In the name of

GOD

Sara Sadri

Long-acting insulin analogues versus NPH human insulin intype 2 diabetesA meta-analysis

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 ?

PICOPATIENT OR PROBLEMA 50 years old woman known case of diabet type 2 that diabet not controlled with metformin INTERVENTIONStart Insulin GlarginCOMPERTIONInsulin NPHOut comes Witch of insulin is the best choice for this patient

Insulin Glargine Insulin NPH

Basal 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 . .

Introduction

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 .

The two currently available insulin analogues,

glargine and detemir, could have different

effects on body weight the 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

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.

. Research design and methods

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.

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).

. Results

The 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.

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

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 .

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 .

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 not

reach statistical significance . Symptomatic

hypoglycemic episodes were reported in seven

trials .

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 .

. Discussion

Long-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.

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 .

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; this

somewhat aggressive approach may reduce potential

differencesin efficacy between treatments.

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.

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;

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.

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.

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.

– Differences (with 95%CI) between long-actinganalogues and NPH insulin in the incidence of any, severe,symptomatic, and nocturnal hypoglycaemia.

– Differences (with 95%CI) between long-actinganalogues and NPH insulin in the effects on HbA1c atendpoint.

– Differences (with 95%CI) between long-actinganalogues and NPH insulin in the effects on BMI atendpoint.

Thanks a lot