Drug review Oral antidiabetic drugs

Oral antidiabetic drugs: their properties and recommended use

Ian Campbell FRCP
Skyline Imaging Ltd

There are now five classes of oral antidiabetic drugs available, with metformin remaining the cornerstone of drug therapy in type 2 diabetes. Our Drug review considers their mode of action, properties and recommended use, followed by sources of further information, an analysis of prescription data and the Datafile.

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iabetes mellitus is now recognised as a major world-wide public health problem. At present about 150 million people have diabetes mellitus, a figPrescriber 19 March 2007

ure that is estimated to reach 250-300 million by the year 2010. In the UK approximately 3 per cent of the population have recognised diabetes mellitus, and another 3 per cent will have unrecognised type 2 diabetes. This rise in type 2 diabetes is a result of high calorie intake, limited physical activity and obesity, with about 70-80 per cent of type 2 diabetes patients being overweight. The treatment of type 2 diabetes is not purely a matter of glucose control, and it is recognised that morbidity and premature mortality are closely related to the different components of type 2 diabetes, which is now often referred to as the metabolic syndrome or insulin resistance syndrome. In addition to hyperglycaemia, these components include
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Oral antidiabetic drugs

Class Sulphonylureas

Examples gliclazide, glibenclamide, glipizide, glimepiride repaglinide, nateglinide metformin pioglitazone, rosiglitazone acarbose

Principal mode of action stimulate insulin secretion (acting 12-24 hours)

Postprandial glucose regulators Biguanide Thiazolidinediones Alpha-glucosidase inhibitor

stimulate insulin secretion (short acting, <6 hours) improves insulin action PPAR-gamma agonists, increase insulin action slows down rate of carbohydrate ingestion

Table 1. Available oral antidiabetic agents and their mode of action

central obesity, hypertension, dyslipidaemia (raised triglycerides and small, dense LDL and lowered HDL) and a procoagulant state. Therefore any treatment plan for type 2 diabetes patients also requires weight loss where obesity occurs, blood pressure reduction, plasma lipid abnormalities to be corrected, and antiplatelet agents to be prescribed according to national guidelines.1,2 Such an integrated approach will be beneficial and is now well recognised in clinical practice.
Oral antidiabetic drugs

(Starlix). These two agents are rapidly absorbed and also quickly eliminated, so that their insulin-secreting effect is short lived, with a maximum effect at two to four hours and a duration of less than six hours. Drugs that reduce insulin resistance: metformin and thiazolidinediones Metformin Metformin is the only biguanide in the UK. It increases insulin action at some unknown intracellular locus, and has no direct action on the pancreatic beta-cells. In type 2 diabetes, the main action of metformin is to potentiate the action of insulin, thus decreasing hepatic glucose production by reducing both gluconeogenesis and glycogenolysis. In addition metformin improves peripheral glucose utilisation in muscle. Metformin is particularly useful for obese type 2 diabetes patients as it does not cause weight gain, but rather a little weight loss. The United Kingdom Prospective Diabetes Study (UKPDS) showed that, compared with conventional treatment with diet, metformin reduced the risk of diabetes-related deaths by 42 per cent and reduced myocardial infarction (MI) by 39 per cent over a 10year follow-up period.4 These benefits were not seen in overweight type 2 diabetes subjects given a sulphonylurea or insulin therapy. This vascular-protective effect of metformin has now established it as the drug of choice in type 2 diabetes patients with a BMI >25 where diet and lifestyle measures fail to achieve glycaemic control. Thiazolidinediones: pioglitazone (Actos) and rosiglitazone (Avandia) These drugs are also known as TZDs or glitazones. They act at the level of the genome, modifying the transcription of a number of genes that regulate insulin action and lipid metabolism. The TZDs are ligands for peroxisome proliferator-activated receptor gamma (PPAR-gamma). The PPARwww.escriber.com

