Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis

Abstract

Aims/hypothesis: Sulfonylureas are widely prescribed glucose-lowering medications for diabetes, but the extent to which they improve glycaemia is poorly documented. This systematic review evaluates how sulfonylurea treatment affects glycaemic control.

Methods: Medline, EMBASE, the Cochrane Library and clinical trials registries were searched to identify double-blinded randomised controlled trials of fixed-dose sulfonylurea monotherapy or sulfonylurea added on to other glucose-lowering treatments. The primary outcome assessed was change in HbA1c, and secondary outcomes were adverse events, insulin dose and change in body weight.

Results: Thirty-one trials with a median duration of 16 weeks were included in the meta-analysis. Sulfonylurea monotherapy (nine trials) lowered HbA1c by 1.51% (17 mmol/mol) more than placebo (95% CI, 1.25, 1.78). Sulfonylureas added to oral diabetes treatment (four trials) lowered HbA1c by 1.62% (18 mmol/mol; 95% CI 1.0, 2.24) compared with the other treatment, and sulfonylurea added to insulin (17 trials) lowered HbA1c by 0.46% (6 mmol/mol; 95% CI 0.24, 0.69) and lowered insulin dose. Higher sulfonylurea doses did not reduce HbA1c more than lower doses. Sulfonylurea treatment resulted in more hypoglycaemic events (RR 2.41, 95% CI 1.41, 4.10) but did not significantly affect the number of other adverse events. Trial length, sulfonylurea type and duration of diabetes contributed to heterogeneity.

Conclusions/interpretation: Sulfonylurea monotherapy lowered HbA1c level more than previously reported, and we found no evidence that increasing sulfonylurea doses resulted in lower HbA1c. HbA1c is a surrogate endpoint, and we were unable to examine long-term endpoints in these predominately short-term trials, but sulfonylureas appear to be associated with an increased risk of hypoglycaemic events.

Fig. 1

Flow chart of searches

Fig. 2

Mean difference in change in HbA_1c of sulfonylurea monotherapy treatment vs placebo (boxes) and pooled estimates (diamonds) calculated by the random effects DerSimonian and Laird method. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis

Fig. 3

Mean difference in change in HbA_1c of sulfonylurea treatment added on to another oral treatment vs placebo + other treatment (boxes) and pooled estimates (diamonds) calculated by the random effects DerSimonian and Laird method. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis. Doses in parentheses are doses of troglitazone, the background therapy

Fig. 4

Mean difference in change in HbA_1c of sulfonylurea treatment added on to insulin treatment vs insulin + placebo (boxes) and pooled estimates (diamonds) calculated by the random effects DerSimonian and Laird method. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis

Fig. 5

Mean difference in change in HbA_1c of higher sulfonylurea dose vs lower sulfonylurea dose (boxes) and pooled estimates (diamonds) calculated by the random effects DerSimonian and Laird method, stratified by sulfonylurea type. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis. qd, once daily, bid, twice a day

Fig. 6

Relative risk of total adverse events, serious adverse events and hypoglycaemic events during trials of sulfonylurea treatment vs comparator (boxes) and pooled estimates across trials (diamonds) calculated by the fixed effects inverse variance (I–V) method in patients with diabetes. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the I–V analysis

Fig. 7

(a) Sulfonylurea group−change vs baseline HbA_1c. (b) Comparator group−change vs baseline HbA_1c. (c) Difference in HbA_1c vs mean baseline HbA_1c by treatment type. Circles represent monotherapy trials, triangles represent oral therapy combination trials and diamonds represent insulin combination trials. Marker size is proportional to trial size