D I A B E T E S M E L L I T U S UNIT NO. 3 P H A R M A C O L O G Y O F O R A L A N T I - H Y P E R G L Y C A E M I C A G E N T S & I N S U L I N Dr Loh Keh Chuan ABSTRACT ORAL ANTI-HYPERGLYCAEMIC AGENTS Patients with type 2 diabetes require oral Currently available oral agents for the treatment of type 2 antihyperglycaemic drug therapy when diet and exercise diabetes include sulphonylureas, meglitinides, biguanide, fail to control glycaemia. As type 2 diabetes is a progressive thiazolidinediones, and alpha-glucosidase inhibitors. condition in which beta-cell function deteriorates with increasing duration of diabetes, stepwise therapy with Sulfonylureas multiple pharmacologic agents is often needed over time Sulphonylureas (e.g. tolbutamide, chlorpropamide, to maintain target glucose control. Currently available oral glibenclamide, glipizide, gliclazide, glimepiride) are oral agents for the treatment of type 2 diabetes include insulin secretagogues which stimulate insulin release via sulphonylureas, meglitinides, biguanide, thiazolidinediones, activation of sulfonylurea receptor (SUR1) on the membrane and alpha-glucosidase inhibitors. All oral anti- of pancreatic b-cells. SUR1 is closely coupled to the ATP- hyperglycaemic agents are currently not approved by the sensitive, inward rectifying potassium KATP channel on the US FDA for use in pregnant women with gestational or pancreatic b-cells. Under the normal resting state, the KATP type 2 diabetes. The risks of medications are often channel opens with efflux of potassium. Activation of the increased with advancing age. Therefore, it is often safer SUR1 leads to closure of the KATP channel. By inhibiting to consider initial low-dose, short-acting oral anti- the efflux of potassium, the b-cell membrane depolarizes hyperglycemic agents in the elderly. Metformin is the only and opens the voltage-sensitive calcium channels. The oral anti-hyperglycemic agent approved by the US FDA for resultant calcium influx leads to a series of intracellular use in children with type 2 diabetes. Ultimately, up to 40% events that culminates in insulin secretion. of type 2 patients may require insulin therapy, often in Sulfonylureas remain as a cornerstone class of drugs combination with oral agents, to achieve desired targets of for treatment of type 2 diabetes. They are potent insulin glycaemic control. Only recombinant human insulin is secretagogues with mean HbA1c reduction of 1.5-2% recommended for pregnant women as well as women reduction when used alone. As type 2 diabetes is a contemplating pregnancy. degenerative metabolic condition with progressive decline in pancreatic b-cell function over time, sulfonylureas are effective only if the patient still has adequate pancreatic b- INTRODUCTION cell reserves. Patients with type 2 diabetes require oral antihyperglycaemic Chlorpropamide is a first generation sulfonylurea that drug therapy when diet and exercise fail to control has largely fallen out of favour due to significant adverse glycaemia. As type 2 diabetes is a progressive condition in effects, especially severe and protracted hypoglycaemia and which beta-cell function deteriorates with increasing the syndrome of inappropriate anti-diuretic hormone duration of diabetes, stepwise therapy with multiple (SIADH) secretion. The newer generation sulfonylureas pharmacologic agents is often needed over time to maintain generally have more acceptable side-effects profiles. target glucose control. Ultimately, up to 40% of type 2 However, hypoglycaemia remains a major concern, patients may require insulin therapy, often in combination particularly with long-acting agents (e.g. glibenclamide) or with oral agents, to achieve desired targets of glycaemic short-acting drugs with active metabolites that have long control. half-life (e.g. glipizide). This article is focused on reviewing the pharmacology of currently available oral anti-hyperglycaemic agents as Meglitinides well as insulin preparations for treatment of patients with Meglitinides are short-acting non-sulfonylurea insulin type 2 diabetes. The clinical issues in pharmacotherapy of secretagogues (e.g. nateglinide, repaglinide) which become diabetes (e.g. when to initiate therapy, role of combination available over the last few years. These drugs have unique therapy, treatment targets, etc.) will not be discussed here. rapid onset of action and are developed to target at postprandial hyperglycaemia. Like sulfonylureas, meglitinides stimulate insulin secretion by closing the KATP channels on the membrane of LOH KEH CHUAN, Consultant Endocrinologist, Mount the pancreatic b-cell via activation of the benzamido site Elizabeth Medical Centre on the SUR1. Its unique pharmacokinetic profile of rapid T H E S I N G A P O R E F A M I L Y P