As part of this integrated approach to reduce cardiovascular risk in type 2 diabetes patients, glycaemic control is important. There are five classes of oral antidiabetic drugs available for lowering blood glucose (see Table 1). Insulin secretagogues: sulphonylureas and postprandial glucose regulators Two of the classes, sulphonylureas and postprandial glucose regulators, are insulin secretagogues. These agents act at the ATP-dependent potassium channel in the beta-cell membrane to stimulate insulin secretion from the pancreas. Gliclazide, glibenclamide, glimepiride and glipizide are the most commonly used sulphonylureas in the UK, stimulating insulin secretion for 12-24 hours. Gliclazide and glipizide are given twice daily, glibenclamide and glimepiride once daily. The other group of insulin secretagogues are known as postprandial glucose regulators or meglinitides.3 The former name is used as the insulin secretion profile coincides with meal digestion some one to two hours after eating. In the UK there are two postprandial glucose regulators, repaglinide (Prandin) and nateglinide
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Oral antidiabetic drugs

gamma receptors are located in the nucleus of the cell and their activation by TZDs improves insulin action to increase glucose uptake in muscle and suppress hepatic glucose output; TZDs also decrease plasma free fatty acids, decrease plasma triglycerides (pioglitazone but not rosiglitazone), raise HDL cholesterol by 10-20 per cent, and raise plasma LDL cholesterol by 5-15 per cent but reduce the atherogenic small, dense LDL particles. Alpha-glucosidase inhibitors: acarbose (Glucobay) Acarbose is the only available alpha-glucosidase inhibitor. It inhibits alpha-glucosidase enzymes, which break down oligosaccharides into monosaccharides in the small intestine. Acarbose lowers postprandial blood glucose by competing with dietar y carbohydrate for the alpha-glucosidase enzymes, hence delaying glucose absorption. As monotherapy, acarbose, like metformin, will not cause hypoglycaemia or weight gain.
Efficacy

insulin sensitivity) and beta-cell dysfunction. At diagnosis in type 2 diabetes, both insulin sensitivity and beta-cell production of insulin are about 50 per cent of normal. The latter further declines by 4-5 per cent per year over the next five to six years. When 80-90 per cent of beta-cell production of insulin is lost, there is then insufficient endogenous insulin for the oral antidiabetic drugs to be effective, even in combination, and it is at this stage that insulin therapy is necessary to maintain adequate glycaemic control. Sulphonylureas, metformin and acarbose have been available for many years. Postprandial glucose regulators and TZDs are newer agents, and whether their earlier use in combination with metformin will delay insulin therapy remains to be seen (see below).
Side-effects and drug interactions with oral antidiabetic drugs

The side-effects of the oral antidiabetic drugs are summarised in Table 2. Sulphonylureas Hypoglycaemia and weight gain are the most common side-effects of sulphonylureas. Sulphonylureainduced hypoglycaemia is particularly important in older people, in whom an incorrect diagnosis of transient ischaemic attack (TIA) or cerebrovascular accident may be made. The diagnosis of hypoglycaemia should be considered in any diabetic subject treated
Metformin TZDs Acarbose

All the oral antidiabetic drugs mentioned above have about the same blood glucose-lowering effect when the clinical trial results are reviewed. Within the first two to three years of diagnosis, they will lower fasting plasma glucose by about 2-4mmol per litre, the postprandial glucose levels by 4-6mmol per litre and the glycated haemoglobin (HbA1c) by 1.5-2 per cent. Type 2 diabetes is a progressive condition. It has a dual abnormality of insulin resistance (diminished
Side-effect Sulphonylureas

Postprandial glucose regulators + +

hypoglycaemia GI symptoms weight gain oedema lactic acidosis hypersensitivity cholestasis folate, B12 malabsorption

