Summary

Diabetes is a common disabling disease worldwide. It is characterized by heterogeneous degrees of insulin hyposecretion and/or insulin resistance. The incidence of diabetes is increasing and it is one of the leading causes of morbidity and mortality.

This article reviews the pharmacological and clinical aspects of various commonly used oral antidiabetic drugs. Family physicians should be aware of their pharmacology, adverse effects and drug interactions in daily practice.

摘要

在世界各地，糖尿病是甚為普遍而可導致殘障的疾病。其特點是患者均有不同程度的胰島素分泌不足及/或對其產生抗性。糖尿病的發病率正不斷上升，而它亦是引致死亡和多種病患的主原。

本文綜述了各種常用口服糖尿病藥物，包括其藥理學和臨床上的使用。家庭醫生須對這些藥物的藥理、副作用及與其他藥物的相互作用有深入的認識。

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Introduction

Diabetes is a heterogeneous metabolic disorder characterized by various degrees of insulin hyposecretion and/or insulin resistance. It is chronic, progressive, and is associated with elevated blood glucose level, micro- and macrovascular complications causing cardiovascular disease, renal failure, retinopathy and neuropathy. The two main types of diabetes are type 1 (insulin-dependent) and type 2 (non-insulin dependent). The aetiology of the less common type 1 diabetes, is not fully understood. But genetic and environmental factors together with an autoimmune process occurring in the pancreatic islets are believed to be associated with its development.¹ Type 1 diabetes is a T-cell-mediated autoimmune disorder.¹ b-cells destruction in type 1 diabetes usually leads to absolute insulin deficiency.¹ In contrast, type 2 diabetes is more common and accounts for about 90% of all cases.⁶ Its prevalence is increasing worldwide. The disorder is most often diagnosed in patients older than 40 years of age, but there is a shift towards younger ages.^2,6 The pathophysiology of glucose intolerance in type 2 diabetes is complex and involves both genetic and acquired factors such as obesity and physical inactivity.¹⁷ It is characterized by insulin resistance in liver and muscles and impaired insulin secretion by pancreatic b-cells.¹⁷ As diabetes is a leading cause of morbidity and mortality, and insulin resistance is the core pathophysiology of type 2 diabetes, it is important that insulin resistance should be identified and corrected early in order to limit the cascade of sequel and co-morbid disease. The current treatment of type 2 diabetes includes diet, exercise, oral antidiabetic drugs and insulin. This article reviews the pharmacological and clinical aspects of various commonly used oral antidiabetic drugs in type 2 diabetes.

Pathogenesis of type 2 diabetes

Under normal circumstances, when blood glucose concentrations are high, the pancreatic beta cells will respond with appropriate insulin secretion, promoting transport of glucose into cells and reducing release of glucose by the liver.³ Many tissues have insulin receptors which bind with insulin reversibly. The biological response to insulin can be changed by alteration of insulin receptors sensitivity or changes in number of insulin receptors.¹² The number of insulin receptors is decreased in chronic exposure to high insulin levels and in obesity.¹² Obesity is associated with a hyperinsulinaemia, insulin resistance and reduced number of insulin receptors.¹² Considerable evidence also implicates that deranged adipocyte metabolism and altered fat topography are associated with the pathogenesis of glucose intolerance in type 2 diabetes. Fat cells are resistant to insulin's antilipolytic effect, resulting in day-long elevations of the plasma free fatty acid concentration, which fail to suppress normally following ingestion of a mixed meal or glucose load or in response to insulin.¹⁷ These abnormalities in free fatty acid metabolism have been documented in individual with impaired glucose tolerance and nondiabetic, insulin resistant obese individuals.^17,18 Chronically elevated plasma free fatty acid concentrations can cause insulin resistance in muscle and liver^17,18,20 and impaired insulin secretion in genetically predisposed individuals.^17,22 These free fatty acids induced metabolic disturbances are known as lipotoxicity.¹⁷ In insulin resistance, metabolically active tissues (i.e. skeletal muscle, adipose tissue and hepatocytes) become more resistant to insulin, resulting in decreased glucose uptake and increased hepatic glucose production. Initially, there is compensatory pancreatic beta-cell insulin hypersecretion in response to insulin resistance.⁴ Overtime, beta-cell decompensation occurs, thereby resulting in impaired glucose tolerance, presenting with hyperglycaemia, especially after meals (postprandial hyperglycaemia).^3,4 With progressive beta-cell failure, fasting hyperglycaemia results from hepatic glucose output, which is normally attenuated by insulin, increases.⁴ The combination of insulin resistance and insulin deficiency finally result in persistent hyperglycaemia or type 2 diabetes mellitus.

