerular Filtration Rate/physiology
- Humans
- Hypoglycemia/chemically induced
- Hypoglycemia/epidemiology
- Hypoglycemia/etiology
- Hypoglycemia/therapy
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Insulin/adverse effects
- Insulin/therapeutic use
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/epidemiology
- Risk Factors
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Affiliation(s)
- Mazen Alsahli
- Faculty of Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John E Gerich
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
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Schnell O, Alawi H, Battelino T, Ceriello A, Diem P, Felton AM, Harno K, Satman I, Vergès B. The role of self-monitoring of blood glucose in patients treated with SGLT-2 inhibitors: a European expert recommendation. J Diabetes Sci Technol 2014; 8:783-90. [PMID: 24876442 PMCID: PMC4764233 DOI: 10.1177/1932296814534366] [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] [Indexed: 11/16/2022]
Abstract
The role for the novel treatment approach of sodium-glucose cotransporter-2 (SGLT-2) in type 2 diabetes is increasing. Structured self-monitoring of blood glucose (SMBG), based on a less intensive and a more intensive scheme, may contribute to an optimization of SGLT-2 inhibitor based treatment. The current expert recommendation suggests individualized approaches of SMBG, using simple and clinically applicable schemes. Potential benefits of SMBG in SGLT-2 inhibitor based treatment approaches are early assessment of treatment success or failure, timely modification of treatment, detection of hypoglycemic episodes, assessment of glucose excursions, and support of diabetes management and education. The length and frequency of SMBG should depend on the clinical setting and the quality of metabolic control.
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Affiliation(s)
- Oliver Schnell
- Forschergruppe Diabetes e.V., Helmholtz Center, Munich, Germany
| | | | | | - Antonio Ceriello
- Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Peter Diem
- Bern University Hospital, Bern, Switzerland
| | | | - Kari Harno
- University of Eastern Finland, Joensuu, Finland
| | - Ilhan Satman
- Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
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Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124:499-508. [PMID: 24463454 DOI: 10.1172/jci72227] [Citation(s) in RCA: 867] [Impact Index Per Article: 78.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 11/14/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. METHODS We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. RESULTS Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. CONCLUSIONS In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.
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Arnouts P, Bolignano D, Nistor I, Bilo H, Gnudi L, Heaf J, van Biesen W. Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephrol Dial Transplant 2013; 29:1284-300. [PMID: 24322578 DOI: 10.1093/ndt/gft462] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The achievement of a good glycaemic control is one of the cornerstones for preventing and delaying progression of microvascular and macrovascular complications in patients with both diabetes and chronic kidney disease (CKD). As for other drugs, the presence of an impaired renal function may significantly affect pharmacokinetics of the majority of glucose-lowering agents, thus exposing diabetic CKD patients to a higher risk of side effects, mainly hypoglycaemic episodes. As a consequence, a reduction in dosing and/or frequency of administration is necessary to keep a satisfactory efficacy/safety profile. In this review, we aim to summarize the pharmacology of the most widely used glucose-lowering agents, discuss whether and how it is altered by a reduced renal function, and the recommendations that can be made for their use in patients with different degrees of CKD.
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Affiliation(s)
- Paul Arnouts
- Nephrology-Diabetology Department, AZ Turnhout, Belgium
| | - Davide Bolignano
- European Renal Best Practice Methods Support Team, Ghent University Hospital, Ghent, Belgium CNR-IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Calabria, Italy
| | - Ionut Nistor
- European Renal Best Practice Methods Support Team, Ghent University Hospital, Ghent, Belgium Nephrology Department, Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania
| | - Henk Bilo
- Departments of Internal Medicine, Isala Clinics, Zwolle, the Netherlands University Medical Center, Groningen, the Netherlands
| | - Luigi Gnudi
- Unit For Metabolic Medicine, Department Diabetes and Endocrinology, Cardiovascular Division, Guy's and St Thomas Hospital, King's College London, London SE1 9NH, UK
| | - James Heaf
- Department of Nephrology B, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Wim van Biesen
- European Renal Best Practice Methods Support Team, Ghent University Hospital, Ghent, Belgium Renal Division, Ghent University Hospital, Ghent, Belgium
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Janero DR. Relieving the cardiometabolic disease burden: a perspective on phytometabolite functional and chemical annotation for diabetes management. Expert Opin Pharmacother 2013; 15:5-10. [PMID: 24156826 DOI: 10.1517/14656566.2014.852538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes (T2D) is both a complex, multifactorial disease state and an unsolved, intensifying public-health problem. To help reduce disease burden, some T2D patients have embraced plant-derived substances for use with - if not in place of - prescription medicines, a trend based mainly upon historical precedent and anecdotal observations of human health benefit. Preclinical research has emphasized phytometabolite interactions with purported T2D pathogenic targets and the effects of botanical preparations on experimental T2D symptomology as induced in laboratory animals. More holistic, systems-oriented profiling of phytochemicals with functional-biology, omics, and chemical-fingerprinting tools now appears necessary to increase our appreciation of phytometabolite actions potentially beneficial to the T2D patient. The resultant, multidimensional view of phytometabolite pharmacology should help provide a more rational basis for evaluating the potential of natural plant products as T2D pharmacotherapy. Such information may also help substantiate and legitimize (pre)clinical demonstrations of phytochemical health benefits, advance our understanding of T2D pathogenesis, and offer scope for better T2D medicines. Public-private partnerships are invoked for conducting this research with the ultimate aim of improving the global cardiometabolic profile.