++ + + +

+ + +

+ +

++

Table 2. Side-effects of oral antidiabetic agents

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with a sulphonylurea who develops signs of altered behaviour. The action of sulphonylureas may be prolonged in patients with liver or renal impairment. In these situations, gliclazide may be preferred as less than 5 per cent of this drug is excreted unaltered in the urine. Glibenclamide should be used with caution in older people as it is the most likely to cause hypoglycaemia. Postprandial glucose regulators Hypoglycaemia and weight gain are again the most significant side-effects of postprandial glucose regulators, although both are less severe than with the sulphonylureas due to the shorter duration of action of repaglinide and nateglinide. These can be used in patients with renal impairment as they are metabolised in the liver and excreted in the faeces. Metformin GI side-effects, with anorexia, abdominal discomfort and diarrhoea, and a metallic taste in the mouth (due to the drug being concentrated in salivary glands) can occur with metformin. If metformin is started at a dose of 500mg daily and built up slowly, and the tablets taken after meals, less than 5 per cent will be intolerant of the drug. A slow-release preparation of metformin is now available (Glucophage SR) which reduces the frequency of these GI side-effects by up to 50 per cent. Metformin-associated lactic acidosis is well recognised but rare if the prescribing recommendations are adhered to, namely to exclude patients with liver and renal disease and withdrawal of the drug in patients with severe acute illness that can cause hypoxia, especially respiratory or acute cardiac failure. The drug may be used in stable cardiac decompensation. Age is not a contraindication to metformin use as was once thought, provided the renal function is satisfactory with a serum creatinine level below 130mol per litre. Thiazolidinediones The original TZD troglitazone was withdrawn because of hepatotoxicity, but there is no such reported adverse hepatic effects with either pioglitazone or rosiglitazone. However it is recommended that liver function tests (LFTs) are carried out at the start of therapy. The original recommendation that twomonthly LFTs should be done for the first year of therapy have now relaxed and it is probably satisfactory to check the LFTs on an annual basis. If the alanine transaminase (ALT) is more than twice normal before therapy, then TZDs should not be started, and they should be stopped if the ALT rises to more than three times normal during treatment.
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Decreased antihyperglycaemic effect furosemide not bumetanide thiazides

Increased antihyperglycaemic effect warfarin salicylates fibrates

Blunt hypoglycaemia response beta-blockers clonidine

steroids MAOIs phenytoin rifampicin

Table 3. Drug interactions with sulphonylureas

The cautious use of glitazone therapy can be considered in patients with mild hepatic dysfunction as many of these cases will have nonalcoholic steatohepatitis (NASH) and the TZDs can improve hepatic function in these cases. Regular monitoring of LFTs is required in these situations, and observance of current indications for discontinuation of therapy applied if necessary. The other side-effects of the TZDs are weight gain, usually 3-4kg in the first six months of therapy, mild peripheral oedema in up to 5 per cent of patients, and a mild dilutional anaemia in some patients. TZDs should not be prescribed for patients with congestive cardiac failure and significant fluid retention.5 Acarbose The principal side-effects, seen in about 20-25 per cent of patients, are GI with flatulence, abdominal discomfort and diarrhoea. These side-effects are due to undigested carbohydrate from the small bowel reaching the colon and may be reduced in frequency with a low starting dose followed by a gradual increase. In high doses of 300mg three times daily, there may be a mild rise in liver transaminases.
Important drug interactions

Of the five classes of oral antidiabetic drugs described, important drug interactions are only seen with sulphonylureas. The drugs that antagonise and potentiate the sulphonylureas, as well as drugs that mask the awareness of impending hypoglycaemic, are summarised in Table 3.
Recommended management of type 2 diabetes

National clinical guidelines have been issued for blood glucose management using antidiabetic drugs.6 The
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Monotherapy first agent metformin

Combination therapy agent to add pioglitazone+ or rosiglitazone sulphonylurea, repaglinide or nateglinide acarbose metformin pioglitazone or rosiglitazone acarbose metformin* sulphonylurea, repaglinide or nateglinide acarbose sulphonylurea, repaglinide or nateglinide metformin

sulphonylurea or postprandial glucose regulator pioglitazone or rosiglitazone

However the postprandial glucose regulators may have a role to play when younger patients have a lifestyle with variable eating patterns as the drugs can be taken immediately before a meal, and in older patients where there may be a risk of hypoglycaemia with sulphonylureas, especially if there is impaired renal function. Thiazolidinediones The National Institute for Health and Clinical Excellence (NICE) has recommended that TZDs be used only as combination therapy, with metformin in obese patients if a combination of metformin with a sulphonylurea is not appropriate and with sulphonylureas if metformin is not appropriate.7 However, since the NICE guidance was issued, both TZDs have been granted licences for monotherapy if metformin is inappropriate. This is likely to confuse prescribers until NICE updates its guidance, which was expected in July 2006 but is now not due until early 2008. The potential value for TZDs is that there is good scientific evidence that they have pleiotrophic actions that may prevent the progression of atherosclerosis.8 The NICE guidance in 2003 recommends relatively limited use of these drugs based on the fact that there were as yet no end-point studies at that stage to show that TZDs reduce microvascular or macrovascular complications or how they will perform in this respect against metformin or sulphonylureas. In the meantime there have been four major new studies involving TZDs. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study9 showed that pioglitazone in type 2 diabetes subjects with macrovascular disease caused a 16 per cent decrease in the principal secondary end-point of death, heart attack and stroke. The Carotid intima-media tHICkness in Atherosclerosis using pioGlitazOne (CHICAGO) study 10 showed that pioglitazone, but not the
Sulphonylureas: recommended use sulphonylureas should be used with metformin in overweight or obese people when glucose control becomes unsatisfactory sulphonylureas should be considered as an option for first-line therapy when metformin is not tolerated or is contraindicated, and in people who are not overweight a generic sulphonylurea should normally be chosen a long-acting sulphonylurea may be useful when compliance is a problem