Types of oral antidiabetic drugs

Oral antidiabetic drugs can be classified according to their modes of action.

1.	Biguanides
		Metformin
2.	Thiazolidinediones (TZDs)
		Pioglitazone
		Rosiglitazone
3.	Insulin secretagogues (Insulin secretion stimulators)
		Sulphonylureas (e.g. chlorpropamide,tolbutamide, glibenclamide, gliclazide, glipizide, glimepiride)
		Non-sulphonylurea insulin secretagogues (meglitinide analogues)(e.g. repaglinide, nateglinide)
4.	Alpha-glucosidase inhibitors
		Acarbose

Among these antidiabetic drugs, metformin and thiazolidinediones are proved to improve insulin sensitivity or reducing insulin resistance.^24,27

Biguanides

Metformin is the only biguanide available in Hong Kong. It is the first-line therapy for adults with type 2 diabetes, especially for the overweight patients. The results of the United Kingdom Prospective Diabetes Study (UKPDS) showed that metformin was significantly better than sulphonylurea/insulin therapy in the overweight group for any diabetes related endpoint and all cause mortality.²⁴ It is indicated for type 2 diabetes as monotherapy when hyperglycaemia cannot be controlled on diet alone, or in combination with sulphonylureas/non-sulphonylureas secretagogues/insulin and thiazolidinedione derivatives. Metformin acts as an insulin sensitizer. It decreases hepatic glucose production, decreases intestinal absorption of glucose and to a lesser extent enhances glucose uptake by peripheral tissues.³ It also lowers triglycerides, LDL cholesterol, and total cholesterol (-16%, -8% and -5% respectively).^3,16 When used as a monotherapy, metformin is associated with less weight gain than that seen in sulphonylureas and insulin, and may even promote weight loss.² In a recent clinical trial when metformin and rosiglitazone were used as monotherapy, they demonstrated an increase in hepatic glucose uptake in type 2 diabetes. However, only metformin is associated with weight loss (p<0.02 vs placebo).³⁹ As metformin does not increase insulin secretion, it confers nearly no risk of hypoglycaemia.²

Adverse effects of metformin

The most serious complication of metformin is lactic acidosis (<1%),²¹ which can be fatal.¹⁵ As metformin is renally excreted, the risk of acidosis is increased in renal insufficiency.¹⁵ Metformin is thus contraindicated in patients with elevated serum creatinine above 130mmol/L¹⁵ or low creatinine clearance.¹⁵ It should be used with caution in patients with heart failure or other cardiovascular disease which can cause acute renal failure.² Metformin should also be withheld when renal function may potentially be impaired such as in radiographic contrast procedure (not restarted for 48 hours),¹⁵ concomittant use of nephrotoxic antibiotics or procedures that can cause significant blood loss.²

Gastrointestinal disturbances (>10%)²¹ such as nausea/vomiting (6-25%),²¹ dyspepsia and diarrhoea are commonly associated with metformin (reported in up to 50% of patients).³ Patients usually become more tolerant to metformin with time.

Thiazolidinediones

Examples in this group include rosiglitazone maleate (Avandia)and pioglitazone hydrochloride (Actos). Troglitazone was removed from the market because of hepatotoxicity.

