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Abstract
BackgroundTo identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH].MethodsOne phase 2 (12-week) and 6 phase 3 (26 to 78-week) randomized studies of BIL compared to IG or NPH, in patients with type 1 or type 2 diabetes, were included. The participants were diverse with respect to demographics, baseline glycemic control, and concomitant disease or medications, but treatment groups were comparable in each study. For any potential CV or neurovascular event, relevant medical information was provided to a blinded external clinical events committee (C5Research, Cleveland Clinic, Cleveland, OH, USA) for adjudication. Cox regression analysis was used to compare treatment groups. The primary endpoint was a composite of adjudicated MACE+ [CV death, myocardial infarction (MI), stroke, or hospitalization for unstable angina].ResultsThe pooled population included 5862 patients in the safety evaluation, with randomization to BIL:IG:NPH of 3578:2072:212. Mean age was 54.1 years, 27 % had type 1 diabetes, 56 % were male, and 88 % were white. Baseline demographic and clinical characteristics, including use of statins or other lipid-lowering drugs, were comparable between BIL and comparators. A total of 83 patients experienced at least 1 MACE+ and 70 patients experienced at least 1 MACE (CV death, MI, or stroke). Overall, there were no treatment-associated differences in time to MACE+ [hazard ratio (HR) for BIL versus comparator insulin (95 % CI): 0.82 (0.53–1.27)] or MACE [0.83 (0.51–1.33)]. In 4297 patients with type 2 diabetes, there were 71 MACE+ events [HR: 1.02 (95 % CI: 0.63–1.65), p = 0.94]. In 1565 patients with type 1 diabetes, there were only 12 MACE+ [0.24 (0.07–0.85), p = 0.027]. There were no differences in all-cause death between BIL and comparators. Sub-group analyses did not identify any sub-population with increased risk with BIL versus comparator insulins.ConclusionsTreatment with BIL versus comparator insulin in patients with type 1 diabetes or type 2 diabetes was not associated with increased risk for major CV events in the studies analyzed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0393-6) contains supplementary material, which is available to authorized users.
Highlights
To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or isophane insulin (NPH)]
In the ORIGIN trial, insulin glargine use versus standard of care in patients with impaired glucose tolerance or early diabetes was not associated with any cardiovascular disease (CVD) benefit or risk [3]
The UKPDS, a study in patients newly diagnosed with type 2 diabetes, suggested a CVD benefit in those individuals randomized to an intensive policy using oral glucose-lowering medications or insulin, compared to those who received the conventional policy [4,5,6]
Summary
To identify possible differences in cardiovascular (CV) risk among different insulin therapies, we performed pre-specified meta-analyses across the clinical program for basal insulin peglispro (BIL), in patients randomized to treatment with BIL or comparator insulin [glargine (IG) or NPH]. Diabetes mellitus is associated with an increased risk for cardiovascular disease (CVD). In the ORIGIN trial, insulin glargine use versus standard of care in patients with impaired glucose tolerance or early diabetes was not associated with any CVD benefit or risk [3]. The UKPDS, a study in patients newly diagnosed with type 2 diabetes, suggested a CVD benefit in those individuals randomized to an intensive policy using oral glucose-lowering medications or insulin, compared to those who received the conventional policy [4,5,6]. In type 1 diabetes, the single large intervention trial (DCCT) and post-trial follow up (EDIC) compared intensive versus conventional insulin therapy and showed a reduction in CVD with intensive glycemic treatment in the long-term follow-up study [10, 11]
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