Updates from new, old diabetes trials shed light on intervention benefits

BOSTON — Recent follow-up data from both older and more recent diabetes trials demonstrate the continued, long-term benefits of early intervention efforts and the surprise CV benefits of several new therapies, according to a speaker at the Cardiometabolic Health Congress.

In an update on recent late-breaking clinical trials and new follow-up analyses of older landmark diabetes studies, 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.

Jay S. Skyler

DCCT-EDIC

In the DCCT-EDIC study, researchers continued to follow 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% RR for any CV outcome for those assigned to intensive management, along with a 57% RR for standard major adverse CV events.

Follow-up data at 30 years after randomization, published this year in Diabetes Care, revealed continued benefit for the intensive treatment group, Skyler said: A 30% RR for any CV outcome for those assigned to intensive management, along with a 32% RR for standard major adverse CV events. In addition, new mortality results showed a 33% reduction in cumulative mortality in those assigned to intensive therapy.

The results were striking, Skyler said, because the treatment was only for an average of 6.5 years; after mean HbA1c in the intensive treatment group fell to 7% (vs. 9% in the standard care group), HbA1cs for both groups later converged, he noted.

“This is a residual effect from 6.5 years of original HbA1c separation,” Skyler said. “You can see that, for any predefined CVD events, there is still a 30% reduction. There is a memory of that early intervention to control glucose.”

STENO-2

In 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.

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.

CV benefits

Major CV outcome trials for new diabetes drugs have yielded surprising results over the last 2 years, Skyler said. In September 2015, data from the EMPA-REG OUTCOME trial revealed that the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) 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, 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, Skyler said.

Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for HF, according to researchers.

In June, results from the highly anticipated LEADER trial demonstrated that the glucagon-like peptide 1 receptor agonist liraglutide (Victoza, Novo Nordisk), 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 (Novo Nordisk), significantly lowers the risk for CV death, nonfatal MI or nonfatal stroke in adults with type 2 diabetes at high CV risk.

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

There are key differences in the three CV outcome trials, Skyler noted. 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.

“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.” – by Regina Schaffer

Reference:

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.