Like metformin, thiazolidinediones (TZDs) are also insulin sensitizers. They are slow in onset of action and the hypoglycaemic effect is usually apparent only after 4 weeks treatment.⁴ The full impact may not be seen until 3 to 4 months of therapy.⁴ TZDs are effective as monotherapy but due to their slow onset, they are generally not preferred as first-line therapy in poorly controlled type 2 diabetes.¹⁵ They are very effective in combination with other antidiabetic agents such as sulphonylureas, metformin or insulin.¹⁵

TZDs have several biological actions, namely fat redistribution and improvement in insulin sensitivity by altering hormone production by adipocytes.²⁸ They exert their effect by activating nuclear receptor called peroxisome proliferator-activated receptor-g (PPARg) in metabolically active tissues such as adipose tissue.⁴ They can also improve insulin sensitivity in parallel with a major change in fat metabolism, including a substantial reduction in circulating free fatty acids.^28,33

By activation of PPARg receptors in non-visceral (peripheral or subcutaneous) adipocytes, they facilitate non-visceral adipocytes to increase uptake of free fatty acids, which leads to reduction in the fat stored in muscle, liver and visceral fat deposits. This "lipid-steal" effect of TZDs will lead to lowering of circulating free fatty acids and reduced concentrations of triglycerides in muscle and liver.²⁸ TZDs do not increase insulin level. In fact, with the reduction in circulating free fatty acids, the insulin level reduces acutely. In long term, TZDs can arrest the decline in b-cell function that occurs in type 2 diabetes, perhaps by protecting the b-cell from lipotoxicity.^28.34

TZDs also lead to an increase in the secretion of adiponectin, a hormone which can increase fat oxidation, improve insulin action and have anti-atherogenic properties, and reduce the secretion of substances which impair insulin action, such as tumour necrosis factor a and resistin.^27,28

As TZDs act by increasing insulin sensitivity instead of increasing insulin secretion, they do not induce hypoglycaemia.³

In the lipid profile, TZDs cause a slight increase in low-density-lipoprotein (LDL) levels and a substantial increase in high-density lipoprotein (HDL) levels. Thus, the LDL-to-HDL ratio actually decreases. There is also a slight reduction in both systolic and diastolic blood pressure.⁴ They also remarkably reduce triglycerides (particularly pioglitazone)^28,34 and may also reduce fatty liver.⁴ All these biological effects of TZDs, except for increased LDL, are potential benefits to the metabolic syndrome and cardiovascular disease.

As a monotherapy, pioglitazone and rosiglitazone have different effects on plasma lipids independent of glycaemic control or concomitant lipid-lowering or other antihyperglycaemic therapy. Pioglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size comparing to rosiglitazone.¹⁶

Adverse effects of TZDs

All TZDs cause dose-related weight gain.³ This is partially due to their effect on adipocyte differentiation and proliferation, particularly in peripheral adipocytes, which result in increase in body weight and fat mass.²⁸ However, visceral fat, which is more harmful metabolically than peripheral fat, is not increased and may in fact, decreased with TZDs therapy.²⁸ Another contributing factor for the weight gain is fluid retention.¹⁵ In some patients, fluid retention may exacerbate congestive heart failure.¹⁵ Hence, TZDs should be used with caution in patients with suboptimal cardiac reserve or when other drugs that may cause fluid retention are used in conjunction with TZDs, e.g. calcium channel blockers.⁴ Diuretics may sometimes be required to reduce peripheral oedema.⁴ Troglitazone was withdrawn from the market due to hepatotoxicity. The other TZDs such as rosiglitazone and pioglitazone, appear to be safer in this respect according to various pre- and post-marketing trials.^4,35 However, liver enzymes should be measured before initiation of therapy and then monitored bimonthly for the first 12 months of therapy and periodically thereafter. Initiation of therapy is not recommended if the liver enzymes are more than 2.5 times the upper limit of normal range.⁴ Therapy should also be discontinued if liver enzymes are more than 3 times the upper limit of normal.⁴

Another concern is the possible complication of macula oedema associated with the use of rosiglitazone. It results from fragile and leaking blood vessels in the eye and can lead to blurry vision; it affects the part of the eye where sharp, straight-ahead vision occurs. Patients on rosiglitazone treatment are advised to seek medical advice if any changes in vision such as blurred vision, decreased colour sensitivity, or impaired vision in the dark, are experienced.³⁶

Insulin secretagogues

Sulphonylureas

Sulphonylureas are indicated as an adjunctive therapy for patients with type 2 diabetes uncontrolled by diet and exercise. They are only effective in patients with some residual pancreatic beta-cells activity and are not indicated for patients with type 1 diabetes.