acarbose

+Competact

(combination of metformin and pioglitazone) now available

Avandamet (combination of metformin and rosiglitazone) now available

Table 4. Oral antidiabetic drugs that can be used together in combination therapy (based on current European licensing)

recommendations for the five classes of oral antidiabetic drugs will be discussed. Metformin The UKPDS has provided evidence that early intensive control with metformin in overweight type 2 diabetes subjects is a particularly effective approach to reduce vascular complications and improve survival.4 Metformin therapy is therefore the cornerstone of type 2 diabetes management with oral antidiabetic drugs. Sulphonylureas The sulphonylureas have been the most commonly prescribed antidiabetic agent until the UKPDS results, but have now been overtaken by metformin as the first-line drug of choice. However they are still widely prescribed and a sulphonylurea prescribed with metformin is the most commonly used antidiabetic drug combination at present. Postprandial glucose regulators Repaglinide and nateglinide have not been widely prescribed since their introduction compared to the longer-acting sulphonylureas. They are relatively expensive drugs and are seen as being very similar to the older sulphonylureas in terms of their pharmacological action. The lesser risk of hypoglycaemia is not seen to be of major benefit as most GPs do not see the severe hypoglycaemia when the sulphonylureas (other than glibenclamide) are prescribed.
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Oral antidiabetic drugs

Postprandial glucose regulators: recommended use the same recommendations as for sulphonylureas are given for insulin secretagogues in general, but it is clearly stated that the insulin secretagogue choice should be a generic sulphonylurea, eg gliclazide or glipizide rapidly-acting insulin secretagogues, eg repaglinide or nateglinide, may have a role in attaining tight glucose control in patients with nonroutine daily patterns

comparator sulphonylurea agent glimepiride, showed a regression in carotid atherosclerotic disease using carotid ultrasonography to measure carotid intimamedia thickness (CIMT). The Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study 11 showed that rosiglitazone could reduce the progression to type 2 diabetes in patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). However, rosiglitazone is not currently licensed for use in IFG or IGT. The ADOPT (A Diabetes Outcome Progression Trial) study12 showed that rosiglitazone as monotherapy sustained glycaemic control better than metformin or glibenclamide monotherapy over a mean period of four years. The mean HbA1c was 0.13 per cent less than the rosiglitazone group at four years compared with the metformin group and 0.42 per cent less compared with the glibenclamide group. These small changes in glycated haemoglobin would suggest, in the authors opinion, that metformin should still remain the treatment of choice when starting drug therapy in type 2 diabetes, but a TZD would be a preferred combination agent with metformin. The DREAM and ADOPT studies support beta-cell preservation by TZDs in type 2 diabetes with better sustained glycaemic control;13 the PROactive and CHICAGO studies support a role for TZDs in preventing macrovascular disease, the principal killer in type 2 diabetes.
Metformin: recommended use in people who are overweight (BMI >25) and whose blood glucose is inadequately controlled using lifestyle interventions alone, metformin should normally be used as the first-line glucose-lowering therapy metformin should be considered as an option for firstline or combination therapy for people who are not overweight

