More CV, Renal Outcomes at ADA: CREDENCE, CARMELINA, CAROLINA

The final day of the 79th Scientific Sessions of the American Diabetes Association (ADA) opened with an in-depth discussion of CREDENCE, the first dedicated renal outcomes trial for a type 2 diabetes (T2D) therapy. CREDENCE investigators made news in April when they reported that canagliflozin, the sodium glucose co-transporter 2 (SGLT2) inhibitor sold as Invokana, cut the risk of renal failure and death 30% patients with T2D and chronic kidney disease.

The results from CREDENCE have wowed the diabetes community, prompting ADA to update clinical practice guidelines on June 3, 2019, and causing Robert H. Eckel, MD, of the University of Colorado to exclaim while moderating a press briefing: “CREDENCE—that just knocks your socks off, doesn’t it?”

On Tuesday, co-principal investigator Kenneth Mahaffey, MD, of Stanford University shared new data with the remaining attendees in San Francisco, California, about the implications of the results for primary and secondary prevention.

Mahaffey presented a series of slides showing cardiovascular (CV) and renal outcomes for patients with and without existing cardiovascular disease (CVD), based on screening the patients received at the start of the trial. Those in the secondary prevention group had a history of coronary, cerebrovascular, or peripheral vascular disease, procedures or events.

The primary prevention group had 49.6% of the participants, was younger, had more women, but had similar measures of glycated hemoglobin (A1C) and low-density lipoprotein (LDL) cholesterol. As expected, the secondary prevention group had higher rates of hypertension, heart failure, CVD, peripheral vascular disease, and amputations. The 2 groups had similar duration of T2D and level of renal function.

Overall, the data Mahaffey shared showed that canagliflozin demonstrated “important reductions in cardiovascular death and hospitalization for heart failure,” in both the primary and secondary prevention groups:

• There was a 26% reduction in hazard of CV death or hospitalization for heart failure in the primary prevention group.
• There was 34% reduction in the hazard of CV death or hospitalization for heart failure in the secondary prevention group.
• For the combined endpoint of CV death, myocardial infarction or stroke, there was a 32% reduction in the primary prevention group, and a 15% reduction in the secondary prevention group.
• For cardiovascular death, Mahaffey said there were “very similar” hazard ratios, translating into a 25% reduction in the primary prevention group and a 21% reduction in the secondary prevention group.

“These data show, for the first time, important reductions in these endpoints with an agent to treat type 2 diabetes and chronic kidney disease in both primary and secondary prevention groups,” Mahaffey said.

Data showed similar results for the composite renal endpoint between the primary and secondary prevention groups, “very different from the cardiovascular results,” he said.

In a statement, Mahaffey said the new analysis shows that canagliflozin can manage serious complications from T2D, including CV and kidney disease. “We're particularly excited about this new analysis because it's the first time a type 2 diabetes medicine has shown a cardiovascular benefit in patients who did not have preexisting CV disease. This is an important, clinically meaningful finding as it uncovers the potential of canagliflozin to offer a protective effect in this patient population.”

CARMELINA, CAROLINA in Linagliptin

Tuesday’s program also featured presentations on CARMELINA, which evaluated the effect of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on CV and kidney safety. During a briefing ahead of the program, investigators emphasized that patients with T2D and kidney disease have had less attention in trials of DPP-4 inhibitors.

Compared with placebo, results showed there was no significant difference in the 3-part MACE (major adverse cardiovascular events), and neutral findings for renal outcomes in the elderly.

Boehringer Ingelheim and Eli Lilly, which market linagliptin as Tradjenta, also announced results for CAROLINA, which compared linagliptin with glimepiride, a second-generation sulfonylurea. Officials touted CAROLINA as “the only active comparator outcome trial” for a DPP-4 inhibitor, with the results showing that linagliptin was not inferior to glimepiride in the first occurrence of 3-part MACE and was similar in a secondary endpoint of 3-part MACE plus hospitalization for unstable angina.

More patients taking linagliptin achieved a second composite outcome, of reaching an A1C of 7% without a rescue medication, moderate or severe hypoglycemia, or 2% weight gain.

When asked during a briefing where DPP-4 inhibitors generally, and linagliptin specifically, fit in among T2D therapies, investigator Julio Rosenstock, MD, of the Dallas Diabetes Research Center said the results from CARMELINA show that linagliptin is safe to use for older patients who need help with glycemic control. “We can state with a great deal of confidence that using a DPP-4, including linagliptin, is safe from a cardiovascular point of view, and safe if they have kidney disease—and safe in older people,” he said. “That’s my take home message.”

Reference

Petrovic V, Rosenstock J, chairs. CREDENCE and CARMELINA—Results from two major clinical trials in kidney and cardiovascular disease in diabetes. Symposium at the 79^th Scientific Sessions of the American Diabetes Association; San Francisco, California; June 7-12, 2019.