Pharmacy U

Two for the price of one – Cardioprotection and glucose-lowering!


Two landmark studies have made an impact on what recommendations we will make for pharmacologic management of patients with type 2 diabetes.


By Shelley Diamond, BScPhm

Illustration by Martin Bregman


One has been incorporated into a recent revision to the Canadian Diabetes Association Clinical Practice Guidelines, specifically the Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update, addressing several studies completed since the launch of the last set of diabetes guidelines in 2013.

The 2016 interim update includes cardiovascular safety (‘neutrality’) information for alogliptin, saxagliptin, sitagliptin, and lixisenatide (the first three belonging to the DPP-4 class of antihyperglycemics, the last one belonging to the GLP-1 group). Plus, the EMPA-REG OUTCOME trial, which studied the cardioprotective impact of empagliflozin, an SGLT-2 inhibitor, demonstrated significant clinical benefits and therefore was included in the update.

Look for a second recently-published study, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), which also demonstrated cardiovascular protective benefit, to join the current guidelines in a subsequent update.


This is the first study to demonstrate improved cardiovascular outcomes in high-risk patients with type 2 diabetes. The trial involved 7,020 patients with type 2 diabetes and established cardiovascular disease. Two doses of empagliflozin – 10 and 25mg – were used in addition to standard care, and this was compared to placebo plus standard care. Empagliflozin significantly reduced deaths from cardiovascular disease (a relative reduction of 38%), and also reduced all-cause mortality by 32%.

A1C was lower for both empagliflozin groups throughout the study, although many participants in the empagliflozin groups still did not reach their glycemic targets. Side effects were similar in both groups, except that genital infections, a known side effect of SGLT2 inhibitors, were higher in the empagliflozin groups.

The dramatic effects of this therapy may have started as early as within three-six months of starting therapy. Experts feel the effect is likely associated with the strong osmotic diuretic effect of the drug, a probable benefit for patients with heart failure. Weight loss, decreased blood pressure, improved endothelial function and better cardiac function were also seen in the patients treated with empagliflozin.

The LEADER Trial

The LEADER trial was a multicentre, international, randomized, double-blind, placebo-controlled clinical study. LEADER evaluated the cardiovascular safety of liraglutide (Victoza®) added to standard care, compared to placebo plus standard care in over 9,000 people with type 2 diabetes who were at high risk for cardiovascular events. The primary endpoint of the study was defined as the composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. Over five years, liraglutide demonstrated superiority in reduction of cardiovascular events compared to placebo for all three endpoints.

Other benefits included weight loss, reduced A1C, and less hypoglycemia. The most common side effects – gastrointestinal and increased heart rate – were the same as in previous trials with liraglutide.

So what does this mean for you?

Despite the fact that 40-60% will die from it, no other studies until now have been shown to provide cardiovascular benefits in people with type 2 diabetes and clinical cardiovascular disease, rather than just ‘lack of harm’. Diabetes healthcare professionals, deciding which pharmacologic agent to add to metformin when blood glucose targets are not being met, can now favour specific therapy for these patients – a clearer direction in the myriad pharmacologic options for reaching glycemic targets. As patients understand the added value, the ‘buy-in’ and adherence for these medications should be a ‘no-brainer’!