Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Heart Association (AHA) Scientific Sessions 2011

Orlando, Florida / November 12-16, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

There is evidence that better glucose control, measured over time by hemoglobin A_1c (HbA_1c) or more acutely by blood sugar levels, leads to protection from cardiovascular (CV) events, by far the most common cause of death in diabetic patients.

New data presented at the AHA demonstrate that type 2 diabetes mellitus (DM2) even has an impact on the risk of sudden cardiac death (SCD). “Although it has not been clear that the elevated rates of SCD in DM2 were directly related to glucose control, we demonstrated that the relative degree of impaired fasting blood glucose (FBG) can improve risk prediction when added to other common risk factors,” stated Dr. Jari Laukkanen, University of Eastern Finland, Kuopio. These data suggest that tighter glucose control will reduce SCD risk.

The population-based study that generated these data included 2641 men 42 to 60 years of age with elevated FBG. The presence of DM2 was not required. Over a 17-year follow-up, there was a 2.44-fold increase (95% CI, 1.42-4.16; P=0.001) in SCD risk with an FBG >5.6 mmol/L. When evaluated as a continuous variable, SCD risk was increased 10% with every 1 mmol/L increment in FBG (adjusted risk of 1.10; 95% CI, 1.02-1.19; P=0.009). The relationship was seen after adjusting for age, body mass index (BMI), systolic blood pressure (SBP), serum LDL-C, smoking, C-reactive protein (CRP) and physical activity.

This study was not designed to show a reduction in SCD with an improvement in FBG, but previous studies such as the Diabetes Control and Complications Trial (DCCT) have shown the risk of CV events can be reduced with tight glycemic control.

Meta-Analysis of the Influence of SGLT2 Inhibition on CV Events

The investigational agent dapagliflozin is a highly selective inhibitor of sodium glucose co-transporter 2 (SGLT2) that promotes renal glucose excretion. This action is independent of the action of insulin. The SGLT2 inhibitor is also associated with mild osmotic diuresis and an increase in calorie loss. As part of the clinical data collection mandated by the US Food and Drug Administration for all new agents being tested for DM2, a meta-analysis of the influence of this drug on CV events was prespecified.

In this meta-analysis, data from 11 phase III studies and 3 phase IIb studies were pooled. The CV events among the 4287 patients treated with dapagliflozin and the 1941 control patients underwent blinded adjudication. On average, patients in both groups were approximately 55 years old, had a 6-year duration of DM2 and a BMI of 31.5 kg/m². Fewer than 20% of patients had prior CV disease. The studies tested dapagliflozin as a monotherapy and with a variety of other anti-diabetic drugs, including metformin, pioglitazone, sulfonylureas and insulin.

“Over follow-up out to 2 years, the hazard ratio [HR] for MACE [major adverse cardiovascular events] was 0.67” (Figure 1), reported clinical researcher Dr. Anna Maria Langkilde, Gothenburg, Sweden. Although the CIs for MACE—a composite of myocardial infarction (MI), stroke and CV death—extended beyond 1.0 (95% CI, 0.38-1.18), there was consistency of effect across end points, doses and patient subgroups. According to Dr. Langkilde, “The driver of the effect was the reduction in MIs,” which occurred at a rate 58% lower in the active treatment group relative to the placebo group. “We are now committed to perform the phase III studies that will test the hypothesis that dapagliflozin reduces CV risk,” Dr. Langkilde told delegates.

Figure 1.

Additional Data on BP Reduction

Data from 3 of the phase III trials was used to conduct a separate analysis of the novel agent’s effect on systolic and diastolic BP reduction. In study 1, it was compared to glipizide as an add-on to metformin. While those on the combination with glipizide had a slight increase in SBP, there was a 4.3 mm Hg decrease (P<0.0001) in SBP in patients on the dapagliflozin arm. In study 2, which compared several doses of dapagliflozin to placebo when added to the sulfonylurea glimepiride, those on the sulfonylurea had a 1.2 mm Hg reduction in SBP while the 3 SGLT2 inhibitor doses (2.5 mg, 5 mg, 10 mg) reduced SBP by 4 to 5 mm Hg. In study 3, comparing dapagliflozin or placebo added to insulin, insulin alone reduced SBP by 3.9 mm Hg but each of the 3 dapagliflozin doses produced a greater incremental reduction ranging from 0.7 to 3.0 mm Hg.

“The reductions in SBP were observed without any significant increase in the hazard of experiencing orthostatic hypotension,” reported the senior investigator Dr. Vincent Woo, University of Manitoba, Winnipeg. He noted that in the third study, which assessed a subgroup of patients with a baseline SBP >140 mm Hg, the SGLT2 inhibitor produced even greater relative reductions of SBP.

Efficacy was not the focus of this analysis, but Dr. Woo reported that dapagliflozin was associated with a stepwise increase in urinary excretion of glucose as doses were increased. Stepwise dose increases also produced stepwise reductions in HbA_1c in these studies. In the study comparing dapagliflozin to the sulfonylurea glipizide in combination with metformin, the reduction in HbA_1c was similar, but patients on the sulfonylurea had an average 1.44 kg weight gain over the course of the study vs. a 3.22 kg average weight decrease in the arm receiving the SGLT2 inhibitor. Stepwise weight loss relative to stepwise dose increases of dapagliflozin was also seen in the glimepiride and insulin studies.

According to Dr. Woo, new agents in the control of DM2 are always welcome because 51% of patients with DM2 are not at guideline-mandated treatment goals. While dapagliflozin was characterized as “a novel antiglycemic agent,” Dr. Woo indicated that the meaningful benefits on non-glycemic targets, such as weight and SBP, make this a promising compound.

Glucose Control Essential

However, improvement in glucose control by any mechanism might be expected to reduce the risk of CV events. In another AHA presentation, the focus was on the effect of the PPAR-? agonist pioglitazone. In this study, 205 DM2 patients receiving a zotarolimus-eluting stent were randomly assigned to receive pioglitazone or placebo and then followed over 2 years.

The HR for MACE—defined as non-fatal MI, death, stroke and target lesion revascularization—was 2.3-fold higher in the placebo group (95% CI, 1.17-4.6; P=0.016) than in those receiving active therapy. Although the data in regard to the effect of the active therapy on blood glucose control were not presented, this agent has typically lowered HbA_1c by about 1% in clinical trials.

“The rates of MACE in DM2 patients receiving a coronary stent can be reduced significantly with pioglitazone,” confirmed Dr. Soon Jun Hong, Korea University Anam Hospital, Seoul, who noted that the largest benefit was a reduction in revascularization. Again, the data support the concept of treating DM2 in order to treat the CV risk.

Summary

New evidence presented here at the AHA suggests that efforts to improve glucose control in DM2 are essential to preventing the rise in CV events generated by the growing incidence of DM2. The new supporting data indicate that levels of FBG can be linked as a continuous variable to increasing risk of SCD, and that a PPAR-? agonist can reduce the risk of CV events in patients receiving a coronary stent. Other data on the CV safety and BP reduction with an investigational SGLT2 inhibitor were also presented. ?

Note: At press time, dapagliflozin is not approved in Canada.