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1.
Ertugliflozin: First Global Approval.
Markham, A
Drugs. 2018;(4):513-519
Abstract
Ertugliflozin (Steglatro™) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (Segluromet™) and ertugliflozin and sitagliptin (Steglujan™) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM.
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Effects of Concomitant Administration of Sodium Glucose Co-transporter 2 Inhibitor with Insulin on Hemoglobin A1c, Body Mass Index and Serum Lipid Profile in Japanese Type 2 Diabetic Patients.
Kusunoki, M, Natsume, Y, Miyata, T, Tsutsumi, K, Oshida, Y
Drug research. 2018;(12):669-672
Abstract
In patients with type 2 diabetes mellitus who show suboptimal blood glucose control under insulin therapy alone, concomitant treatment with an additional hypoglycemic agent that differs in its mechanism of action from insulin may be considered. We conducted this clinical trial to explore whether further control of increased blood glucose level can be achieved with concomitant use of sodium glucose co-transporter 2 (SGLT2) inhibitor as concomitant with other hypoglycemic therapy, as compared to SGLT2 inhibitor monotherapy, in patients with type 2 diabetes mellitus showing decrease in blood glucose level but less than the effect of insulin monotherapy and there was no significant differences. In the SGLT2 inhibitor monotherapy group, decreases of the serum hemoglobin A1c (HbA1c) level, body weight, body mass index (BMI) and serum triglyceride, and elevation of the serum high density lipoprotein cholesterol concentration were observed as compared to the baseline values. In the type 2 diabetic patients under insulin therapy who received combined insulin plus SGLT2 inhibitor therapy, however decreases in the body weight and BMI, with only a tendency towards decrease of the serum HbA1c value, not reaching statistical significance, were observed. The combined therapy group also showed no appreciable changes of the serum triglyceride level, while the serum adiponectin level increased. The present study data indicate that combined insulin plus SGLT2 inhibitor treatment failed to afford any further improvement of the blood glucose control, as compared to SGLT2 monotherapy, in Japanese type 2 diabetic patients.
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3.
Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA.
Khat, DZ, Husain, M
Current diabetes reports. 2018;(7):45
Abstract
PURPOSE OF REVIEW In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits. RECENT FINDINGS SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system. This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.
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4.
SGLT2 Inhibitors and Cardiovascular Outcomes: Current Perspectives and Future Potentials.
Jia, X, Mehta, PB, Ye, Y, Alam, M, Birnbaum, Y, Bajaj, M
Current diabetes reports. 2018;(9):63
Abstract
PURPOSE OF REVIEW Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to exert benefit on cardiac outcomes. In this review, we provide updates on available clinical data, studies on potential mechanisms for the CV effects, as well as discuss potential clinical implications of these new findings. RECENT FINDINGS Since the publications of the EMPA-REG and CANVAS trials, large multi-national cohort studies have further shown the cardioprotective effects of SGLT2i. Moreover, new studies examining SGLT2i action on sodium-hydrogen exchanger proteins in both the heart and the kidney, on myocardial energetics and impact on inflammation and atherosclerosis continue to shed light on the multitude of pleotropic effects of these agents. Though more data is needed to substantiate the safety and efficacy, SGLT2i should be considered as a valuable therapy to help reduce CV risk in patients with diabetes. Ultimately, SGLT2i may have utility in preventing progression to diabetes or providing CV protection in patients who do not have diabetes.
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Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study.
Fadini, GP, Zatti, G, Baldi, I, Bottigliengo, D, Consoli, A, Giaccari, A, Sesti, G, Avogaro, A, ,
Diabetes, obesity & metabolism. 2018;(7):1781-1786
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Abstract
In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.
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6.
Reduced Mortality With Sodium-Glucose Cotransporter-2 Inhibitors in Observational Studies: Avoiding Immortal Time Bias.
Suissa, S
Circulation. 2018;(14):1432-1434
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Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2.
Packer, M, Kitzman, DW
JACC. Heart failure. 2018;(8):633-639
Abstract
Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin, and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat.
