Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus

Simple application of a single daily insulin injection in addition to oral hypoglycaemic agents may facilitate the initiation of insulin therapy in type 2 diabetes mellitus.This review examined 20 trials including 1,811 participants which compared insulin monotherapy with insulin in combination with oral hypoglycaemic agents (OHA) in insulin-requiring patients with type 2 diabetes. The results suggest that a bedtime NPH insulin-oral hypoglycaemic agent combination therapy regimen provides comparable glycaemic control to insulin monotherapy. Due to lack of studies it remains unclear whether insulin-OHA combination regimens with metformin alone are superior to those with metformin plus a sulphonylurea. In most cases no significant differences in hypoglycaemic events were observed between insulin mono- and OHA combination therapy. No study assessed diabetes-related morbidity or mortality.

Authors' conclusions: 

Bedtime NPH insulin combined with oral hypoglycaemic agents provides comparable glycaemic control to insulin monotherapy and is associated with less weight gain if metformin is used.

Read the full abstract...

It is unclear whether patients with type 2 diabetes who have poor glycaemic control despite maximal oral hypoglycaemic agents (OHAs) should be commenced on insulin as monotherapy, or insulin combined with oral hypoglycaemic agents (insulin-OHA combination therapy).


To assess the effects of insulin monotherapy versus insulin-OHA combinations therapy.

Search strategy: 

Eligible studies were identified by searching MEDLINE, EMBASE, and The Cochrane Library.

Selection criteria: 

Randomised controlled trials (RCTs) with 2 months minimum follow-up duration comparing insulin monotherapy (all schemes) with insulin-OHA combination therapy.

Data collection and analysis: 

Data extraction and assessment of study quality were undertaken by three reviewers in pairs.

Main results: 

Twenty RCTs (mean trial duration 10 months) including 1,811 participants, with mean age 59.8 years and mean known duration of diabetes 9.6 years. Overall, study methodological quality was low. Twenty-eight comparisons in 20 RCTs were ordered according to clinical considerations. No studies assessed diabetes-related morbidity, mortality or total mortality. From 13 studies (21 comparisons), sufficient data were extracted to calculate pooled effects on glycaemic control. Insulin-OHA combination therapy had statistically significant benefits on glycaemic control over insulin monotherapy only when the latter was applied as a once-daily injection of NPH insulin. Conversely, twice-daily insulin monotherapy (NPH or mixed insulin) provided superior glycaemic control to insulin-OHA combination therapy regimens where insulin was administered as a single morning injection. In more conventional comparisons, regimens utilising OHAs with bedtime NPH insulin provided comparable glycaemic control to insulin monotherapy (administered as twice daily, or multiple daily injections). Overall, insulin-OHA combination therapy was associated with a 43% relative reduction in total daily insulin requirement compared to insulin monotherapy. Of the 14 studies (22 comparisons) reporting hypoglycaemia, 13 demonstrated no significant difference in the frequency of symptomatic or biochemical hypoglycaemia between insulin and combination therapy regimens. No significant differences in quality of life related issues were detected. Combination therapy with bedtime NPH insulin resulted in statistically significantly less weight gain compared to insulin monotherapy, provided metformin was used ± sulphonylurea. In all other comparisons no significant differences with respect to weight gain were detected.