NICE also highlights that there is no evidence that TZDs are of added benefit when given as triple therapy with metformin and a sulphonylurea, although both pioglitazone and rosiglitazone now have a licence for triple therapy. In the authors experience, this triple combination works very well in some patients but not others, and there is no harm in giving this therapy a trial if the diabetes patient is reluctant to consider insulin therapy. The PROactive study showed that pioglitazone added to metformin and sulphonylurea therapy could delay the progression to insulin by up to 50 per cent over three years.9 The author prefers the Association of British Clinical Diabetologists (ABCD) position statement in 2004 on glitazones as giving a better guide to the clinical use of these agents,14 with the new approved indication that pioglitazone may be used in conjunction with insulin therapy where there is insufficient glycaemic control on insulin when metformin is inappropriate because of contraindications or intolerance. The combination of pioglitazone and insulin may reduce the dosage of insulin required in obese insulinresistant type 2 diabetes subjects who require insulin for glycaemic control. It is important to remember that after starting TZDs, there may be a delay of six to eight weeks before their full effect is seen due to their mode of action of inducing transcription of genes that regulate proteins involved in insulin action and lipid metabolism. Acarbose Acarbose lowers blood glucose in type 2 diabetes patients as a single agent or in combination therapy, but because it has a high incidence of GI side-effects its use has been much less than metformin and sulphonylureas.
Achieving best practice

For practical purposes the aim in clinical practice when treating type 2 diabetes patients is to achieve an HbA1c of 7 per cent or less, except in older patients or those with severe co-morbidities where acceptable control is met by simply keeping the patient free of hyperglycaemic symptoms and ignoring tight HbA1c targets. The UKPDS showed that less than 50 per cent of patients treated with either metformin or a sulphonylurea will reach a 7 per cent HbA1c target at three years after diagnosis15 and it is becoming increasingly recognised that early combination therapy is necessary.16 Table 4 gives a simple outline of those antidiabetic drugs that can be used together for combination therapy.
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Oral antidiabetic drugs

Thiazolidinediones (TZDs): recommended use (adapted from reference 14) addition of TZD to metformin is preferred second-line oral antidiabetic therapy in obese type 2 diabetes TZDs should be considered as monotherapy in those patients unable to take metformin consider TZDs in place of metformin in renal impairment triple therapy with a TZD plus metformin plus a sulphonylurea may be considered in obese patients or those patients unwilling to consider insulin therapy pioglitazone may be used with insulin where metformin has contraindications or intolerance; if such treatment is considered in severe case of insulin resistance, watch for oedema and heart failure

Alpha-glucosidase inhibitors: recommended use acarbose may be considered as an alternative glucoselowering therapy in type 2 diabetes patients unable to use other drugs

There are no clinical trials to show which drug combination is best. Meglitinides and acarbose are not commonly prescribed and at the present time the choice lies between the traditional metformin plus sulphonylurea or the newer combination of metformin plus a TZD. The addition of a sulphonylurea to metformin has been shown in a retrospective analysis to offer maintained control for as little as six months before deterioration in control occurs. 17 Therefore the combination of a TZD plus metformin offers an alternative that is being increasingly used. Pioglitazone has lipid advantages compared with rosiglitazone, especially with regard to benefits in triglycerides and HDL,18 which are still seen when patients are on statin therapy.19 The traditional treatment approach to management of newly diagnosed type 2 diabetes has been to start with diet and lifestyle advice, then when glycaemic control is lost to progress to monotherapy, usually with metformin, and after some years to combination therapy with a sulphonylurea. This failure-orientated strategy is better replaced by an intensive goal-orientated strategy to treat early for success rather than to await failure.16 In a recent study performed in the authors unit, a combination of metformin plus pioglitazone was prescribed in addition to lifestyle advice for newly diagnosed type 2 diabetes subjects at diagnosis (if HbA1c >8 per cent), or three to six months after diagnosis if HbA1c >7 per cent. This combination was compared with metformin plus gliclazide and metformin plus repaglinide. Over a three-year follow-up period those patients treated with the metformin/pioglitazone combination showed a 0.1 per cent increase in HbA1c per year compared with a 0.5 per cent increase seen in the other two combinations, suggesting there are beta-cell prowww.escriber.com

tective properties with the pioglitazone therapy.20 This is in keeping with the ADOPT trial results mentioned above.12 The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have proposed a treatment algorithm for type 2 diabetes mellitus (see Figure 1),21 advocating metformin at diagnosis with lifestyle measures. The authors preference at three to six months after diagnosis is to then move on to a metformin/pioglitazone combination where the HbA1c is above 7 per cent, based on experience with other drug combinations followed up for three years after diagnosis (see above).20 There is no danger of hypoglycaemia when metformin and a TZD are used in combination at such an early stage as they are both insulin sensitisers. When treating to target there is always a risk of hypoglycaemia where metformin is used in combination with an insulin secretagogue or insulin itself. This is the authors personal view but is a treatment regimen that will maintain glycaemic control much longer than that seen in the UKPDS study and sustain good glycaemic control with a delay in the need for insulin therapy.
Newer drugs

