2 Long-acting insulin analogues versus NPH human insulin in type 2 diabetes A meta-analysis Sara Sadri
3 case scenarioA 50 years old woman who is known case of diabet type 2 with uncontrolled diabet despite use of metformin TDS, now we want to start basal insulin for her.Which type of insulin is the best choice for treatment the patient ?
4 PICO PATIENT OR PROBLEM A 50 years old woman known case of diabet type 2 that diabet not controlled with metforminINTERVENTIONStart Insulin GlarginCOMPERTIONInsulin NPHOut comesWitch of insulin is the best choice for this patient
8 IntroductionBasal insulin can be provided using either NPH human insulin or long-acting insulin analogues. Analogues, which are more expensive than NPH insulin, should warrant a greater reproducibility of absorption after subcutaneous injection, providing better metabolic control with reduced hypoglycemic risk ..
9 A recent meta-analysis of eight randomized clinical trials failed to detect any difference in HbA1c, while confirming an advantage with regard to incidence of hypoglycemia.Some further trial has been published in the last few months, potentially adding relevant information .
10 The two currently available insulin analogues, glargine and detemir, could have different effects on body weightthe aims of the present meta-analysis is the assessment of differences with respect to weight gain between NPH human insulin and each long-acting analogue.This parameter had not been considered in the meta-analysis cited above
11 . Research design and methods A meta-analysis was performed including all randomized clinical trials, either with a cross-over or a parallel series design, enrolling patients with type 2 diabetes, with a duration of at least 12 weeks, comparing a long-acting insulin analogue (detemir or glargine) and human NPH insulin, either combined with oral hypoglycemic agents or with a prandial insulin comparable in all treatment arms.
12 Trials with a shorter duration were excluded, due to the fact that they could not yield relevant information on glycated hemoglobin, which had been chosen as the principal outcome variable.An extensive Medline search for ‘‘detemir’’ and ‘‘glargine’’ was performed, collecting all randomized clinical trials on humans up to 10th February 2008.
13 The principal outcome was the effect of long-acting analogues, compared with NPH human insulin, on HbA1c at the end of the trial. Secondary outcomes included body mass index (BMI) at the end of the trial. Furthermore, data on the incidence of symptomatic, nocturnal, severe, or any hypoglycemia(number of patients with at least one event) were extracted. Whenever possible, separate analyses were performed for trials with different insulin analogues (detemir and glargine).
15 . ResultsThe trial flow is summarized in Fig. 1, and the characteristics of the trials included in the meta-analysis are summarized in Table 1, while outcomes are reported in Table 2 Of the 14 retrieved trials, which were all open-label, three reported a significant improvement of HbA1c with analogues ,while in the remaining 11 studies no difference was detected between groups with respect to HbA1c.
16 Overall , long-acting analogues did not produce any significant improvement of HbA1c, in comparison with NPH human insulin. When trials with different analogues were analysed separately, NPH showed a significant superiority (by 0.1%) over detemir, but not over glargine
17 Two out of three trials with detemir , and one out of 11 trials with glargine , reported a significantly smaller weight gain in comparison with NPH insulin. BMI at the end of the trial was reported in 11 trials; combining the results of those studies, detemir, but not glargine, was associated with a significantly smaller weight gain than human insulin .
18 The total number of patients reporting at least one episode of hypoglycemia was reported only in six studies ;meta-analysing those results, long-acting analogues were associated with a significant reduction of hypoglycemic risk in comparison with NPH insulin .
19 The incidence of severe hypoglycemia was reported by all trials except 5,with a total number of patients experiencing at least one episode of 32 and 36 in the analogue and NPH group, respectively; the difference between treatment arms did notreach statistical significance . Symptomatic hypoglycemic episodes were reported in seven trials .
20 while the incidence of nocturnal hypoglycemia was described for all trials except 4 . For both these parameters, long-acting analogues showed a significant advantage over NPH insulin .
23 . DiscussionLong-acting insulin analogues have been suggested as an alternative to NPH insulin in the treatment of both type 1 and type 2 diabetes . The higher cost of these drugs should be justified by a greater reproducibility of absorption, leading to better glycemic control and reduced risk of hypoglycemia.
24 Although some trials showed a reduction in HbA1c with long-acting analogues in comparison with NPH , no such difference was detected when combining the results of all available studies. This result confirms a previous metaanalysis performed on a smaller number of trials .
25 It should be considered that many of the recent trials on basal insulin in type 2 diabetes are performed following the so-called ‘‘treat to- target’’ scheme, which provides algorithms based on fasting glucose for an adjustment of insulin doses; thissomewhat aggressive approach may reduce potential differencesin efficacy between treatments.
26 Once the desired glycemic target has been reached, the drug to be preferred should be the one associated with the lowest hypoglycemic risk. The present meta-analysis confirms that long-acting analogues are associated with a significant reduction in the rate of overall, nocturnal and symptomatic hypoglycemia, as previously reported in patients with type 2 and type 1 diabetes.No difference was detected for severe hypoglycemia,but this could be due to the relatively small number of events.
27 Detemir, unlike glargine, appears to determine a smaller weight gain in comparison with NPH insulin, as previously suggested by the results of two trials .This observation is consistent with the results of a direct comparison between the two long-acting insulin analogues, showing a similar efficacy on HbA1c, with smaller weight gain for detemir .The difference in BMI between detemir and NPH insulin is relatively small;
28 Some limitation of this meta-analysis should be recognized. Most of the trials were sponsored by manufacturers of long-acting analogues. Furthermore, the description of trials in available papers was often inadequate.
29 Differences in the criteria used for the definition of hypoglycemia should also be considered when interpreting results on the rates of nocturnal, symptomatic, or any hypoglycemia; the only consistent definition of hypoglycemia across trials is that of severe hypoglycemia, i.e. low blood glucose requiring help from a third party.
30 In conclusion, the use of long-acting insulin analogues in type 2 diabetic patients does not seem to provide a better glycemic control in comparison with NPH insulin, whereas it reduces the risk of nocturnal and symptomatic hypoglycemia.Detemir, but not glargine, could be associated with smaller weight gain than NPH insulin. Further studies are needed to assess possible differences among long-acting analogues.
31 – Differences (with 95%CI) between long-acting analogues and NPH insulin in the incidence of any, severe,symptomatic, and nocturnal hypoglycaemia.
32 – Differences (with 95%CI) between long-acting analogues and NPH insulin in the effects on HbA1c atendpoint.
33 – Differences (with 95%CI) between long-acting analogues and NPH insulin in the effects on BMI atendpoint.