Status of Oral Hypoglycaemics in Diabetes Mellitus

STATUS OF ORAL HYPOGLYCAEMICS IN DIABETES MELLITUS

After 8 years of prospective study involving large number of patients, the University Group Diabetes Programme (UGDP) of USA (1970) presented findings that cardiovascular mortality was higher in patients treated with oral hypoglycaemics than in those treated with diet and exercise alone or with insulin. A decline in their use followed. Subsequent studies both refuted and supported these conclusions.

The controversy has now been settled; UK PDS found that both sulfonylureas and metformin did not increase cardiovascular mortality over > 10 years observation period. Related to degree of glycaemia control, both insulin and sulfonylureas reduced microvascular complications in type 2 DM, but did not have significant effect on macrovascular complications. Metformin, however, could reduce macrovascular complications as well; it decreased risk of death and other diabetes related endpoints in overweight patients. This may be related to the fact that both sulfonylureas and exogenous insulin improve glycaemic control by increasing insulin supply rather than by reducing insulin resistance, while metformin can lower insulin resistance. The thiazolidinediones are another class of drugs which reverse insulin resistance, and have been found to reduce macrovascular complications and mortality in type 2 DM. All oral hypoglycaemics do however control symptoms that are due to hyperglycaemia and glycosuria, and are much more convenient than insulin.

Oral hypoglycaemics are indicated only in type 2 diabetes, when not controlled by diet and exercise. They are best used in patients with—

       i.            Age above 40 years at onset of disease.

     ii.            Obesity at the time of presentation.

  iii.            Duration of disease < 5 years when starting treatment.

   iv.            Fasting blood sugar < 200 mg/dl.

      v.            Insulin requirement < 40 U/day.

   vi.            No ketoacidosis or a history of it, or any other complication.

Introduced in the prediabetic ‘impaired glucose tolerance phase’, sulfonylurea + dietary regulation has been shown to postpone manifest type 2 DM. This may be due to the fact that hyperglycaemia is a self perpetuating condition. The Diabetes Prevention Programme (2002) has established that in middle aged, obese prediabetics metformin prevented progression to type 2 DM, but not in older nonobese prediabetics. Glitazones appear to have similar potential. Longterm acarbose therapy can also prevent type 2 DM.

Oral hypoglycaemics should be used to supplement dietary management and not to replace it. Metformin is preferred in obese type 2 patients: its anorectic action aids weight reduction and it has the potential to lower risk of myocardial infarction and stroke. The g.i. tolerance of metformin is poorer and its patient acceptability is less than that of sulfonylureas. Moreover, the sulfonylureas appear to produce greater blood sugar lowering. As such, many patients are treated initially with a sulfonylurea alone. Metformin can be used to supplement sulfonylureas in patients not adequately controlled by the latter.

There is no difference in the clinical efficacy of different sulfonylureas. This however does not signify that choice of drug is irrelevant. Differences between them are mainly in dose, onset and duration of action which governs flexibility of regimens. The second generation drugs are dose to dose more potent, produce fewer side effects and drug interactions, and are commonly used, but no spectacular features have emerged.

Chlorpropamide is not recommended because of long duration of action, greater risk of hypoglycaemia, jaundice, alcohol flush, dilutional hyponatraemia and other adverse effects. Tolbutamide is less popular due to low potency, but may be employed in the elderly to avoid hypoglycaemia. Glibenclamide and glyclazide are suitable for most patients, but have been found to cause hypoglycaemia more frequently. Glipizide is preferred when a faster and shorter acting drug is required. Glimepiride is a newer sulfonylurea, claimed to have stronger extrapancreatic action by enhancing GLUT4 translocation to the plasma membrane, thus causing lesser hyperinsulinaemia.

A low incidence of hypoglycaemic episodes has been reported with glimepiride. This may be due to its ability to preserve hypoglycaemia induced glucagon release and suppression of insulin release, responses that are attenuated by glibenclamide. Glimepiride is suitable for once daily dosing due to gradual release from tissue binding.

Even in properly selected patients, sulfonylureas may fail from the beginning (primary failure 5–28%) or become ineffective after a few months or years of satisfactory control (secondary failure 5–10% per year): may be due to progressive loss of β cells, reduced physical activity, continuing insulin resistance, drug and dietary noncompliance or desensitization of receptors. If one sulfonylurea proves ineffective in a patient, another one (especially a second generation) may still work. Combined use of a sulfonylurea and a biguanide may be tried if either is not effective alone and the glitazones are now available as add on/alternative drugs. Patients with marked/only posprandial hyperglycaemia may be treated with repaglinide/ nateglinide. Upto 50% patients of type 2 DM initially treated with oral hypoglycaemics ultimately need insulin. Despite their limitations, oral hypoglycaemics are suitable therapy for majority of type 2 DM patients. However, when a diabetic on oral hypoglycaemics presents with infection, severe trauma or stress, pregnancy, ketoacidosis or any other complication or has to be operated upon—switch over to insulin (see Fig. 19.5).

Sulfonylureas and metformin can also be combined with insulin, particularly when a single daily injection of longacting insulin is used to provide basal control, the oral hypoglycaemics given before meals serve to check postprandial glycaemia.

Guargum

It is a dietary fibre (polysaccharide) from Indian cluster beans (Guar), which forms a viscous gel on contact with water. Administered just before or mixed with food, it slows gastric emptying, intestinal transit and carbohydrate absorption: postprandial glycaemia is suppressed but overall lowering of blood glucose is marginal. It also reduces serum cholesterol by about 10%.

Guargum can be used to supplement diet and to lower sulfonylurea dose, and as a hypocholesterolemic. It is not absorbed but fermented in the colon. Side effects are flatulence, feeling of fullness, loss of appetite, nausea, gastric discomfort and diarrhoea. Start with a low dose (2.5 g/day) and gradually increase to 5 g TDS.

DIATAID, CARBOTARD 5 g sachet.

Glucomannan

This powdered extract from tubers of Konjar is promoted as a dietary adjunct for diabetes. It swells in the stomach by absorbing water and is claimed to reduce appetite, blood sugar, serum lipids and relieve constipation.

DIETMANN 0.5 g cap, 1 g sachet; 1 g to be taken before meals.