Sulphonylureas reduce blood glucose by directly stimulating pancreatic b-cells to produce insulin. They act by the inhibition of K_ATP channels in the pancreatic beta-cells, which is then followed by the influx of Ca²⁺ and subsequent insulin secretion from these cells.^3,5 They increase circulating insulin and reduce both fasting and postprandial glucose. They lower HbA_1C (mean glycosylated haemoglobin) by an average of 0.8-2% and offer effective glycaemic control in up to 75% of patients.^1,3,7,31 However, their efficacy declines overtime, with about 5-10% of patients per year failing to maintain the initial glycaemic control.^3,7,8 First generation sulphonylureas are now less frequently prescribed because the newer second generation sulphonylureas have less side effects and less drug interactions.

Newer preparations of sulphonylureas

Gliclazide is a commonly used sulphonylureas agent. It has immediate release and modified release formulations. The modified release formulation is to be taken once daily. It provides gradual release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus.¹⁹ Gliclazide is highly selective for pancreatic b-cells, and no cardiovascular K_ATP channel interaction has been observed at therapeutic concentrations.¹⁹ Significant HbA_1C reductions of 0.9% and 0.95% were seen at 10 and 24 months in patients on gliclazide modified release 30 to 120mg once daily.¹⁹ Gliclazide is unique among the sulphonylureas for its antioxidant effect and reduced progression or improvement in retinopathy.³⁷

Glimepiride (Amaryl) is the newest compound of this group. It has quick onset and lower incidence of hypoglycaemia in comparing to the first generation sulphonylureas.^5,9 It demonstrates extrapancreatic (liver, adipose tissue, muscle) effect⁵ and has insulin-sparing effect when administered with insulin in patients with secondary sulphonylurea failure.^9,14 It increases the action of insulin both at the receptor and postreceptor sites. It lowers blood glucose even in absence of insulin either by reduction of glucagons release or by activation of glucose transport and non-oxidative glucose metabolism.^5,25 This results in equal or better glycaemic control with less insulin secretion than other agents of this group.⁵

Mocanu et al recently demonstrated that both glimepiride and glibenclamide inhibit sarcolemmal K_ATP channels, but only glibenclamide inhibits mitochondrial K_ATP channels. It was also found that mitochondrial K_ATP channels mediate ischaemic preconditioning. This thus suggested that glimepiride, which did not inhibit mitochondrial K_ATP channels, had no adverse effect on ischaemic preconditioning or infarct size.²⁹ In another study, Inukai K et al found that glimepiride had the potential to induce PPARg receptors activity in adipocytes and muscle cells, an effect also found in TZDs, thereby improving insulin resistance.³⁰

In general, sulphonylurea agents have similar efficacy.⁹ The choice of therapy is based on their pharmacokinetics, safety profiles, dosage frequency (which affects the compliance), patient age, renal function, and costs.

Comparisons on their pharmacokinetic profiles and dosage recommendations in different populations such as elderly, patients with renal or hepatic insufficiency are summarized in Table 1.

Adverse effects of sulphonylureas

Significant adverse effects include hypoglycaemia, increase in cardiovascular events, weight gain, water retention with hyponatremia, gastrointestinal disturbances (nausea, vomiting and diarrhoea) and haematological disorders (aplastic anaemia, thrombocytopenia, leukopenia, agranulocytosis.)