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8.
SGLT2 Inhibition for the Prevention and Treatment of Diabetic Kidney Disease: A Review.
Alicic, RZ, Johnson, EJ, Tuttle, KR
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2018;(2):267-277
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and the world alike, and there is a great unmet need for treatments to reduce DKD development and progression. Inhibition of sodium/glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment, leading to regulatory approval of several first-generation SGLT2 inhibitors for the treatment of type 2 diabetes. In follow-on clinical trials for the cardiovascular safety of the SGLT2 inhibitors, secondary effects to prevent or reduce albuminuria and decline in estimated glomerular filtration rate spurred further investigation into their potential application in DKD. This review summarizes the current understanding of mechanisms by which SGLT2 inhibitors block glucose reabsorption in the proximal tubule and improve systemic glucose homeostasis, the hypothesized mechanisms for kidney-protective effects of SGLT2 inhibition, and current recommendations for use of this class of antihyperglycemic agents in diabetic patients with low estimated glomerular filtration rates. Results of ongoing clinical trials in patients with DKD are eagerly awaited to expand knowledge of how SGLT2 inhibitors might be used for prevention and treatment.
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Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin for type 1 diabetes mellitus: Systematic review and meta-analysis of randomized controlled trials.
Yamada, T, Shojima, N, Noma, H, Yamauchi, T, Kadowaki, T
Diabetes, obesity & metabolism. 2018;(7):1755-1761
Abstract
New treatments for type 1 diabetes are an unmet need. We investigated the efficacy and safety of adding sodium-glucose co-transporter-2 (SGLT2) inhibitors to insulin for type 1 diabetes by conducting a meta-analysis of prospective randomized, placebo-controlled trials. A search of electronic databases up to October 2017 identified 1361 studies, of which 14 were investigated (N = 4591). Meta-analysis showed that SGLT2 inhibitor therapy significantly reduced glycated haemoglobin (HbA1c) concentration by 0.4% (95% confidence interval [CI] 0.35, 0.46; P < .001, I2 = 0%), fasting plasma glucose by 1.14 mmol/L (95% CI 0.8,1.47), body weight by 2.68 kg (95% CI 2.0, 3.36), and systolic blood pressure by 3.37 mmHg (95% CI 1.46, 5.28). In addition, bolus insulin decreased by 3.6 units/day (95% CI 2.0, 5.3), and basal insulin decreased by 4.2 units/day (95% CI 2.2, 6.3). Continuous glucose monitoring showed a decrease in glucose excursions compared with placebo, with reduced variation of mean blood glucose, glucose standard deviation, and mean amplitude of glucose excursion. There was no significant increase in the rate of hypoglycaemia or severe hypoglycaemia; however, SGLT2 inhibitor therapy increased diabetic ketoacidosis (odds ratio [OR] 3.38) and genital tract infection (OR 3.44). Add-on SGLT2 inhibitor therapy might be advantageous for type 1 diabetes, but its use should be considered carefully.
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10.
[The mechanisms and clinical potential: sodium-glucose cotransporter 2 (SGLT-2) inhibitors treating diabetic kidney disease].
Wang, YJ, Hao, CM
Sheng li xue bao : [Acta physiologica Sinica]. 2018;(6):663-669
Abstract
The employment of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in the treatment of diabetes mellitus and diabetic kidney disease (DKD) becomes a hot topic in recent years. Compared with traditional glucose-lowering drugs, SGLT-2 inhibitors present distinctive advantages in renal and cardiovascular protection. The mechanisms for renal protection include attenuating glomerular hyperfiltration, lowering serum uric acid, alleviating tubular lesions and regulating intrarenal renin-angiotensin-aldosterone system (RAAS) dysfunction. In addition, the lowering blood pressure, blunting blood glucose fluctuation, increasing insulin sensitivity, optimizing energy metabolism and body fat distribution account for the cardiovascular protective effects of SGLT-2 inhibitors. However, their potential adverse reactions and safety concerns should be carefully addressed in clinical usage.