Managing hyperglycaemia in patients with type 2 diabetes and known cardiovascular disease

People with type 2 diabetes are more likely to develop cardiovascular disease (CVD), and are more likely to have adverse outcomes following acute myocardial infarction (AMI). There is considerable uncertainty about the management of hyperglycaemia following AMI, due to the inconsistent findings of the Diabetes Insulin Glucose Acute Myocardial Infarction (DIGAMI) studies. ^1,2 A number of recent randomized controlled trials (RCTs) also suggest that certain hyperglycaemic therapies may increase cardiovascular risk in diabetes subjects with known CVD. ³ Moreover, some studies have raised concerns that tight glycaemic control may be deleterious in older patients with established or subclinical CVD. ⁴

Immediate management of hyperglycaemia in patients with type 2 diabetes during AMI

Hyperglycaemia on admission in people with AMI increases death and morbidity. The DIGAMI study aimed to determine whether tight glycaemic control during, and post AMI would improve outcomes. ¹ Six hundred and twenty patients with diabetes and AMI were randomized to intensive insulin therapy (intravenous glucose-insulin-potassium [GIK] infusion followed by subcutaneous insulin for at least three months) or conventional therapy (no insulin therapy unless the patients clinical state absolutely required) if admission glucose was above 11 mmol/L. In-hospital and three-month mortality were not significantly different, but at one year, mortality in the control group was 26.1% versus 18.6% in the infusion group (relative risk reduction 29% [95% confidence interval 4–51%, P = 0.0273]).

DIGAMI 2 was undertaken to test this finding in a larger group, and to establish whether the initial, or subsequent glucose control was important in reducing mortality. ² A total of 1253 patients with diabetes and AMI were randomized to: acute insulin infusion followed by insulin-based long-term glucose control; insulin glucose infusion followed by standard glucose control; routine metabolic management. No difference in mortality or CVD outcomes was seen between the groups at one year.

Similarly inconclusive results were seen in the Hyperglycaemia: Intensive Insulin Infusion in Infarction (HI-5) study, ⁵ which aimed to randomize 850 subjects with AMI and admission glucose >7.8 mmol/L to intravenous glucose-insulin for 24 hours maintaining glucose under 10 mmol/L, or conventional therapy (supplemental insulin if blood glucose went above 16 mmol/L). Only 240 patients were randomized, and no significant difference in mortality to six months was seen, although there was less heart failure and re-infarction in the intensive therapy group. Similar negative findings have been published from a multicentre study in Latin America using glucose-insulin-potassium (GIK) infusions immediately post AMI. ⁶

Revert guidelines from the National Institute for Health and Clinical Excellence (NICE) suggest that hyperglycaemia (blood glucose concentration >11.0 mmol/L) in patients admitted to hospital for acute coronary syndrome should be managed by keeping blood glucose concentrations to below 11.0 mmol/L while avoiding hypoglycaemia with a dose adjusted insulin infusion and regular monitoring of blood glucose. ⁷

Management of hyperglycaemia in type 2 diabetic patients with established cardiovascular disease

Recent studies have added to the controversy over the management of hyperglycaemia in type 2 diabetic patients with known established CVD. A number of large RCTs of intensive versus non-intensive glycaemic control have been undertaken. Ten-year follow-up of the UK Prospective Diabetes Study shows that, despite early loss of glycaemic differences between the tight and conventionally treated groups, a risk reduction for myocardial infarction and mortality is seen, particularly with metformin therapy. ⁷ In contrast, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study suggested an increase in deaths in people subjected to very tight glycaemic control (glycated haemoglobin [HbA_1c] ≤6.0% [48 mmol/mol]). ⁴ Observational study of the effect of glucose lowering treatment in 28,000 patients with type 2 diabetes suggested HbA_1c concentration of 7.5% (58 mmol/mol) was associated with the lowest mortality. ⁸

There is concern that some hyperglycaemic therapies may increase cardiovascular risk, such as sulphonylureas and insulin therapy. ³ Concerns over rosiglitazone and excess risk of CVD have led to the drug being withdrawn. With this in mind, it has been suggested that licensing of newer hyperglycaemic drugs should only be undertaken when they have demonstrated improved cardiovascular outcomes in people with diabetes. ⁹ New classes of hyperglycaemic agents have been launched (glucagon-like peptide-1 inhibitors, dipeptidylpeptidase-4 inhibitors), and new classes are on the way (sodium glucose transporter-2 inhibitors – dapagliflozin). While these newer agents have a positive impact on body weight, they have yet to demonstrate cardiovascular benefits in patients with diabetes, with or without CVD. Their use, therefore, in such patients should be undertaken with caution.

What should we do in practice?

Based upon current observational data, it is reasonable to treat hyperglycaemia (glucose >11 mmol/L) with intravenous insulin, aiming for glucose <11 mmol/L in people admitted with AMI for the first 24 hours of their admission, avoiding hypoglycaemia. Thereafter, individualized glycaemic management is necessary, based on duration of diabetes, other co-morbidities (such as microvascular disease) and age. Metformin should be continued in patients post AMI if not contraindicated, particularly in patients with heart failure. Glitazones are absolutely contraindicated. There is no justification for withholding sulphonylureas or pioglitazone in AMI patients based on current evidence, but further study of these drugs is required.

There is a growing consensus that tight glycaemic control may be beneficial in primary prevention of CVD in younger patients with diabetes, but may become deleterious in older patients with established or subclinical CVD. ¹⁰ NICE guidelines for the management of type 2 diabetes suggest a target glycated haemoglobin of 6.5% for most people with type 2 diabetes, but an individual glycated haemoglobin target level, may be ‘above that of 6.5% set for people with type 2 diabetes in general’. Many clinicians are increasingly concerned about tight glycaemic control having an adverse impact on patients with established CVD. ¹¹ In such patients, prioritizing lifestyle change (exercise, diet and smoking) with careful management of hypertension and lipids should be the priority. Glycaemic management should aim to reduce risk of microvascular disease, without significantly increasing hypoglycaemia. A target glycated haemoglobin of 7.5% (58 mmol/mol) may be the most sensible to achieve this aim.

DECLARATIONS

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TAC

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Both authors contributed equally

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