Newer agents will become available in the UK in 2007 to aid in the management of type 2 diabetes and these new drugs will need to be evaluated, especially against metformin, the TZDs and sulphonylureas. Exenatide is an injectable peptide, a glucagon-like peptide-1 (GLP-1) analogue that is effective against beta-cell dysfunction and promotes weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors, also known as gliptins, are oral agents to reduce the degradation of endogenous GLP-1 as well as decreasing appetite. Two examples of these DDP-4 inhibitors are sitagliptin and vildagliptin. Type 2 diabetes subjects are often obese and rimonabant (Acomplia) is a satiety-inducing cannabinoid-1 receptor antagonist, now available in the UK, that can promote weight loss in type 2 diabetes subjects and also improve glycaemic and lipid control.
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lifestyle + metformin

HbA1c 7%

add sulphonylurea

add basal insulin

add TZD

HbA1c 7%

add TZD

add basal insulin

intensify insulin

add sulphonylurea

add basal insulin

HbA1c 7%

further intensify insulin or add basal insulin + metformin +/- TZD

Figure 1. Simplified ADA-EASD consensus algorithm for type 2 diabetes (adapted from reference 21)

References

1. British Cardiac Society, British Hypertension Society, Diabetes UK, et al. JB2: Joint British Societies guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(suppl 5):V1-V52. 2. NICE. Clinical Guideline H. Management of type 2 diabetes: management of blood pressure and lipids. London: NICE, 2002. 3. Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001;358:1709-16. 4. United Kingdom Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65. 5. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive cardiac failure. A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004;27: 256-63. 6. NICE. Clinical Guideline G. Management of type 2 diabetes: management of blood glucose. London: NICE, 2002. 7. NICE. Technology Appraisal 63. Guidance on the use of glitazones for the treatment of type 2 diabetes. London: NICE, 2003. 8. Patel CB, De Lemos JA, Wyne KL, et al. Thiazo66 Prescriber 19 March 2007

lidinediones and risk for atherosclerosis : pleiotrophic effects of PPar gamma agonism. Diab Vasc Dis Res 2006;3:65-71. 9. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondar y prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89. 10. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid initima-media thickness in type 2 diabetes: a randomised trial. JAMA 2006;296:2572-81. 11. The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368: 1096-105. 12. Kahn SE, Haffner SM, Heise MA, et al. Glycaemic durability of rosiglitazone, metformin or glyburide monotherapy. N Eng J Med 2006;355:2427-43. 13. Leiter LA. Beta-cell preservation: a potential role for thiazolidinediones to improve clinical care in type 2 diabetes.
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Diabetic Med 2005;22:963-72. 14. Higgs ER, Krentz AJ, on behalf of the Association of British Clinical Diabetologists. ABCD position statement on glitazones. Pract Diab Int 2004;21(8):293-5. 15. Turner RC, Cull CA, et al; for the UK Prospective Diabetes Study Group. Glycaemic control with diet, sulfonylurea, metformin or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies. JAMA 1999;281:2005-12. 16. Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000;7: 625-31. 17. Cook MN, Girman CJ, Stein PP, et al. Glycaemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes. Diabetes Care 2005;28:995-1000. 18. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycaemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidaemia.

Diabetes Care 2005;28:1547-54. 19. Berhanu P, Kipnes MS, Khan MA, et al. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diab Vasc Dis Res 2006;3:39-44. 20. Chalmers J, Hunter JE, Robertson SJ, et al. Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes. Submitted for publication, 2007. 21. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2006;49:1711-21.

