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Randomized Controlled Trial
. 2017 May;19(5):664-671.
doi: 10.1111/dom.12871. Epub 2017 Feb 27.

Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial

Simon R Heller  1 , Richard M Bergenstal  2 , William B White  3 , Stuart Kupfer  4 , George L Bakris  5 , William C Cushman  6 , Cyrus R Mehta  7 , Steven E Nissen  8 , Craig A Wilson  4 , Faiez Zannad  9 , Yuyin Liu  10 , Noah M Gourlie  10 , Christopher P Cannon  10 ; EXAMINE Investigators
Affiliations
Randomized Controlled Trial

Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial

Simon R Heller et al. Diabetes Obes Metab. 2017 May.

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] Diabetes Obes Metab. 2017 Sep;19(9):1333. doi: 10.1111/dom.13076. Diabetes Obes Metab. 2017. PMID: 28834341 Free PMC article. No abstract available.

Abstract

Aims: To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).

Methods: The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.

Results: Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (Pinteraction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27-4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20).

Conclusions: There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Keywords: HbA1c; alogliptin; cardiovascular disease; coronary disease; diabetes; hypoglycaemia; myocardial infarction; stroke.

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Conflict of interest statement

S.R. Heller: Research Grant; Takeda, NovoNordisk, Eli Lilly, Sanofi Aventis. Consultant/Advisory Board; Takeda, NovoNordisk, Eli Lilly. R.M. Bergenstal: Consultant/Advisory Board; Abbott Diabetes Care, Amylin, AstraZeneca, Bayer, Takeda, Becton Dickinson, Calibra, Eli Lilly, Halozyme, Johnson and Johnson, Medronic, NovoNordisk, Resmed, Roche, Sanofi. W.B. White: consulting/personal fees as Chair, Steering Committee for EXAMINE, Takeda. S. Kupfer: Full time employee of Takeda. G.L. Bakris: Research Grant; Takeda, Medtronic, Relypsa. Consultant/Advisory Board; Abbvie, CVRx, Janssen, Eli Lilly, Medtronic, Novartis, GSK, Bayer. W.C. Cushman: Research Grant; Boehringer‐Ingelheim, Lilly. C.R. Mehta: None. S.E. Nissen: None. C. Wilson: Full time employee of Takeda. F. Zannad: Consultant/Advisory Board; Servier, Resmed, Janssen, Novartis, Air Liquide, Cardiorenal diagnostics, CVCT, Biotronik, St. Jude, Boston Scientific. Consultant/Advisory Board; Takeda, Pfizer. Yuyin Liu: Full time employee of Takeda. Noah M. Gourlie: Full time employee of Takeda. C.P. Cannon: Research Grant; Takeda, Accumetrics, Arisaph, Astra Zeneca, Boehringer‐Ingelheim, GlaxoSmithKline, Janssen, Merck, Regeneron, Sanofi. Consultant/Advisory Board; Modest; CSL Behring, Essentials, Takeda.

Figures

Figure 1
Figure 1
Change in HbA1c from baseline to last visit by baseline HbA1c category and treatment group analysed using Cox proportional hazards models without adjustment for multiple comparisons. LS, least squares.
Figure 2
Figure 2
Percentage of patients experiencing MACE and composite by baseline HbA1c category and treatment group: HRs and P values for the primary endpoint of composite MACE with alogliptin vs placebo. Relationships between MACE and baseline HbA1c were analysed using Cox proportional hazards models without adjustment for multiple comparisons.
Figure 3
Figure 3
Risk of MACE outcomes based on HbA1c at 1 month. Combined event rate (both treatment groups). For analysis of MACE by categories of HbA1c, only the first event after 1‐month HbA1c measurement is included in the analysis for each patient. HRs and 95% CIs are derived from Cox proportional hazards models with a factor for HbA1c categories at 1 month and adjusted by age, sex, duration of diabetes, smoking status, renal function eGFR, index ACS type, glycaemic medication (insulin, metformin and sulphonylureas) at baseline and stratified by screening renal function and geographic region. The group of patients with HbA1c < 7% at 1 month is the reference group.
Figure 4
Figure 4
Risk of MACE outcomes based on reported hypoglycaemia for (A) any MACE and (B) subsequent MACE. Hypoglycaemia incidence is based on reported adverse events of the hypoglycaemia preferred term coded according to the Medical Dictionary for Regulatory Activities. HRs and 2‐sided 95% CIs are derived from Cox proportional hazards models with a factor for hypoglycaemia incidence and adjusted by baseline age, sex, treatment, HbA1c and glycaemic medication (insulin, metformin and sulphonylureas) and stratified by screening renal function and geographic region.
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