Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity
                    in Patients with Prediabetes

Ramírez-Rodríguez, Alejandra M.; González-Ortı́z, Manuel; Martı́nez-Abundis, Esperanza

doi:10.1055/a-0664-7583

Cited by 40 publications

(33 citation statements)

References 17 publications

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“…26 27 Up to 2.7 kg weight loss was observed in patients with type 2 diabetes with SGLT2-inhibitor therapy, and there are some studies suggesting weight loss in prediabetic patients. 28 29 However, there is currently no evidence to suggest that it can cause weight loss in patients with heart failure…”

Section: Weight Reduction and Improved Glycaemic Controlmentioning

confidence: 99%

Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Joshi

Singh

Newby

et al. 2021

Heart

101

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Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.

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Section: Weight Reduction and Improved Glycaemic Controlmentioning

confidence: 99%

Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Joshi

Singh

Newby

et al. 2021

Heart

101

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“…The objective of this study was to evaluate the strategy of adding two anti‐hyperglycaemic agents (DAPA plus SAXA) simultaneously compared with the more common approach of adding one agent at a time (SITA) in patients with type 2 diabetes that is uncontrolled by MET. Adding two therapies simultaneously led to more rapid glucose control, which was sustained over 52 weeks, suggesting that there may be underlying improvements in insulin sensitivity and β‐cell function . Treatment with DAPA plus SAXA add‐on to MET provided greater reductions in HbA1c and FPG than treatment with SITA add‐on, although, even with triple therapy, mean final HbA1c values were greater than 7% (53 mmol/mol), probably the result of the patients' high baseline HbA1c levels.…”

Section: Discussionmentioning

confidence: 99%

“…Adding two therapies simultaneously led to more rapid glucose control, which was sustained over 52 weeks, suggesting that there may be underlying improvements in insulin sensitivity and β-cell function. [10][11][12][13][14][15] Treatment with DAPA plus SAXA add-on to MET provided greater reductions in HbA1c and FPG than treatment with SITA add-on, although, even with triple therapy, mean final HbA1c values were greater than 7% (53 mmol/mol), probably the result of the patients' high baseline HbA1c levels. However, a significantly greater proportion of patients achieved HbA1c less than 7% (<53 mmol/mol) with DAPA plus SAXA add-on therapy than with SITA add-on after 26 and 52 weeks, despite high baseline HbA1c levels.…”

Section: Discussionmentioning

confidence: 99%

Sustained 52‐week efficacy and safety of triple therapy with dapagliflozin plus saxagliptin versus dual therapy with sitagliptin added to metformin in patients with uncontrolled type 2 diabetes

Handelsman

Mathieu

Prato

et al. 2019

Diabetes Obesity Metabolism

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Aims To compare the efficacy and safety of an intensification strategy of early triple combination therapy with dapagliflozin (DAPA) plus saxagliptin (SAXA) to a dual therapy strategy with sitagliptin (SITA) in patients with type 2 diabetes who are inadequately controlled with metformin (MET) monotherapy. Materials and methods This multinational, active‐controlled, parallel‐group phase 3b trial randomized 461 patients, at least 18 years of age, with glycated haemoglobin (HbA1c) of 8%–10.5% (64–91 mmol/mol), to either DAPA plus SAXA or SITA, added to MET, for a 26‐week double‐blind treatment period and an extension of a 26‐week blinded treatment period. Results Mean (± SD) baseline HbA1c was 8.8% ± 0.9% (73.0 ± 9.3 mmol/mol). DAPA plus SAXA (n = 232) provided a greater reduction from baseline in HbA1c at Weeks 26 and 52 compared with SITA (n = 229) (adjusted mean ± SE change, Week 26: −1.41 ± 0.07% vs −1.07 ± 0.07% [−15.4 ± 0.8 mmol/mol vs 11.7 ± 0.8 mmol/mol]; P = 0.0008; Week 52: −1.29 ± 0.08% vs −0.81 ± 0.09% [14.1 ± 0.9 mmol/mol vs 8.9 ± 1.0 mmol/mol]). The between‐group difference in adjusted mean (95% CI) change from baseline in HbA1c increased from −0.34 (−0.54, −0.14) at Week 26 to −0.48 (−0.71, −0.25) at Week 52. DAPA plus SAXA was generally well tolerated and the incidence of adverse events was similar in both treatment arms. Conclusions Early intensification to triple therapy with DAPA plus SAXA results in better, more durable glycaemic control than addition of SITA only (dual therapy) in patients with high HbA1c levels who are uncontrolled with MET monotherapy.

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“…One study in people with prediabetes and a mean BMI of 30.3 kg/m 2 received either dapagliflozin 10 mg or placebo for 12 weeks. The authors reported dapagliflozin use was associated with a 3.0 kg weight loss as well as improvements in several other metabolic markers [64]. One trial explored the impact of combining dapagliflozin with the GLP-1 analogue exenatide in obese participants without diabetes, finding a mean weight loss 4.5 kg over 24 weeks [65].…”

Section: Dapagliflozinmentioning

confidence: 99%

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

2020

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Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodiumglucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging. Key Summary PointsObesity is a complex metabolic disorder, with several licensed drug and surgical therapies currently available.Current therapies are often associated with inadequate efficacy or complications and side effects, limiting their use.Multiple pathophysiological mechanisms of obesity are recognized, though only few of these are manipulated using currently licensed therapies.Whilst most drug classes are in early stages of development and/or clinical trials, results are promising for multiple drug targets.

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Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients with Prediabetes

Abstract: Dapagliflozin administration in patients with prediabetes decreased body weight, body mass index, waist circumference, fasting glucose, and uric acid, with a tendency to increase the insulin sensitivity without changes in insulin secretion.

Cited by 40 publications

References 17 publications

Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Sustained 52‐week efficacy and safety of triple therapy with dapagliflozin plus saxagliptin versus dual therapy with sitagliptin added to metformin in patients with uncontrolled type 2 diabetes

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

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