Professor Campbell is consultant physician at Victoria Hospital, Kirkcaldy, and honorary professor in the Department of Biological Sciences, Bute Medical School, University of St Andrews

Resources
Further reading BMJ Collected Resources. All articles published in the BMJ on diabetes since January 1998. http://www. bmj.com/collections. Management of hyperglycaemia in type 2 diabetes: the end of recurrent failure. Heine RJ, Diamant M, Mbanya J-C, et al. BMJ 2006;333:1200-4. NICE Technology Appraisal 63. Glitazones in the treatment of type 2 diabetes. 2003. www.nice.org.uk/cat. asp?c=83263. Clinical Guideline E. Management of type 2 diabetes retinopathy. 2002. www.nice.org.uk/cat. asp?c= 27915. Clinical Guideline F. Management of type 2 diabetes renal disease, prevention and early management. 2002. www.nice.org.uk/cat.asp?c=39385. Clinical Guideline G. Management of type 2 diabetes blood glucose. 2002. www.nice.org.uk/cat. asp?c= 36733. Clinical Guideline H. Management of type 2 diabetes blood pressure and blood lipids. 2002. www.nice. org.uk/cat.asp?c=38551.
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Groups and organisations Diabetes UK offers help and information to diabetes patients and supports research into the condition. They also produce publications for patients and health professionals. Diabetes UK Central Office, Macleod House, 10 Parkway, London NW1 7AA; tel: 020 7424 1000; fax: 020 7424 1001; e-mail:info@diabetes.org.uk. Website: www.diabetes.org.uk. Diabetes Insight (www.diabetes-insight.info) produces publications and provides support for patients with diabetes and information for healthcare professionals. Diabetes Monitoring Forum (www.dmforum.org.uk) helps patients to understand the role of blood glucose and ketone monitoring in diabetes management and produces a series of advice leaflets. E-mail: info@dmforum.org.uk. Guidance PRODIGY guidance diabetes type 2 (blood glucose management). www.prodigy.nhs.uk. Patient information Diabetes and oral hypoglycaemic agents. PatientUK factsheet: www.patient.co.uk/showdoc/40001626/. Treatments for type 2 diabetes. PatientUK factsheet. www.patient.co.uk/showdoc/27000260/.
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Prescription review
Prescribing of oral antidiabetic agents has increased significantly over the last five years from 2.5 million items a quarter to 4.5 million (see Figure 2). The biggest growth has been in the use of metformin, and prescriptions for the glitazones and the glitazone/
Items (millions) 5

metformin combinations have also increased. Sulphonylurea prescribing has remained steady. Looking at costs the picture is very different. Despite accounting for over 80 per cent of items, metformin and sulphonylureas only make up under 50 per cent of costs (see Figure 3). The glitazones and glitazone/metformin combinations are responsible for most of the steep rise in spending on oral diabetic drugs in recent years.

sulphonylureas biguanides (metformin) pioglitazone and rosiglitazone nateglinide and repaglinide other antidiabetics rosiglitazone with metformin

0 2001 2002 2003 2004 Year, by quarter 2005 2006

Figure 2. Number of prescriptions for oral antidiabetic drugs in England by quarter, 2001-06

NIC (millions) 50 sulphonylureas biguanides (metformin) pioglitazone and rosiglitazone nateglinide and repaglinide other antidiabetics rosiglitazone with metformin

40

30

20

10

0 2001 2002 2003 2004 Year, by quarter 2005 2006

Figure 3. Cost of prescriptions for oral antidiabetic drugs in England by quarter, 2001-06
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Datafile
Oral antidiabetic drugs
Drug group alpha-glucosidase inhibitor Drug acarbose Available as Glucobay Form/strength 50mg, 100mg tabs Typical dosage 50-100mg 3 times daily Cost1 6.16-11.68

biguanides

metformin

Glucophage SR

500mg sust-rel tabs

Glucophage metformin

500mg, 850mg tabs 500mg, 850mg tabs

1 tab daily, increasing dose by 1 tab at 10-15 day intervals to max. 4 tabs daily 500mg 3 times daily or 850mg twice daily

3.20-12.80

2.88-3.20 2.33-2.36

sulphonylureas

glibenclamide

gliclazide

Daonil Semi-Daonil glibenclamide Diamicron MR Diamicron gliclazide Amaryl glimepiride

5mg tabs 2.5mg tabs 2.5mg, 5mg tabs 30mg mod-rel tabs 80mg tabs 80mg tabs 1mg, 2mg, 3mg, 4mg tabs 1mg, 2mg, 3mg, 4mg tabs 5mg tabs 2.5mg, 5mg tabs 5mg tabs 30mg tabs 500mg tabs

