Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes

US Endocrinology, 2014;10(1):8–15 DOI: http://doi.org/10.17925/USE.2014.10.01.8

Abstract:

Currently available medications for the treatment of type 2 diabetes have limitations, and many patients do not achieve glycemic control. Recently, a new approach has emerged using sodium glucose co-transporter 2 (SGLT2) inhibitors that decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. These agents offer the potential to improve glycemic control independently of insulin pathways while avoiding hypoglycemia. Two drugs of this class, canagliflozin and dapagliflozin, have been approved by the US Food and Drug Administration (FDA); another, empagliflozin, has been filed for regulatory approval and several others are in advanced development. These drugs have been shown to effectively reduce blood glucose, fasting plasma glucose, and glycated hemoglobin (HbA1C) levels in phase III clinical trials when used as monotherapy and as add-on therapy to other diabetes medications, including insulin. Another advantage of the SGLT2 inhibitors over existing treatments is the improvement in cardiovascular risk factors, particularly in terms of reductions in blood pressure and body weight. SGLT2 inhibitors have been generally well tolerated. While more long-term safety data are required to elucidate the benefit–risk profile of SGLT2 inhibitors, the rationale for their use in type 2 diabetes therapy is strong.

Keywords: Type 2 diabetes, sodium glucose co-transporter-2 inhibitors, canagliflozin dapagliflozin, empagliflozin
Disclosure: The authors have no conflicts of interest to declare
Acknowledgments: Editorial assistance was provided by Katrina Mountfort, PhD, and James Gilbart, PhD, at Touch Medical Media.
Received: May 30, 2014 Accepted June 02, 2014
Correspondence: Robert J Chilton, DO, FACC, Professor, Division of Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, US. E: chilton@uthscsa.edu
Support: The publication of this article was supported by Boehringer Ingelheim. The views and opinions expressed are those of the authors and not necessarily those of Boehringer Ingelheim.
An erratum to this article can be found below.

Diabetes imposes a substantial burden on societies worldwide: approximately 25 million individuals in the US have diabetes, of which more than 95 % is type 2.1 Furthermore, its incidence is increasing, a further 79 million adults in the US have pre-diabetes and one in three US adults could have diabetes by 2050.1 In addition, the age of diagnosis of type 2 diabetes is decreasing.2 Lifestyle interventions remain essential to the management of type 2 diabetes; however, most patients will not reach their therapeutic goals with these interventions alone and will require pharmacologic therapies.3 Diabetes is associated with substantially increased cardiovascular (CV) risk; diabetic patients requiring glucose-lowering therapy aged 30 years or over have a CV risk comparable to nondiabetics with a prior myocardial infarction.4 Therefore antidiabetic therapies should not only reduce glycated hemoglobin ( HbA1c), but also CV mortality.

Currently, there are several classes of pharmacologic agents approved for the treatment of diabetes in the US, involving numerous mechanisms of action including the stimulation of insulin production in the pancreas; decreasing sugar release from the liver; or decreasing or delaying sugar uptake from the gut. However, despite the widespread availability of these therapies, only half of patients with type 2 diabetes attain the American Diabetes Association (ADA) recommended target of HbA1c of 7.0 %, blood pressure (BP) targets of <130/80 mmHg, and low-density lipoprotein-cholesterol (LDL-C) targets of <100 mg/dl.5 Furthermore, the incidence of CV mortality in patients with type 2 diabetes has not substantially decreased in the last decade.6 The CV safety of antidiabetic medications has become an area of concern since treatment with the thiazolidinedione medication rosiglitazone was associated with an increased risk for CV events.7 As a result, the US Food and Drug Administration (FDA) now requires evidence that new treatments for diabetes do not increase CV risk.8

Uncertainty remains regarding the CV safety of existing therapies. Dipeptidylpeptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have not been associated with increased CV risks,9,10 and the latter may be cardioprotective.10,11 Saxagliptin has been associated development with an increased risk for hospitalizations for heart failure.12 Studies investigating the CV risks associated with insulin, sulfonylureas (SU), and metformin have yielded mixed results.13,14

Since over 85 % of people with diabetes are overweight or obese,15 and excess weight is a major contributor to the development of insulin resistance and impaired glucose tolerance,16 as well as being a major CV risk,17 the impact of antidiabetic therapies on weight is also important. Most oral antidiabetic agents (OADs) have been associated either with weight gain (thiazolidinediones,18 SU,19 meglitinides20) or are weight-neutral (metformin,21 alpha-glucosidase inhibitors,22 DPP-4 inhibitors,23 bile acid sequestrants24). Treatment with insulin and insulin analogs is also associated with weight gain, which may be substantial.25 GLP-1 analogs have been associated with moderate weight loss,10 but their use is limited by the need for administration by injection and gastrointestinal side effects.26

The increasing prevalence of type 2 diabetes, in combination with limitations of current therapies, has driven the search for alternative glucose-lowering agents. This review will consider the safety and efficacy of a new class of oral drug, sodium glucose co-transporter 2 (SGLT2) inhibitors and the key clinical trial evidence supporting their use in diabetes treatment.

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Keywords: Type 2 diabetes, sodium glucose co-transporter-2 inhibitors, canagliflozin dapagliflozin, empagliflozin