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EASD: Another New Diabetes Drug Reduces CV Risk

Semaglutide reduced major cardiovascular events by 26% in adults with type 2 at high cardiovascular risk.

Major adverse cardiovascular event risk dropped a relative 26% with the novel glucagon-like peptide-1 (GLP-1) analogue semaglutide in high-risk type 2 diabetes patients in SUSTAIN 6, the third such cardiovascular safety outcomes trial to show benefit.

The drug lowered the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke to 6.6% compared with 8.9% in the placebo group getting usual care.  Steven Marsok MD of HCA Midwest Health Research in Kansas City reported that,  “This lower risk was principally driven by a significant (39%) decrease in the rate of nonfatal stroke and a nonsignificant (26%) decrease in nonfatal MI, with no significant difference in the rate of cardiovascular death.

In this outcomes trial, from an overall mean baseline of 8.7%, semaglutide 0.5 mg and 1.0 mg significantly reduced HbA1c by -1.1% and -1.4% vs -0.4% for both placebo 0.5 mg and 1.0 mg at 104 weeks, when added to standard of care. In addition, from a mean baseline of 92.1 kg, adults treated with semaglutide 0.5 mg and 1.0 mg experienced superior and sustained weight loss of -3.6 kg and -4.9 kg, vs -0.7 kg for placebo 0.5 mg and -0.5 kg for placebo 1.0 mg.[1]

Fewer serious adverse events were seen with semaglutide vs placebo; however, treatment discontinuation due to adverse events was more frequent with semaglutide, mainly due to gastrointestinal events. The incidence of pancreatitis was lower with semaglutide vs placebo. In terms of microvascular complications, significantly fewer people treated with semaglutide (62 [3.8%]) vs placebo (100 [6.1%]) had new onset or worsening nephropathy while significantly more people treated with semaglutide (50 [3.0%]) vs placebo (29 [1.8%]) experienced diabetic retinopathy complications.[1]

“The results of SUSTAIN 6 support the strong potential of once-weekly semaglutide in type 2 diabetes treatment and we look forward to regulatory submission later this year,” said Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk.

Last year, the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) showed a relative 14% reduction in the same major adverse cardiovascular event (MACE) composite compared with placebo in the EMPA-REG trial, although an FDA advisory panel was split on giving it an indication for reducing risk of cardiovascular mortality. Earlier this year, the GLP-1 drug liraglutide (Victoza) was shown to cut major cardiovascular event rates by 13% in the LEADER trial.

But while both of those trials showed significant reductions in cardiovascular mortality and all-cause mortality as individual endpoints with their respective diabetes drugs, SUSTAIN 6 found no such advantage with semaglutide. Rates of death from cardiovascular causes were similar with the drug as with placebo.

The impact on nonfatal MI, which included silent infarcts, was not statistically significant either.  But for nonfatal stroke, the difference between semaglutide and placebo was significant (1.6% versus 2.7%, HR 0.61, P=0.04).

Even more exciting is the potential for combining both classes that have shown a cardiovascular impact — GLP-1 and SGLT2 which will certainly go into a new trial.

The added value is they reduce cardiovascular death.  SUSTAIN 6 included 3,297 patients with type 2 diabetes on a standard diabetes care regimen randomized to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 2.1 years. Among them, 83% qualified for the high-risk criteria by being age 50 or older with established cardiovascular disease and 17% by being age 60 or older with at least one cardiovascular risk factor.

Overall, fewer serious adverse events but more treatment discontinuations (mainly due to GI effects) occurred with semaglutide in a safety profile similar to that of other GLP-1 receptor agonists.

While new or worsening nephropathy was less common with semaglutide, rates of retinopathy complications — vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation — were significantly and “unexpectedly” higher.

Practice Pearls:

  • Semaglutide 0.5 mg and 1.0 mg significantly reduced HbA1c by -1.1% and -1.4% vs -0.4% for both placebo 0.5 mg and 1.0 mg at 104 weeks.
  • Semaglutide reduced major cardiovascular events by 26% in adults with type 2 diabetes.
  • The drug lowered the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke to 6.6% compared with 8.9% in the placebo group getting usual care.

Source Reference: Marso SP, et al “Semaglutide and cardiovascular outcomes in patients with type 2 diabetes” N Engl J Med 2016; DOI: 10.1056/NEJMoa1607141.