Cardioprotective effects of diabetes drugs examined

AHA Scientific Sessions 2011

ORLANDO, Fla. — In the past, research has linked various diabetes medications, including acarbose and insulin, with cardiovascular benefits. Now, physicians and researchers are investigating both old and new diabetes treatments as potential preventive therapies for CVD.

Promise for SGLT2 inhibitors

During a presentation here, Bruce Neal, PhD, of the George Institute for Global Health in Sydney, Australia, highlighted SGLT2 inhibitors as one new class of drugs that may have cardioprotective effects. Clinical trials currently associate SGLT2 inhibitors, such as dapagliflozin (Bristol-Myers Squibb, AstraZeneca), with reductions in HbA1c, weight loss, systolic and diastolic blood pressure, and slight positive changes in lipid profiles. Studies have also confirmed the initial CV safety of SGLT2 inhibitors, Neal said.

"SGLT2 inhibitors have moderate impact on HbA1c, but just how this translates to effects on CVD remains uncertain," Neal said. "However, setting aside possible independent effects [that might also affect the development of CVD], the decreases in HbA1c and BP alone would likely lead to a 15% reduction in risk for major adverse CV events — an effect that would make this class a very reasonable prospect. We don't have clear evidence of CV protection, but at the moment, the data look positive rather than negative."

Acarbose re-examined

The older, already FDA-approved drug acarbose may also be a viable option, as it could potentially target postprandial glycemia as a risk factor for CVD, Rury R. Holman, FRCP, of the Oxford Centre for Diabetes, Endocrinology & Metabolism in the United Kingdom, said.

Several trials have associated acarbose with reductions in postprandial glucose and subsequent decreases in CVD risk factors. The Study to Prevent Noninsulin-Dependent Diabetes Mellitus (STOP-NIDDM), for example, revealed a 49% RR reduction for development of CV events in patients with impaired glucose tolerance in a secondary analysis. Similarly, data from a study in Japan linked acarbose with improved postprandial flow-mediated dilation and, thus, improved endothelial function.

To further investigate this association, Holman and colleagues are conducting the Acarbose Cardiovascular Evaluation (ACE) study - a multicenter, double blind, randomized controlled trial designed to assess potential CV benefits of acarbose in 7,500 patients with preexisting CVD and IGT. The study will be at 50% recruitment by the end of 2011 and results are expected in 2017, he said.

"When acarbose first came to the market in the late 1990s, it was seen as a head-to-head HbA1c-lowering drug," Holman said. "If its only impact is on postprandial glucose, it can only ever modestly reduce HbA1c. The drug is really meant to be given in combination, so if it was to be a CV-protecting drug, maybe there is some way to easily roll it out in other doses."

Insulin-based therapy

Hertzel C. Gerstein, MD, of McMaster University in Ontario, Canada, said some data also support the potential CV benefits of using insulin to normalize glucose for both patients with type 1 and type 2 diabetes.

For example, he said, the DCCT in patients with type 1 diabetes indicated that those who were randomly assigned to receive intensive insulin therapy vs. less intensive therapy had a 42% lower risk for CV events after 20 years.

Similarly, in the United Kingdom Protective Diabetes Study (UKPDS), patients with type 2 diabetes who were randomly assigned to a policy of intensive glucose control with insulin therapy or a sulfonylurea as a first-line therapy had a 15% reduction in risk for myocardial infarction and a 13% reduction in risk for all-cause mortality during 20 years of follow-up, Gerstein noted. Furthermore, a meta-analysis of trials comparing intensive glucose-lowering with less intensive treatment, including the UKPDS, ACCORD, ADVANCE and the Veterans Affairs Diabetes Trial (VADT), suggested that intensive glycemic control was associated with a modest 9% reduction in risk for major adverse CV events and a 15% reduction in risk for MI.

Gerstein and colleagues are also conducting their own large, international study, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, to determine whether insulin glargine (and/or omega-3 fatty acids can decrease CV events in patients with early dysglycemia, defined as impaired fasting glucose, IGT, new diabetes or diabetes treated with no more than one oral agent). In the process, they also hope to address the effect of insulin on other outcomes such as cancer and cognitive decline. Enrollment occurred between 2003 and 2005, and complete results will be presented in 2012.

"Although there is sufficient evidence to hypothesize that early insulin therapy with basal insulin may reduce serious health outcomes, we need clear evidence regarding the risks and benefits of such an approach," Gerstein said. "The ORIGIN trial should shed more light on this important question that has remained unanswered since insulin was first used to treat diabetes almost 90 years ago." - by Melissa Foster

For more information:

• McGuire DK. Drugs for diabetes: Current knowledge and ongoing trials. Presented at: American Heart Association 2011; Nov. 12-16, 2011; Orlando, Fla.

Disclosure: Dr. Gerstein has received research grants or honoraria from or has been a consultant, speaker or advisory board member for Bayer, GlaxoSmithKline, Janssen Ortho, Lilly, Sanofi Aventis and Novo Nordisk. Dr. Holman has received research grants or honoraria from or has been a consultant, speaker or advisory board member for Amylin, Bayer, Lilly, Merck, Novartis and Novo Nordisk. Dr. Neal has received research grants or honoraria from or has been a consultant, speaker or advisory board member for AstraZeneca, Pepsico, Unilever and United Health Care Group.

Follow EndocrineToday.com on Twitter.