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Updates on Diabetes Trials, Old and New

Early intervention in treating diabetes has shown long term benefits, follow-up data for both old and new studies show.

At the recent Cardiometabolic Health Congress in Boston, Jay S. Skyler, MD, MACP, professor of medicine, pediatrics and psychology in the division of endocrinology, diabetes and metabolism at the University of Miami Miller School of Medicine, highlighted the impact of even short-term, intensive intervention, and the differences between three large diabetes drug trials, including the cardiovascular benefits of several new therapies.

The DCCT-EDIC study is one of the longest studies where they continued to follow type 1 patients who were initially assigned to either standard care or intensive blood glucose control (HbA1c goal of 6% or less) for a mean of 6 years. In 2005, 20-year follow-up outcome revealed a 42% Risk Reduction (RR) for any CV outcome for those assigned to intensive management, along with a 57% RR for standard major adverse CV events.

After 30 years, as published this year in Diabetes Care, they discovered there was a continued benefit to the intensive management group, with a 32% risk reduction for adverse CV events, plus a 30% RR for any CV outcome. And even more surprising was a 33% reduction in cumulative mortality in those assigned to intensive therapy.

Skyler then added that, in the intensive management group, in the 20-year follow-up of the EDIC continuation of the DCCT Trials, there was a 30% reduction of CV risk that was a mirror effect from intensive control for the 9.5 year DCCT Trial.

Looking at another large study, the STENO-2 study, 160 Danish patients with type 2 diabetes and persistent microalbuminuria were randomly assigned to either standard treatment or intensive therapy with medication and behavior modification for a mean of 8 years. Again, the follow-up data at 20 years after randomization (published in August in Diabetologia) revealed that patients assigned to intensive intervention experienced a 45% reduction in both the composite CV endpoint and death from any cause.

“There were continuing effects of the early intervention even though, subsequently, the degree of glycemic, BP and lipid control converged,” Skyler said.

Skyler added that we can look at some new drugs with outstanding results over just the last couple of years. Major CV outcome trials for new diabetes drugs have yielded surprising results over the last two years. In September 2015, data from the EMPA-REG OUTCOME trial revealed that the SGLT-2 inhibitor empagliflozin significantly reduced the risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CVD. When combined with standard care, and not intensive care, empagliflozin reduced the risk for CV death by 38% vs. placebo, with no significant difference in the risk for non-fatal myocardial infarction or stroke.

According to the researchers, patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for HF. So we now have a treatment that can help prevent the risk that most people with diabetes die from, CV death.

In June, results from the LEADER trial demonstrated that the glucagon-like peptide 1 receptor agonist liraglutide reduced risk for 3-point major adverse CV events by 13%, for all-cause death by 15%, and for CV death by 22% vs. placebo, while reducing HbA1c and body weight.

At the European Association for the Study of Diabetes meeting last month, results from SUSTAIN-6 showed another GLP-1 receptor agonist, semaglutide, significantly lowers the risk for CV death, nonfatal MI or nonfatal stroke in adults with type 2 diabetes at high CV risk.

Skyler said, “This is the third diabetes drug now to show CV benefit…Up until last year, with EMPA-REG, we didn’t have any. These are crucial kinds of observations.”

Skyler noted that there are key differences in the three CV outcome trials. In SUSTAIN-6, there was a 26% RR in nonfatal MI that did not reach statistical significance; a 39% RR in nonfatal stroke; and a 2% RR in CV death.

“In summarizing the results from these trials, this is the opposite of what we saw in EMPA-REG,” Skyler said. “In EMPA-REG, we saw CV death was decreased, but no impact on nonfatal MI or nonfatal stroke. Whereas with SUSTAIN, we see no impact on CV death, but a significant impact on nonfatal MI and nonfatal stroke. So, one of the things we have to contemplate is how we think about these composite endpoints, and whether or not they represent the same thing in each case.”

Practice Pearls:

  • The EMPA-REG OUTCOME Trial revealed that the SGLT-2 inhibitor empagliflozin reduced the risk for CV death by 38% vs. placebo.
  • The LEADER Trial showed that the agonist liraglutide reduced risk for 3-point major adverse CV events by 13%, for all-cause death by 15%, and for CV death by 22% vs. placebo, while reducing HbA1c and body weight.
  • The SUSTAIN-6 Trial showed another GLP-1 receptor agonist, semaglutide, significantly lowers the risk for CV death, nonfatal MI or nonfatal stroke in adults with type 2 diabetes at high CV risk.

Skyler JS. Late-Breaking Clinical Trials and FDA Update. Presented at: Cardiometabolic Health Congress; Oct. 5-8, 2016; Boston.

Disclosure: Skyler reports financial relationships with multiple pharmaceutical companies.