RISK OF ADVERSE-EFFECTS OF INTENSIFIED TREATMENT IN INSULIN-DEPENDENTDIABETES-MELLITUS - A METAANALYSIS

While the benefits of intensified insulin treatment in insulin-depende nt (Type 1) diabetes mellitus (IDDM) are well recognized, the risks ha ve not been comprehensively characterized. We examined the risk of sev ere hypoglycaemia, ketoacidosis, and death in a meta-analysis of rando mized controlled trials. The MEDLINE database, reference lists, and sp ecialist journals were searched electronically or by hand to identify relevant studies with at least 6 months of follow-up and the monitorin g of glycaemia by glycosylated haemoglobin measurements. Logistic regr ession was used for calculation of combined odds ratios and 95 % confi dence intervals (95 % CI). The influence of covariates was examined by including covariate-by-treatment interaction terms. Methodological st udy quality was assessed and sensitivity analyses were performed. Four teen trials were identified. These contributed 16 comparisons with 102 8 patients allocated to intensified and 1039 allocated to conventional treatment. A total of 846 patients suffered at least one episode of s evere hypoglycaemia, 175 patients experienced ketoacidosis and 26 pati ents died. The combined odds ratio (95 % CI) for hypoglycaemia was 2.9 9 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for death from al l causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was determ ined by the degree of normalization of glycaemia achieved (p = 0.005 f or interaction term), with the results from the Diabetes Control and C omplications Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the type of intensified treatment used. Odds ratios ( 95 % CI) were 7.20 (2.95-17.58) for exclusive use of pumps, 1.13 (0.15 -8.35) for multiple daily injections and 1.28 (0.90-1.83) for trials o ffering a choice between the two (p = 0.004 for interaction). Mortalit y was significantly (p = 0.007) increased for causes potentially assoc iated with acute complications (7 vs 0 deaths, 5 deaths attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p = 0.16) d ecreased for macrovascular causes (3 vs 8 deaths). We conclude that th ere is a substantial risk of severe adverse effects associated with in tensified insulin treatment. Mortality from acute metabolic causes is increased; however, this is largely counterbalanced by a reduction in cardiovascular mortality. The excess of severe hypoglycemia in the DCC T is not exceptional. Multiple daily injection schemes may be safer th an treatment with insulin pumps. (C) 1997 by John Wiley & Sons, Ltd.