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ABSTRACT Objectives To provide a meta-analysis of the clinical efficacy and safety of sodium glucose co-transporter 2 inhibitors (SGLT2-i), as a combination treatment with metformin in type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with metformin alone. Materials and methods We have searched randomized controlled trials (RCTs) in the database: MEDLINE, Embase and Cochrane Collaborative database. We used mean differences (MD) to assess the efficacy of glycemic and other clinical parameters, and risk ratios (RR) to evaluate the adverse events for safety endpoints. The heterogeneity was evaluated by I2. Results Finally 9 studies were included. SGLT2-i plus metformin had higher reduction level in HbA1C [MD = -0.50, 95% CI (-0.62, -0.38), p < 0.00001], FPG [MD = -1.12, 95%CI (-1.38, -0.87), p < 0.00001], body weight [MD = -1.72, 95% CI (-2.05, -1.39), p < 0.00001], SBP [MD = -4.44, 95% CI (-5.45, -3.43), p < 0.00001] and DBP [MD = -1.74, 95% CI (-2.40, -1.07), p < 0.00001] compared with metformin monotherapy. However, SGLT2-i plus metformin group had higher risk of genital infection [RR = 3.98, 95% CI (2.38, 6.67), p < 0.00001]. No significant difference was found in the risk of hypoglycemia, urinary tract infection or volume related adverse events. Conclusions Although the risk of genital infection may increase, SGLT2-i plus metformin may provide an attractive treatment option to those T2DM patients who are unable to achieve glycemic control with metformin alone, based on its effects on glycemic control, reducing body weight and lowering blood pressure.

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) such as dapagliflozin, canagliflozin, and empagliflozin, are a promising new therapy in the treatment of type 2 diabetes mellitus (T2DM). SGLT2is can effectively reduce hyperglycemia thus improving glycemic control and they offer some beneficial effects on the cardiovascular (CV) system which can benefit patients with heart failure in addition toT2DM. The United States Food and Drug Administration requires new diabetes mellitus therapies to show a CV safety profile. Empagliflozin was the first SGLT2i that, when added to the standard of care for patients withT2DM at high risk for CV events, showed improved CV outcomes including reduced deaths from CV causes. Evidence also exists in favor of dapagliflozin for use in patients with T2DM with CV risk factors and heart failure. This review focuses on the effects, safety, and benefits of dapagliflozin on the CV system. Clinical trials have shown that dapagliflozin improves glycemic control without variation. It is safe and well-tolerated in the general population including older patients and those with high-risk CV factors or preexisting CV disease. There may be a renal protective role by an unknown mechanism. Dapagliflozin also lowers blood pressure due to its natriuresis effect. It improves levels of visceral fat and reduces body weight, and thus ameliorates metabolic syndrome. Dapagliflozin reduces oxidative stress and may delay atherosclerosis. Recent findings indicate SGLT2is may also reduce the atrial natriuretic peptide levels. Additional trials are required to validate these benefits and further evaluate if these are class effects. Trials such as DECLARE-TIMI58 are ongoing to evaluate the CV outcomes of dapagliflozin. More research is needed to design better antihyperglycemic regimes with clinical benefits in addition to good glycemic control., Competing Interests: The authors have declared that no competing interests exist.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors improve hyperglycemia, and the usefulness of co-administration of DPP-4 inhibitors and insulin therapy has been well established. However, it has been still uncertain whether combination therapy of SGLT2 inhibitors and insulin is superior to that of DPP-4 inhibitors and the latter. Therefore, we investigated the superiority of dapagliflozin on glucose fluctuation compared with DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) on insulin using a continuous glucose monitoring (CGM) system., Methods: In this prospective, randomized, open-label controlled trial, 36 patients with T2DM and treated with DPP-4 inhibitors and insulin therapy, were enrolled and allocated into two groups. The patients either switched their DPP-4 inhibitors to dapagliflozin 5 mg for 12 weeks, or continued their DPP-4 inhibitors for the same period. CGM analyses and metabolic markers were assessed before and after treatment periods., Results: In total, data from 29 patients were analyzed. There were no significant differences in the mean amplitude of glycemic excursions and other CGM profiles in either group after treatment. Within the dapagliflozin treatment group, significant reductions of body mass index and albuminuria, and increases of HbA1c, hemoglobin and hematocrit were observed, but improvement of albuminuria was not significant if compared with the DPP-4 continuation group., Conclusions: Combination therapy of dapagliflozin and insulin was not superior in glucose fluctuation to DPP-4 inhibitors on insulin. However, dapagliflozin may in part provide favorable effects on metabolism in patients with T2DM treated with insulin therapy. Trial registration UMIN-CTR: UMIN000015033. Registered 2 September 2014.

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest class of drugs to be introduced for the treatment of type 2 diabetes mellitus. These drugs improve glycemic control by increasing urinary glucose excretion and exert additional benefits of weight loss and blood pressure reductions. Areas covered: This review outlines the background to SGLT2 inhibitors and provides details on the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin and discusses the cardiovascular outcome trial. Expert opinion: Empagliflozin was the first from a new group of antidiabetic drugs to show benefits in a cardiovascular outcome trial. There were significant reductions in cardiovascular and all-cause mortality and empagliflozin treatment reduced hospitalizations for heart failure and reduced the progression of diabetic nephropathy. These benefits, which occurred at a very early stage during the study, may be related to a reduction in circulating volume or changes in metabolic fuel utilization in the heart and kidneys. Whether these effects are shared by other SGLT2 inhibitors is not yet known, but there may be differences between drugs related to selectivity for inhibition of SGLT2 compared to SGLT1 or other pharmacological effects. Currently the outcome evidence is only available to support the use of empagliflozin in this drug class.

Type 2 diabetic patients are known to have a tendency to develop cardiovascular (CV) disease (CVD), and related unfavourable outcomes such as heart failure, myocardial infarction (MI), cerebrovascular events (e.g. stroke), and related mortality. Long- term clinical trials have revealed contradictory findings regarding the relationship between glycemic control and CV benefits due to variations in the key characteristics of the study population. During the last decade, number of pharmacological agents used for glucose- lowering in the treatment of type 2 diabetes mellitus (T2DM) has increased owing to the introduction of dipeptidyl peptidase- IV (DPP- IV) inhibitors, glucagon- like peptide- 1 (GLP- 1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT- 2) inhibitors. This review aims to focus on the mechanisms of action of these drugs in the cardiovascular system and the trials evaluating their impact on CVD. Furthermore, trials in the last decade evaluating the impact of traditional glucose- lowering drugs on CVD are included. For this purpose, we searched PubMed for articles in English using the search terms "type 2 diabetes mellitus, glucose- lowering drugs, antidiabetic medications, cardiovascular, cardiovascular disease, cardiovascular system" between inception to September 2016. We also searched separately for each medication in addition to the keyword "cardiovascular disease" on PubMed. To identify further articles, we hand searched related citations in review articles and commentaries., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes., Areas Covered: Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined., Expert Opinion: Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin., Competing Interests: Declaration of Interest SN Davis is a consultant to Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.