Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses
D. S. Lasserson,1P. Glasziou,1R. Perera,1R. R. Holman,2A. J. Farmer1
1Division of Public Health and Primary Health Care, University of Oxford, Oxford, UK, and2Diabetes Trials Unit, Oxford Centre of Diabetes, Epidemiology and Metabolism, University of Oxford, Oxford, UK
Diabetologia 2009; 52: 1990–2000
Background: To compare the effects of different insulin regimens (biphasic, basal or prandial insulin supplementation) on glucose control, clinical outcomes and adverse events in patients with type 2 diabetes.
Methods: A systematic review and meta-analyses of randomised controlled trials reported up to October 2008 were carried out.
Results: Twenty-two trials with altogether 4379 randomised patients were included. Pooled data from insulin-naïve patients were used in the meta-analyses. Using basal insulin supplementation as reference, greater HbA1c reductions were registered with biphasic insulin (0.45%; 95% CI 0.19–0.70, p = 0.0006) and prandial insulin (0.45%; 95% CI 0.21–1.65, p = 0.002), but with smaller decreases in fasting glucose of 0.93 mmol/l (95% CI 0.21–1.65, p = 0.01) and 2.20 mmol/l (95% CI 1.70–2.70, p < 0.00001), respectively. Larger insulin doses at study end were observed with biphasic and prandial insulin regimens. There were no differences between the three insulin regimens with regard to major hypoglycaemic events, whereas minor hypoglycaemic episodes with biphasic or prandial insulin were variably observed as higher than or similar to basal insulin therapy. Compared with basal insulin, prandial insulin therapy resulted in a larger increase in body weight (1.86 kg; 95% CI 0.80–2.92, p = 0.0006).
Conclusions: A more favourable effect on glycaemic control may be achieved by initiating insulin therapy in patients with type 2 diabetes with biphasic or prandial insulin rather than with basal insulin supplementation, but the risk of hypoglycaemia may be increased with the former regimens.
Three-year efficacy of complex insulin regimens in type 2 diabetes
R. R. Holman,1,2A. J. Farmer,2,3M. J. Davies,4J. C. Levy,2J. L. Darbyshire,1,2J. F. Keenan,1,2S. K. Paul,1,2for the 4-T Study Group
1Diabetes Trials Unit,2Oxford Centre for Diabetes, Endocrinology and Metabolism, and3Department of Primary Health Care and National Institute for Health Research, School of Primary Care Research, University of Oxford, Oxford, UK, and4Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
N Engl J Med 2009; 361: 1736–47
Background: To investigate the optimal insulin regimen in patients with type 2 diabetes.
Methods: The three-year, open-label, multicentre trial included patients with type 2 diabetes (n = 708) with suboptimal glycaemic control despite on-going combination therapy with metformin and sulphonylurea. The patients were randomised to insulin therapy based on biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal supplementation with insulin detemir once or twice daily. During the first year, sulphonylurea therapy was substituted by an additional type of insulin in the case of unacceptable hyperglycaemia (HbA1c > 10% or ≥ 8% on two consecutive occasions at or after 24 weeks of therapy), and thereafter if HbA1c was greater than 6.5%. Effects on HbA1c, proportion of patients with HbA1c ≤ 6.5%, hypoglycaemia frequency and body weight were evaluated.
Results: Median HbA1c was similar with the three insulin therapies: biphasic insulin 7.1%, prandial insulin 6.8%, and basal insulin supplementation 6.9%, respectively. Of the patients receiving biphasic insulin 31.9% attained HbA1c ≤ 6.5%, which was less than in the prandial group (44.7%, p = 0.006) and in the basal group (43.2%, p = 0.03). In total, 67.7% in the biphasic, 73.6% in the prandial and 81.6% in the basal insulin group, respectively, received an additional type of insulin (p = 0.002). Median rate of hypoglycaemia was highest in the prandial group (5.7 hypoglycaemic events per patient per year), intermediate in the biphasic group (3.0) and lowest in the basal group (1.7) (p < 0.001). The increase in body weight was higher in the prandial insulin group than in the biphasic and basal insulin groups. No differences in other adverse events were registered.
