(1) There are few clinical trials comparing combination
therapy with a sulphonylurea and
metformin after oral
antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of
insulin therapy in patients in whom oral
antidiabetic therapy fails is based solely on
surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose
glucose levels were no longer controlled by a sulphonylurea, the addition of
metformin or a daily injection of
insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However,
metformin caused less
weight gain. (4) There are no randomised controlled trials comparing the addition of
insulin versus a sulphonylurea when ongoing
metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus
metformin, adding a daily
insulin injection is more effective in lowering HbA1c levels than the addition of
acarbose and as effective as adding a glitazone. The adjunction of
insulin appears to have a better risk-benefit balance than an oral three-
drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral
antidiabetic to ongoing
insulin therapy reduces HbA1c levels in patients with
type 2 diabetes. The addition of
metformin is also beneficial in terms of
body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with
metformin, have compared the addition of a bedtime injection of
insulin isophane versus replacement of the oral
antidiabetics by several daily
insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less
weight gain when the oral
antidiabetics were continued and a single
insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea,
metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of
insulin isophane. (9)
Insulin isophane is the first-choice
insulin for combination
therapy with an oral
antidiabetic. In comparative trials, when combined with an oral
antidiabetic,
insulin glargine was no more effective than
insulin isophane in terms of HbA1c levels or
weight gain.
Insulin glargine seems to provoke less hypoglycaemia but, in the absence of adequate follow-up, its
long-term adverse effects are not known. (10) When a bedtime
insulin injection plus an oral
antidiabetic fail to control hyperglycaemia, indirect comparisons support the use of several daily
insulin injections plus
metformin, or three
injections of an ultrarapid
insulin analogue plus a sulphonylurea.