Impact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival

Abstract

AimsTo characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia.MethodsData were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable.ResultsThere were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.ConclusionsThe pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus—a choice determined by metabolic phenotype

“…The goals of therapy should be tailored to each metabolic phenotype. It has been shown that lower HbA1c (< 7%) to be associated with increased mortality risk compared with moderate levels (≥ 7% < 8.5%) in patients using regimens that are associated with hypoglycaemia [ 139 ]. High levels of HbA1c were consistently associated with elevated mortality risk in those regimens that have a lower risk of hypoglycaemia.…”

“…High levels of HbA1c were consistently associated with elevated mortality risk in those regimens that have a lower risk of hypoglycaemia. These data suggest that, in the individualisation of glycaemic targets, consideration needs to be given to the classes of glucose-lowering therapy that are being used, with less aggressive targets in those patients who are being treated with therapies associated with hypoglycaemia [ 139 ]. Goals of therapy are, therefore, depends on the metabolic phenotype of the frail older patient with diabetes (Fig.…”

“…The general recommendation by the guidelines for relaxed targets in frail older people should not be applicable to this metabolic phenotype. Lower HbA1c was associated with increased mortality risk compared with moderate control in those regimens associated with hypoglycaemia [ 139 ]. Therefore, the use of GLP-1RAs and SGLT-2 inhibitors are ideal in this phenotype due their lower risk of hypoglycaemia and their properties of reducing cardiovascular risk early on therapy independent of glycaemic control.…”

“…The use of weight limiting agents especially GLP-1RA and SGLT-2 inhibitors should be avoided. As insulin is likely to be used early on in this phenotype, relaxed targets are appropriate as aggressive lowering of HbA1c with hypoglycaemic agents with high hypoglycaemia risk may be associated with increased mortality [ 139 ]. Therefore, deintensification of therapy and a focus on good quality of life are main goals of therapy in this metabolic phenotype.…”

Insulin in Frail, Older People with Type 2 Diabetes—Low Threshold for Therapy

“…Not only glycaemic targets, but also the choice of hypoglycaemic agent and the physical function of the individual, appear to have had an impact on the outcome. It was shown that a lower HbA1c (<7.0%) was associated with an increased mortality risk, compared with moderate levels (≥7.0% <8.5%) in patients using regimens that were associated with hypoglycaemia [54]. High levels of HbA1c were consis-tently associated with an elevated mortality risk in those regimens that had a lower risk of hypoglycaemia.…”