Insulin provision therapy associated with higher mortality than insulin sensitising therapy in older people

The prevalence of type 2 diabetes is rapidly growing in older people; indeed some estimates suggest that the number of adults ≥75 years of age with type 2 diabetes is expected to increase by 449% from 2005 to 2050, compared with a 220% increase in adults aged 65–74 and a 200% increase in adults <65 years. This growing burden of type 2 diabetes is associated with a significant burden of cardiovascular disease, with as many as 68% of people with type 2 diabetes >65 years of age dying of heart disease. Despite this, treatment strategies for older adults with type 2 diabetes are largely based on opinion rather than definitive evidence. 

With these issues in mind, this study compared the effects of insulin provision (IP) therapy (insulin and insulin secretagogues) versus insulin sensitising (IS) therapy (biguanides and thiazolidinediones) for glycaemic control in older (≥75 years) and younger (<75 years) adults with type 2 diabetes and established stable ischaemic heart disease. Adults enrolled in the Bypass Angioplasty Revascularisation Investigation 2 Diabetes (BARI-2D) trial were studied. All those enrolled with type 2 diabetes and ischaemic heart disease were randomised twice: (1) between revascularisation plus intensive medical therapy versus intensive medical therapy alone; and (2) between IP versus IS therapies. The primary endpoint was all-cause-mortality over 5-year follow-up. In this substudy, outcomes related to IP versus IS therapies were assessed in relation to age.

Compared to younger subjects, the older cohort had lower body mass index, higher diuretic use, worse kidney function and increased history of heart failure. Within the older cohort, the IP and IS subgroups were similar in respect to baseline cardiovascular risk factors, medications and coronary artery disease severity. 

During follow-up, the older subjects receiving IP therapy had higher cardiovascular mortality than those receiving IS therapy (16% vs 11%, P=0.040). Using Cox proportional hazards analysis, the older IP subjects were at increased risk for all-cause mortality (hazard ratio, 1.89; confidence interval, 1.1–3.2; P=0.020). No mortality difference between IP and IS therapies was observed in those <75 years of age. 

This study therefore illustrates that older adults with type 2 diabetes and ischaemic heart disease who received IP therapy had increased risks for all-cause mortality and cardiovascular events compared to those who received IS therapy. Additionally, no differences in treatment effects were evident for adults aged <75 years, implying that optimal therapeutic strategies for older adults may differ from those in younger people. 

Based on this study, insulin-providing therapy in older people with type 2 diabetes and ischaemic heart disease may be associated with adverse outcomes. There is potential biological plausibility related to these observations, specifically around hypoglycaemia and its link with cardiovascular events, with the elderly being particularly vulnerable to the consequences of hypoglycaemia.

While the results of this study provide some insights into potential treatment strategies for older people with type 2 diabetes, it has a major limitation – namely that newer therapies such as SGLT2 inhibitors and GLP-1 receptor agonists are not represented within the analysis. Additionally the cohort comprises a relatively small number of >75-year-olds (around 8% of the total population), while there are limited data on metabolic factors or hypoglycaemic episodes, which would be extremely useful in understanding possible mechanisms underlying these data. Nevertheless, this study clearly suggests that there may be significant outcome differences related to different therapeutic strategies in younger and older people with type 2 diabetes.

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