Intensive glucose-lowering therapy reduces ischaemic heart disease in type 2 diabetes

Gerstein HC, Miller ME, Ismail-Beigi F, et al; ACCORD Study Group
Lancet. 2014 Nov 29;384(9958):1936-41

Background

Increasing glycated haemoglobin A1 (HbA1c) concentrations are related to a higher incidence of ischaemic heart disease (IHD) [1], and people with type 2 diabetes (T2DM) show a two- to three times higher incidence of IHD than people without diabetes, irrespective of other risk factors [2,3].
It has been shown that 10 years of intensive, as compared to standard glucose-lowering therapy reduces the 20-year risk of myocardial infarction (MI) by 15% in patients with newly diagnosed T2DM [4].
The ACCORD trial examined intense (target 6.0%)  vs. standard (target 7.0-7.9%) glucose-lowering therapy in people with established T2DM and additional risk factors for cardiovascular (CV) disease. While the intervention did not affect the primary composite CV outcome [5], non-fatal MI was reduced, but risk of death, specifically from CV causes, was increased after intensive therapy. Exploratory analyses did not reveal a relation between CV mortality and severe hypoglycaemia [6] or the degree or speed of glucose lowering [7].
This article reports the effects of the ACCORD glucose-lowering intervention on indices of IHD, including fatal and non-fatal MI and unstable and new-onset angina, and the degree to which HbA1c levels are related to these effects. After a mean follow-up of 3.7 years, intensive treatment was discontinued after an increase in all-cause and CV mortality had been observed. Patients were then switched to standard therapy. Follow-up then continued for another mean 1.2 years.

Main results

• Fewer MIs, nonfatal MIs or the composite outcome of any MI or unstable angina (UA) were seen in the intensive therapy group, as compared to the standard therapy group in both follow-up periods.
• Participants in the intensive group were 20% less likely to experience any MI during the active treatment period, and 16% during the entire follow-up period. Similar observations were done for the composite IHD outcome of MI, UA or coronary revascularisation.
• Intensive treatment did not affect the incidence of fatal MI or new angina.
• Cumulative incidence curves for all outcomes were lower with intensive therapy in both follow-up periods.
• Addition of the HbA1c-concentration measured during active treatment as a time-dependent variable to the hazard analysis, attenuated all significant hazard ratios to neutral, while it did not affect the significance of non-significant hazard ratios.

Conclusion

Intensive glucose-lowering therapy in persons with T2DM was associated with significantly lower 5-year incidence of ischaemic heart disease (13%), any MI (16%), non-fatal MI (19%), coronary revascularisation (16%) and UA (19%). These effects were seen both before participants were switched to standard therapy and after. The observation that correction for HbA1c concentrations cancelled out significant effects, supports the hypothesis that the degree of glucose lowering or some closely related factor accounts for the effect of the intervention on IHD.
These findings are at odds with previous ACCORD observations that the intensive treatment did not reduce fatal MI and death from CV causes. This may be explained by the finding that much of the mortality in the intensive treatment group occurred in people whose HbA1c levels did not decrease from baseline. The relationship between dysglycaemia and IHD requires further study.

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