Cardiovascular Risks with Insulins

The new basal insulin peglispro is not linked to increased risk of major adverse cardiovascular events compared to insulin glargine or NPH in patients with type 1 and type 2 diabetes, according to a meta-analysis published in Cardiovascular Diabetology.¹

“The current data demonstrated that there was no apparent increased MACE+ or all-cause mortality with peglispro versus comparator insulin, although the upper bound of the 95% CI in patients with type 2 diabetes did not meet the FDA guidance on oral glucose lowering agents for submission without a CV outcomes trial,” wrote first author Byron Hoogwerf, MD, of Eli Lilly and Company (Indianapolis, IN), and colleagues at the Cleveland Clinic.

Results from several large clinical trials have shown unclear and contradictory results regarding the effect of insulin on cardiovascular disease (CVD) risk, though comparing studies is complicated by differences in study populations and methodologies. While some studies like DIGAMI 1² and UKPDS³ support a mortality or cardiovascular (CV) benefit for insulin therapy, others like DIGAMI 2⁴ and ORIGIN⁵ have failed to back this up.

Moreover, some studies have linked insulin to increased CVD risk. Others have linked insulin-related hypoglycemia to cardiac arrythmias. Still others have suggested that CVD risk may vary according to type of insulin or by insulin dosage, though results are inconsistent. Few studies have compared insulins with greater efficacy or decreased risk of hypoglycemia. The only other large meta-analysis on this issue looked at insulin degludec vs conventional insulin, and found no significant difference in MACE+ between insulins.⁶

Studies have shown peglispro to have slower absorption, slower clearance, and a prolonged duration of action compared to conventional insulin. Whether or not cardiovascular risk differs between peglispro and conventional insulin has been an open question.  

The meta-analysis included one phase 2 (12-week) and six phase 3 (26 to 78 week) randomized trials. The pooled population included 5862 participants randomized to peglispro (n=3578), insulin glargine (n=2072), or NPH (n=212). Participants had type 1 (n=1565) or type 2 diabetes (n=4297), a mean age of 54.1 years, and were 56% male and 88% white. A blinded external clinical events committee at the Cleveland Clinic reviewed potential CV and neurovascular events. The primary endpoint was MACE+ (CV death, myocardial infarction, stroke, and hospitalization for unstable angina.) The analysis also evaluated MACE (CV death, MI, or stroke).

Key results for peglispro vs comparators:

• MACE: No difference in risk (HR 0.83 [0.51–1.33])

• MACE+: No difference in risk (HR 0.82 [0.53–1.27])

♦ Type 2 diabetes: No difference in risk (HR: 1.02 [0.63–1.65], p = 0.94)

♦ Type 1 diabetes: No difference in risk (HR 0.24 [0.07–0.85], p = 0.027)

♦ Sub-group analyses: No difference in risk based on diabetes type, sex, age, DM duration, history of CVD, hypertension, use of lipid medications and statins, BMI, and white race

• All-cause mortality: No differences in risk (HR 1.15 [0.54, 2.48]).

Meta-analyses of phase 2/3 studies with DPP-4 inhibitors have generally shown lower hazard or risk ratios compared to results from CV outcome trials, raising the question of whether results from the current meta-analysis are sufficient to inform CV risk, the authors mentioned. Phase 3 programs often enroll patients with low CVD risk, while patients with T2D who need insulin usually have higher CVD risk. Other limitations include the small number of MACE and MACE+ events and relatively short duration of trials, which may have not been long enough to capture CVD risk.

“These results must be interpreted in the context of the limitations of phase 2/3 data to adequately assess CVD risk, as well as the current uncertainty as to whether differences among insulins or the total insulin dose is likely to be associated with CV risk,” they concluded.

Take-home Points

• Meta-analysis of phase 2/3 trials suggests no differences in MACE+ or MACE risk for peglispro compared to insulin glargine and NPH.

• There was also no difference in all-cause mortality.

• Limitations of phase 2/3 trials and questions about whether differences between insulins or insulin dose affect CV risk may limit the results.

Drs. Hoogwerf, Rodriguez, Chen, and Qu are employees and minor stock holders of Eli Lilly and Company.

References:

1. Hoogwerf BJ, et al. Major adverse cardiovascular events with basal insulin peglispro versus comparator insulins in patients with type 1 or type 2 diabetes: a meta-analysis. Cardiovasc Diabetol. 2016 May 17;15(1):78.

2. Malmberg K, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995 Jul;26(1):57-65.

3. Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-1589.

4. Malmberg K, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005 Apr;26(7):650-661.

5. ORIGIN Trial Investigators, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-328.

6. Food and Drug Administration: FDA Briefing Document NDA 203314 and 203313. Insulin degludec/insulin aspart treatment to improve glycemic control in patients with diabetes mellitus-advisory committee meeting, 8 Nov 2012.