H Y S I C I A N O C T - D E C 2 0 0 4 ; V O L 3 0 ( 4 ) : 1 6 P H A R M A C O L O G Y O F O R A L A N T I - H Y P E R G L Y C A E M I C A G E N T S & I N S U L I N absorption coupled with extensive hepatic biotransformation the expression of a large array of genes involved in adipocyte translates into a drug with rapid-onset and rapid-offset differentiation and modulation of insulin sensitivity. effect. This property makes it an ideal prandial glucose Glitazones shows high affinity for PPARg receptor and regulator, targeting at the postprandial hyperglycaemia constitute a new class of drug to reduce insulin resistance. caused by blunted “first phase” insulin secretion in patients Because its action is mediated through gene transcription, with type 2 diabetes. Meglitinides can be taken just before the onset of action is slow and it may take up to 2-3 months the meal, thus allowing greater flexibility in mealtimes. before maximal anti-hyperglycaemic action becomes Because of its short duration of action, it has lower tendency evident. Glitazones achieve mean HbA1c reduction of 1- to induce hypoglycaemia and weight gain as compared to 1.5%. sulfonylureas. Like biguanides, glitazones do not affect insulin Although meglitinides are generally safe and effective secretion. Its predominant antiglycaemic action is via with mean reductions in HbA1c up to 1-2%, it may not increased expression of glucose transporters for peripheral provide adequate control of post-absorptive or fasting glucose uptake. Glitazones also reduce hepatic glucose hyperglycaemia when used alone in patients with type 2 output by inhibiting gluconeogenesis. Troglitazone was the diabetes. prototype PPARg agonist first introduced in 1997; this drug was subsequently withdrawn from the market in March 2000 Biguanide because of its potential in causing fatal hepatotoxicity. Metformin is the only safe biguanide for clinical use after Rosiglitazone and pioglitazone are the currently available the withdrawal of phenformin and buformin due to the glitazones for the treatment of type 2 diabetes, though only potentially high risks of lactic acidosis. Nevertheless, rosiglitazone is available in Singapore. metformin has remained one of the cornerstone drugs for The adverse effects of glitazones include oedema, treatment of obese type 2 diabetic patients. anaemia, and weight gain. Unlike troglitazone, Although the exact cellular mechanism of metformin hepatotoxicity is rare in the second generation glitazones. action is unclear, it primarily reduces hyperglycaemia by As a precautionary measure, liver enzyme measurement is reducing hepatic glucose output. This is achieved by recommended pre-treatment, and on periodic basis whilst inhibition of gluconeogenesis, and to a lesser extent glycogen on treatment. Because of fluid retention, glitazones are breakdown, by the liver. Secondarily, it also enhances contraindicated in patients with moderate to severe cardiac peripheral glucose disposal and delays glucose absorption failure. from the small intestine. Besides improving glycaemic control, metformin leads to favourable reductions in serum Alpha-glucosidase Inhibitors triglycerides concentrations via decreases in very low density Alpha-glucosidase inhibitors slow the digestion and lipoprotein (VLDL) synthesis, as well as mild decrease in absorption of dietary polysaccharides by reversibly total cholesterol and slight increase in high density inhibiting the carbohydrate-digesting enzymes (amylase, lipoprotein (HDL) levels. sucrase, maltase, isomaltase) and thereby attenuating Unlike the insulin secretagogues, metformin may postprandial glycaemic excursions. This class of drugs delays reduce body fat mass and produce weight loss in obese the absorption of postprandial blood glucose via a non- subjects. The UK Prospective Diabetes Study (UKPDS) systemic action, with digestion of carbohydrates most demonstrated particular benefit of metformin therapy in significantly retarded in the duodenum and jejunum. obese diabetics over the use of sulfonylureas or insulin However, its glucose-lowering effect is only modest with therapy in reducing diabetes-related complications. mean HbA1c reduction of 0.5-1.0%. Alpha-glucosidase Metformin is contraindicated in any conditions that inhibitors are associated with a high prevalence of predispose an individual to lactic acidosis; e.g. renal failure, gastrointestinal side-effects like diarrhea, abdominal chronic hypoxaemic states, septicaemia, etc. Because of discomfort and flatulence. the potential danger of acute renal failure precipitated by Acarbose is the prototype alpha-glucosidase inhibitor intravenous iodinated contrast administration, patients are and the only one available locally. Two newer drugs, miglitol advised to temporarily