Sodium Glucose Co-transport 2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

A Meta-analysis of Randomized Double-Blind Controlled Trials

Asres Berhan; Alex Barker


BMC Endocr Disord. 2013;13(58) 

In This Article


The persistent hyperglycemia in patients with type 2 diabetes mellitus is strongly associated with microvascular and macrovascular complications.[1] Chronic hyperglycemia is postulated to contribute to the continuous loss of pancreatic β-cells and the impairment of insulin secretion.[2] Microvascular complications like diabetic retinopathy, nephropathy, and neuropathy are major causes of new cases of blindness and renal insufficiency.[3] Moreover, in type 2 diabetes macrovascular complications, including coronary heart disease and stroke, are major causes of morbidity and mortality.[4] According to a prospective study, in patients with type 2 diabetes, a 1% increase in HbA1c was associated with 20% to 30% increase in mortality or cardiovascular events.[5]

Intensive glycemic control in patients with type 2 can delay the onset and progression of the early stages of diabetic microvascular complications.[6] In the UKPDS, a reduction in mean HbA1c was associated with reductions in both microvascular and macrovascular complications.[1] But the risk reduction of myocardial infarction, stroke, and heart failure was relatively low.[1] Furthermore a meta-analysis of randomized controlled trials reported that an intensive glycemic control resulted in no significant effect on events of stroke or all-cause mortality.[7] As a result, researchers recommend a multidisciplinary approach to the management of the cardiovascular risk factors in patients with type 2 diabetes.[8]

Currently many antidiabetic agents are available with a variety of chemical groups and site of actions. Most of these agents act by either improving the insulin sensitivity or by enhancing insulin secretion. Nevertheless, as the pancreatic β-cells function continues to decline, failure of therapy to achieve adequate glycemic control is inevitable. The cumulative incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide after 5 years of therapy.[9] On the other hand, agents like insulin, sulphonylureas, and thiazolidinediones are associated with significant safety concerns such as weight gain and hypoglycemic events.[9,10]

The discovery of SGLT2 inhibitors, with novel mechanism independent of insulin secretion or sensitization, may possibly expand the armamentarium in the battle against type 2 diabetes mellitus. SGLT2 plays an important role in the kidneys and is responsible for most renal glucose re-absorption in the proximal convoluted tubule.[11] Currently there are a number of SGLT2 inhibitors that are under development or in clinical trials.[12] Prior meta-analyses had established the safety and efficacy of SGLT2 inhibitors as a group.[13,14] However, recently published randomized clinical trials reported more frequent adverse events with SGLT2 inhibitors and no significant difference in the proportion of patients achieving HbA1c levels <7.0% as compared to placebo treated.[15,16] Thus, the primary aim of this meta-analysis is to determine the safety and efficacy of SGLT2 inhibitors alone or in combination with other anti-diabetic drugs relative to placebo or placebo with other anti-diabetic drugs by including both previously and recently published randomized double blind clinical trials.