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PCSK9 inhibitor lowers CV risk in insulin-treated type 2 diabetes
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SAN DIEGO — Results of the ODYSSEY DM-INSULIN trial indicate that adults with dyslipidemia and type 2 diabetes who are taking insulin can reduce their cardiovascular risk with alirocumab, according to new data presented here.
“This is the first report of a PCSK9 inhibitor studied exclusively in an insulin-treated diabetes population,” Lawrence A. Leiter, MD, associate scientist at Li Ka Shing Knowledge Institute at St. Michael’s Hospital, Toronto, and professor in the departments of medicine and nutritional sciences at the University of Toronto, said. “Alirocumab [(Praluent, Sanofi/Regeneron)] treatment significantly reduced LDL vs. placebo [and] also significantly reduced non-HDL, apolipoprotein B and Lp(a) levels, and significantly increased HDL vs. placebo. Alirocumab therapy was generally safe and well-tolerated and, importantly, alirocumab did not affect HbA1c or fasting plasma glucose.”
Leiter and colleagues randomly assigned 441 patients with type 2 diabetes to receive 75-mg alirocumab (n = 294) or placebo (n = 147) twice weekly for 24 weeks. Baseline characteristics for the groups were similar: mean age, approximately 64 years; 55% men; 40% with known atherosclerotic CVD; and 60% with additional CV risk factors. Median diabetes duration was 15 to 16 years. Patients in both groups had been taking insulin for a mean 5 to 6 years; mean baseline HbA1c was 7.5%, and mean FPG was near 153 mg/dL.
All patients had LDL cholesterol levels at least 60 mg/dL, about 75% were receiving prior statin therapy — most being treated with either high-intensity or moderate-intensity statin therapy; 22% to 24% had a history of statin intolerance and so were not on statin therapy. About 22% to 26% were prescribed additional lipid-lowering therapies, primarily ezetimibe or fibrates.
In both groups at baseline, mean calculated LDL cholesterol was near 110 mg/dL, non-HDL cholesterol about 145 mg/dL, apo B 96 to 97 mg/dL, HDL near 45 mg/dL, triglycerides 146 to 153 mg/dL and Lp(a) 14 to 16 mg/dL.
All patients were taking insulin; more than half were also prescribed metformin, with small numbers also taking other antihyperglycemic agents.
The primary endpoint was percent change in calculated LDL cholesterol from baseline to week 24.
Researchers observed a 48.2% reduction in calculated LDL cholesterol from baseline to week 24 (the primary endpoint) vs. 0.8% increase in the placebo group, for an overall 49% reduction in LDL cholesterol vs. placebo (P < .0001). Of note, Leiter said, only 20% of participants in the alirocumab group required up-titration at week 8 to 150 mg twice weekly to reach an LDL cholesterol level less than 70 mg/dL.
“As you’d expect, we saw an early reduction by the first timepoint post-randomization, we had near maximal LDL reduction, with some additional LDL lowering after week 12, because at that point, of course, 20% of the patients had up-titration of their dosage,” he said.
At week 24, 76% of participants in the alirocumab group had LDL cholesterol levels below 70 mg/dL and 71% had non-HDL cholesterol levels below 100 mg/dL.
Researchers observed no difference in treatment-emergent adverse events between the two groups.
“If we look at the LDL reduction in pooled phase 3 diabetes analyses or the [ODYSSEY COMBO II] diabetes analysis — the longest trial completed to date with alirocumab at 2 years — or the overall program, you can see that the LDL reduction observed in ODYSSEY DM-INSULIN is virtually identical to what had been seen in previous analyses,” Leiter said. – by Jill Rollet
Reference:
Leiter LA. 1-AC-SY12. Presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego.
Disclosures: Leiter reports receiving research support and/or serving as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck Canada, Novo Nordisk, Pfizer, Sanofi, Servier and Takeda Canada.
Perspective
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Eliot A. Brinton, MD, FAHA, FNLA
ODYSSEY DM and ODYSSEY DM-Insulin are the first PCSK9 inhibitor trials exclusively in patients with type 2 diabetes, and they show dramatic LDL cholesterol lowering with or without insulin therapy, just as in patients without type 2 diabetes. Although no difference in LDL response was expected, this confirmation is valuable, since PCSK9 inhibitors are often used in patients with type 2 diabetes.
Two issues, however, limit PCSK9 inhibitor use. First, it is off-label to use PCSK9 inhibitors in type 2 diabetes absent either a prior atherosclerotic CVD event or familial hypercholesterolemia. Off-label use, although allowed, is hard to get approved for with these costly agents. A large CV outcome trial of a PCSK9 inhibitor in patients with type 2 diabetes “alone” would be needed to change the label. Second, there is a little-known inverse relationship between type 2 diabetes and familial hypercholesterolemia. Mendelian randomization studies have shown that genetically lower cholesterol levels (via decreased activity of either PCSK9 or HMG CoA reductase) correlate with increased type 2 diabetes prevalence. Conversely, patients with heterozygous familial hypercholesterolemia have about half the usual risk for type 2 diabetes. The mechanism or mechanisms of this recently discovered inverse relationship are not yet fully understood.Perspective
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Yehuda Handelsman, MD, FACP, MACE, FNLA
One of the issues I encounter all the time is that people with diabetes typically have lower LDL levels. This group of patients is often not treated aggressively enough. Patients with established CVD and LDL of 110 mg/dL or so have a substantial risk of up to 50% that they will have a CV event or mortality within 5 years if they have diabetes.
The ODYSSEY-DM trial addressed the question of whether a PCSK9 inhibitor would work as well in this particular group, especially those on insulin. In this trial, the patients were taking statins; the baseline LDL was 110 mg/dL, which in my book is way too high for people with diabetes. They were given either 75 mg or 150 mg of alirocumab (Praluent, Sanofi/Regeneron), and there was an impressive 48% mean LDL reduction, with about three-quarters of the participants seeing an LDL reduction of at least 75 mg/dL.
Often, we’d like to see a reduction in non-HDL, not just LDL, in this population. But when it comes to PCSK9 inhibitors, that really doesn’t make much sense, because these agents do not affect triglycerides or HDL — their primary effect is on LDL. When we measure LDL reduction, whatever we see with non-HDL will only be the same LDL reduction. The point, therefore, is that PCSK9 inhibitors are quite efficacious and may be an important medicine in patients with diabetes on insulin, who are at such high risk for CV events.
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