Conclusions: In patients with type 2 diabetes with inadequate glycaemic control while on combined metformin and sulphonylurea therapy, addition of basal or prandial insulin resulted in better HbA1c control than in those who were given a biphasic insulin regimen. Basal insulin supplementation was associated with fewer hypoglycaemic events and lesser increase in body weight.
- • Comment: Owing to the progressive nature of the disease, many patients with type 2 diabetes will eventually require exogenous insulin supplementation to maintain adequate glucose control. While several types of insulin preparations (human, analogues, various forms of premixed) and a number of different insulin regimens are accessible, the optimal mode of insulin therapy in type 2 diabetes is a matter of uncertainty. Moreover, feasible combination therapies with other glucose-lowering agents as well as unwanted side-effects of the therapy regimens, such as risk of hypoglycaemia and weight gain, need to be considered.
Seemingly, the two referenced studies arrived at contradictory conclusions: the meta-analyses by Lasserson et al. favoured biphasic (premixed) insulin supplementation when combined effects on glycaemic control, risk of hypoglycaemia and weight gain were considered, whereas the prospective trial by Holman and co-workers indicated superior outcomes when insulin therapy was initiated with basal insulin. These dissimilarities may be more apparent than real, however.
The meta-analyses were based on a mixture of short-term studies (3–12 months) in insulin-naïve type 2 diabetes patients who had initiated insulin therapy with conventional or analogue insulins alone or in various combinations with oral hypyglycaemic agents (metformin, sulphonylureas and/or thiazolidinediones). Complete information about titration algorithms, glycaemic targets and insulin doses at study end were not available. Although these variations were accounted for in the statistical evaluation of the data, some of the included trials may have been too short to allow sufficient up-titration of insulin.
The referenced paper by Holman et al. is an extension of the 4-T study, in which patients with inadequate glycaemic control despite maximum tolerable doses of metformin and sulphonylurea were randomised to add-on therapy with biphasic (premixed insulin aspart), prandial insulin aspart or basal insulin supplementation with insulin detemir, using standardised insulin dosing algorithms. The 1-year results of the 4-T study published in 2007 (14) showed that prandial and biphasic insulin therapy resulted in greater reductions in HbA1c levels than basal insulin. The risk of hypoglycaemia and weight gain, on the other hand, were highest in the prandial group, intermediate in the biphasic group, and lowest in patients randomised to basal insulin therapy. Notably, these results were included in the meta-analyses by Lasserson et al., and most probably had a major influence on the outcome of these assessments.
In contrast, in the 3-year evaluation of the 4-T study – which was not included in the meta-analyses – the median HbA1c levels were comparable with the three insulin regimens, albeit with a greater proportion of patients attaining HbA1c ≤ 6.5% in the prandial and basal insulin groups than in the biphasic insulin arm. It should be emphasised that substitution of sulphonylurea therapy with the addition of a second type of insulin supplementation because of insufficient glycaemic control (defined as HbA1c ≤ 6.5%) was necessary in the majority of patients in all three groups; this was done by adding midday prandial aspart insulin in the biphasic group, bedtime basal insulin in the prandial group, and prandial aspart insulin three times daily in the basal insulin group, respectively. This occurred most frequently in the basal insulin group (82%), with intermediate frequency in the prandial group (74%) and least often in the biphasic insulin group (68%). In other words, approximately half the patients in each insulin arm who received additional insulin therapy attained the treatment goal of HbA1c ≤ 6.5%. Hence, within a relatively short period of time, more complex insulin regimens seem to be needed in most patients to maintain the glycaemic target, irrespective of the initial mode of insulin therapy. Considering also the risk of hypoglycaemic events and weight gain, initiating add-on insulin therapy with basal insulin supplementation appears to be a feasible strategy in most patients who fail on oral therapy, with subsequent escalation to basal prandial insulin regimens when needed. Whether this should be carried out with human insulins or with the use of insulin analogues is another disputed issue. However, taking treatment convenience and quality of life aspects into account, less complex biphasic-based insulin regimens may still be appropriate in many cases.