A common adverse effect of sulphonylureas is hypoglycaemia, particularly in the elderly.¹ The long-acting sulphonylureas, chlorpropamide and glibenclamide, are associated with a greater risk and should be avoided in patients with renal impairment and in elderly.^10,13 Therefore, short-acting sulphonylureas such as tolbutamide and gliclazide should be considered for those who are more susceptible to hypoglycaemia.¹⁰

Weight gain is a fairly common side effect in first-generation sulphonylureas administration (Clarke & Campbell, 1977; Holmes et al, 1984).¹¹ This is probably due to anabolic effects of raised insulin levels and/or water retention (Shaw et al,1985).¹¹

The increase in cardiovascular events may be due to the similarity of sulphonylurea receptors in both cardiac myocytes and pancreatic beta-cells.¹ An increase in cardiovascular mortality has been reported with tolbutamide by the University Group Diabetes Program Study (UGDPS) (2.5 times that of patients treated with diet alone) (Meinert et al 1970).^9,11 Although there has been controversy over the interpretation of various studies, physicians should consider that this warning might apply to other sulphonylureas.¹¹

Sulphonylureas stimulate antidiuretic hormone (ADH) release. This results in water retention, dilutional hyponatremia, low osmolality and high urine osmolality. This side effect is less frequent with gliclazide and other second-generation sulphonylureas than with first generation agents, particularly chlorpropamide (AMA, 1986; Krall,1991).²³

Non-sulphonylurea insulin secretagogues (Meglitinides)

The currently available meglitinides are repaglinide and nateglinide. They are indicated as an adjunct to diet and exercise to improve glycaemic control in type 2 diabetes, or in combination with metformin or thiazolidinediones to lower blood glucose in patients whose hyperglycaemia cannot be controlled by diet, exercise and either agent alone.²³

Meglitinides act directly on the pancreatic b-cells to stimulate insulin release. They are differentiated from the sulphonylureas by their receptor binding site, fast onset and short duration of action. They can improve early meal-mediated insulin secretion.

The 2 hours postprandial plasma glucose levels contribute to and are better predictors of long-term glycaemic control than fasting plasma glucoses.^4,32 The rapid onset and short half-life of meglitinides make them ideally suited for prandial regulation of glucose when taken in association with meals, but with minimal risk of hypoglycemia between meals. On average, the HbA_1c reduction seems to be equivalent to the sulphonylureas (0.5-2.0%).²⁶

Adverse effects

The adverse effects of hypoglycaemia and weight gain of meglitinides are probably less pronounced than those with the sulphonylureas.²⁶ In contrast to sulphonylureas, patients on repaglinide or nateglinide can simply avoid the dose accompanying a skipped meal without suffering hypoglycaemia. The main drawback of these agents is the need for frequent dosing before meals.

Alpha-glucosidase inhibitors

Acarbose

Acarbose is the commonly used agent in this group. It is indicated as a monotherapy, as an adjunct to diet in type 2 diabetes patients whose hyperglycaemia cannot be controlled by diet alone. It is also indicated as a combination therapy with a sulphonylurea, metformin, or insulin in patients when diet plus acarbose do not result in adequate glycaemic control.²¹

Acarbose produces mild reduction in postprandial hyperglycaemia by inhibiting the a-glucosidase enzyme, which is responsible for the breakdown of disaccharides to form single sugars, in the brush border of the small intestines.^3,15 Taken right before a meal, it can reduce postprandial glucose level by delaying both the absorption of carbohydrates and entry of glucose into liver and muscle tissues.³ As there is a reduction in the early-phase release of insulin in type 2 diabetes, the lowering of postprandial glycaemic peak enables type 2 diabetes patients to cope more effectively with glucose disposal.¹⁵

When using acarbose as monotherapy, it is associated with low risk of hypoglycaemia both in fasting and postprandial state.¹¹ In UKPDS 44, Holmann RR et al³⁸ demonstrated that acarbose significantly improved glycaemic control over 3 years in patients with established type 2 diabetes, irrespective of concomitant therapy for diabetes. However, there was a lower proportion of patients taking acarbose than placebo towards the end of study. The higher non-compliance rate was due to its gastrointestinal side effects. Careful titration of acarbose dose is thus required.