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Affiliation(s)
- David R Janero
- Northeastern University, Bouvé College of Health Sciences, Center for Drug Discovery, Department of Pharmaceutical Sciences, Health Sciences Entrepreneurs , 360 Huntington Avenue, 116 Mugar Life Sciences Hall, Boston, MA 02115-5000 , USA +1 617 373 2208 ; +1 617 373 7493 ;
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Abstract
Treatment of diabetes mellitus requires, at a certain stage of its course, drug intervention. This article reviews the properties of available antidiabetic medications and highlights potential targets for developing newer and safer drugs. Antidiabetic agents are grouped in the article as parts I, II and III according to the history of development. Part I groups early developed drugs, during the 20th century, including insulin, sulfonylureas, the metiglinides, insulin sensitizers, biguanides and α-glucosidase inhibitors. Part II groups newer drugs developed during the early part of the 21st century, the past decade, including GLP-1 analogs, DPP-VI inhibitors, amylin analogs and SGLT2 inhibitors. Part III groups potential targets for future design of newer antidiabetic agents with less adverse effects than the currently available antidiabetic drugs.
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Yimam M, Zhao J, Corneliusen B, Pantier M, Brownell LA, Jia Q. UP780, a chromone-enriched aloe composition improves insulin sensitivity. Metab Syndr Relat Disord 2013; 11:267-75. [PMID: 23573999 DOI: 10.1089/met.2012.0135] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic individuals experience elevated fasting glucose, glycosylated hemoglobin (HbA1c), and plasma insulin and impaired glucose tolerance. Adiponectin is a hormone inversely correlated with insulin resistance. Here we describe the activity of aloesin, an aloe chromone that increases adiponectin production and, when formulated with an aloe polysaccharide composition, improves the insulin sensitivity in db/db and diet-induced obese-diabetic mice. METHODS Two aloe chromones, aloesin and aloesinol, were tested in vitro for adiponectin production. Following confirmation of glucose-lowering activity in a high-fat diet (HFD)-induced mouse model, aloesin was formulated with an Aloe vera inner leaf gel powder polysaccharide preparation to yield a composition designated UP780. Efficacy of UP780 was evaluated in HDF-induced and db/db mouse models. GW1929, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, was used as a positive control. RESULTS After 3 weeks of treatment of HDF-induced mice, plasma insulin levels were decreased 37.9% and 46.7% by aloesin and aloesinol, respectively. In db/db mice, the chromone- (2% chromone:98% aloe polysaccharide) enriched UP780 aloe composition showed a 33.7% and 46.0% decrease in fasting triglyceride and plasma glucose levels after 10 weeks of oral treatment, respectively. Diabetic mice gavaged with 200 mg/kg of UP780 for 10 weeks showed a 30.3% decrease in fasting blood glucose levels and a 32.2% reduction in plasma insulin. In both animal models, UP780 showed a statistically significant improvement in blood glucose clearance. CONCLUSION These findings indicate that UP780, a chromone-standardized, aloe-based composition, could potentially be used as a natural product option to facilitate the maintenance of healthy blood glucose levels.
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Sivagnanam G. A new drug belonging to a novel class of drugs for type 2 diabetes. J Pharmacol Pharmacother 2013. [DOI: 10.4103/0976-500x.114621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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