Effects of Drugs on Glucose Tolerance in Non-Insulin-Dependent Diabetics (Part I)

Summary

Non-insulin-dependent diabetes mellitus (NIDDM) is being increasingly diagnosed as its importance as a risk factor for the development of cardiovascular disease continues to be recognised. Good metabolic control remains a major goal of drug therapy as it decreases the severity and incidence of diabetic complications. Many drugs have been known to interfere with glucose control, either in a beneficial or, more commonly, in a deleterious fashion. Unfortunately in many instances drug-induced effects have not been looked at specifically in NIDDM.

Thiazide diuretics have been shown to cause a deterioration in glucose control not only in the general population but especially in patients who have impaired glucose tolerance. While the effect appears less with potassium supplementation and the lower dosage employed nowadays, thiazide diuretics are best avoided in diabetic patients. Loop diuretics have been reported to reduce glucose control to a lesser extent than thiazides. Although indapamide would appear not to interfere with blood sugar control in NIDDM, higher doses that cause potassium loss may cause a deterioration.

β-Adrenoceptor antagonists have been reported to cause a rise in blood sugar and glycosylated haemoglobin in NIDDM. The effect may be more marked in patients on oral hypoglycaemic agents as opposed to diet alone and in those on concomitant thiazide diuretics. The greatest effect was seen with propranolol, and the least with cardioselective and the less lipophilic β-blockers. It is of interest that α-blockade with prazosin seems to antagonise β-adrenoceptor blocker-induced deterioration in glucose control.

The calcium antagonists have differing effects which may be structure related. In some, but not all, studies use of the dihydropyridines such as nifedipine has been associated with a deterioration in glucose control in NIDDM. Long term studies are needed to assess definitively their effect on glucose control. Verapamil, on the other hand, has in 1 small study been found to have a beneficial effect on glucose control in NIDDM.

Centrally acting α-agonists such as the antihypertensive drug clonidine have not been shown to result in a deterioration in glucose control when used in NIDDM, although there are isolated case reports. Long term therapy with the more specific agonist guanfacine was reported in 1 uncontrolled study to have a beneficial effect on glucose tolerance in NIDDM. Uncontrolled studies suggest that phenothiazines may aggravate diabetic control.

The significance of a number of recent observations is not fully clear. The balance of endogenous opioid influences over pancreatic β-cell function in NIDDM patients favours the inhibitory effects of met-enkephalin, and the opiate antagonist naloxone partially restores the acute insulin response to glucose. Aspirin appears to have a dual effect in NIDDM — decreased insulin clearance and tissue sensitivity — with no resultant overall change in glucose levels.

There are also a number of drugs that may improve glucose tolerance in NIDDM. A number of studies have reported a fall in glycosylated haemoglobin and 2-hour plasma glucose during treatment with the angiotensin converting enzyme (ACE) inhibitors captopril (post glucose load) and enalapril (postprandial), although the effect is relatively small and nonsignificant in some studies. There are also reports of a reduction in fasting plasma glucose and insulin levels during treatment with the lipid-lowering fibric acid derivatives (clofibrate, bezafibrate and fenofibrate) and possibly nicotinic acid derivatives, suggesting increased tissue sensitivity to insulin. The effect was not seen with gemfibrozil and other lipid-lowering agents.

Mebendazole, through insulin secretion, and chloroquine, through reduced hepatic degradation of insulin, have been shown in 2 small studies to improve glucose tolerance in NIDDM. While induction of hepatic drug metabolising enzyme activity has been advanced as a means of improving glucose control, possibly through enhanced peripheral glucose utilisation, studies to date in NIDDM have produced contradictory results. A number of uncontrolled studies suggest that both monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may improve glucose tolerance.

Close monitoring of glucose and glycosylated haemoglobin is recommended where the abovementioned drugs are used in NIDDM. There is evidence that possible effects of new drugs in NIDDM are being recognised increasingly as a requirement in new drug development, particularly with cardiovascular agents.