Adverse effects of acarbose

Gastrointestinal side effects (>10%)²¹ include abdominal pain (21%), diarrhoea (33%) and flatulence (77%).^4,21 These side effects are probably related to the late absorption and fermentation of carbohydrate which were observed in up to 2/3 of patients.¹ Starting with a low dose and slowly titrated up to the maximum and effective doses can help to make them more tolerable.³

Deranged liver function are reported in patients on high dose of acarbose,¹ so patient on high dose (200mg tds) should be closely monitored.

Therapeutics options

As different oral antidiabetic drugs act by different mechanisms, the choice of treatment should be individualized. The NICE guidance (September 2002) provides guidelines for the use of oral antidiabetic drugs in those patients with inadequately controlled blood glucose level, despite lifestyle interventions:

1.	Metformin should normally be used as the first-line glucose lowering therapy in patients who are overweight (body mass index > 25.0 kg/m2).40 It should also be considered as an option for first line or in combination therapy for patients who are not overweight. It is contraindicated in those with renal impairment (serum creatinine >130mmol/l) and those at risk of sudden deterioration of renal function.40
2.	Insulin secretagogues, including sulphonylureas and the rapid acting insulin secretagogues, should be used in combination with metformin in overweight or obese patients when glucose control becomes unsatisfactory.40 Insulin secretagogues should be considered as an option for first-line therapy when:
		Metformin is not tolerated or is contraindicated
		People are not overweight
3.	Patients should be offered a thiazolidinedione as oral combination therapy if:
		They are unable to take metformin and insulin secretagogues as combination therapy, or
		The HbA1c level remains unsatisfactory despite an adequate trial of metformin with insulin secretagogues.40
4.	Alpha-glucosidase inhibitors may be considered as an alternative glucose-lowering therapy in patients unable to use other oral drugs.40

Conclusion

Biguanides, thiazolidinediones, insulin secretagogues and alpha glucosidase inhibitors work by different mechanisms in improving the glycaemic profile in type 2 diabetes. They all have various advantages and drawbacks (Table 2). In considering the choice of therapy, the physicians must take into consideration these aspects of each agent. It is a common clinical practice to use combination therapy in treating diabetic patients when oral monotherapy begins to fail.⁴ Combination therapy can offer advantages in targeting different aspects of this complicated metabolic disease. Moreover, early use of combination therapy can minimize treatment delays and achieve therapeutic goals (HbA_1c between 6.5% and 7.5%)* faster, which may in turn slow disease progression. It may also be associated with fewer adverse effects due to lower doses required. However, physicians must bear in mind about the drug interactions, adverse effects profile, compliance and drug cost in polypharmacy.

(*A target HbA_1c (Diabetes Control and Complications Trial (DCCT) aligned) should be set between 6.5% and 7.5% based on the risk of macrovascular and microvascular complications. In general, the lower target HbA_1c is preferred for those people at significant risk of macrovascular complications, but higher targets are necessary for those at risk of iatrogenic hypoglycaemia.)⁴⁰

Key messages

1. Type 2 diabetes is the common form of diabetes, and is characterized by insulin resistance and impaired insulin secretion.
2. Metformin can improve insulin sensitivity and is commonly used as first line therapy in type 2 diabetes, especially for overweight patients. However, it is associated with the risk of lactic acidosis, especially in patients with renal insufficiency.
3. Thiazolidinediones act as insulin sensitizers, and can be used in combination with other antidiabetic agents.
4. Insulin secretagogues act directly on pancreatic b-cells to stimulate insulin release, and they have the risk of inducing hypoglycaemia.
5. Alpha-glucosidase inhibitors act by delaying the absorption of carbohydrates in the gut, but gastrointestinal side effect is common.
6. Combination therapy is common in clinical practice, as different groups of oral antidiabetic drugs work by different mechanisms.

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References