5-15mg daily

glimepiride

30-120mg daily 40-320mg daily (in divided doses above 160mg) 2-4mg daily

2.69-8.07 3.46-10.38 1.44-4.32 3.08-12.32 1.06-8.51 0.96-3.88 6.93-13.83 6.30-12.61

glipizide

gliquidone tolbutamide

Glibenese Minodiab glipizide Glurenorm tolbutamide

2.5-20mg daily (in divided doses above 15mg) 45-60mg daily in divided doses 500mg-1.5g daily in divided doses

1.09-8.72 1.48-5.04 1.28-10.24 7.37-9.82 2.54-7.62

postprandial repaglinide glucose regulators nateglinide

Prandin Starlix

0.5mg, 1mg, 2mg tabs 0.5-4mg before each main meal 60mg, 120mg, 180mg 120mg before meals tabs only in combination with metformin

10.98-21.95 22.50

thiazolidinediones

pioglitazone rosiglitazone

Actos Avandia

15mg, 30mg, 45mg tabs 4mg, 8mg tabs

15-30mg once daily 4-8mg once daily or in divided doses

24.14-33.54 24.74-50.78

1NHS

cost of 28 days treatment at the dosage shown. Prices MIMS/Drug Tariff, January 2007

www.escriber.com

Prescriber 19 March 2007

73

Oral antidiabetic drugs

Datafile
Oral antidiabetic drugs (cont.)
Drug group thiazolidinedione plus biguanide Drug pioglitazone plus metformin rosiglitazone plus metformin Available as Competact Avandamet Form/strength Typical dosage Cost1 31.56 27.71-52.45 15mg plus 850mg tabs 1 tab twice daily 2mg plus 500mg tabs 1 x 2mg plus 1000mg 2mg plus 1000mg tabs tab twice daily; if 4mg plus 1000mg tabs greater glycaemic control is required increase to 1 x 4mg plus 1000mg tab twice daily after 8 weeks

1NHS

cost of 28 days treatment at the dosage shown. Prices MIMS/Drug Tariff, January 2007

Forthcoming events
The Forthcoming events section highlights some of the many courses, meetings and conferences of interest to the GP and pharmacist planned over the coming months
Postmenopausal Health
Date: 16-18 April Venue: Royal College of Obstetricians and Gynaecologists Website (for registration): www.rcog.org.uk/meetings Presentations on current issues relating to postmenopausal health and management of the menopause. Follows the recommended syllabus of the BMS/RCOG Menopause Special Skills Module.

Second Meeting of the UK PD Non Motor Group: Non Motor Symptom Complex of Parkinsons Disease
Date: 21 April Venue: Royal Society of Medicine Website (for registration): www.pdnmg.com An international panel will provide an up-to-date summary of various aspects of nonmotor symptoms of PD that affect the day-to-day life of people with Parkinsons, carers and the treating healthcare professionals.

conditions and infections and immunisations; in womens health, polycystic ovarian syndrome, amenorrhoea, contraception and HRT.

BMJ Masterclass for GPs: Respiratory Medicine

Date: 2 May Venue: Manchester Email: masterclasses@ bmjgroup.com Website: www.bmjmaster classes.com/GPs For GPs and nurse prescribers, including managing asthma and COPD in primary care; managing allergic conditions, including asthma and rhinitis; investigation and treatment of patients with pneumonia, bronchiectasis, and tuberculosis; and the role of oxygen therapy. Anyone who wishes to publicise details of events for GPs and pharmacists (at no charge) should e-mail them to: prescriber@wiley.co.uk
www.escriber.com

GP Update Series: Dermatology

Date: 18 April Venue: Kings College London Telephone: 020 7188 7147 Email: cppe-gpcourses@kcl.ac.uk Website: www.gstt.nhs.uk/cppe Aiming to provide GPs with current information on conditions that commonly require referral advice. With a focus on relevant QOF targets, the courses typically comprise presentations, workshops and Q&A sessions.
74 Prescriber 19 March 2007

BMJ Masterclass for GPs: Paediatrics and Womens Health

Date: 1 May Venue: Manchester Email: masterclasses@ bmjgroup.com Website: www.bmjmaster classes.com/GPs Including, in children, constipation, lactose intolerance, atopic