Oral Antidiabetic Agents - Semantic Scholar

REVIEW ARTICLE

Drugs 2005; 65 (3): 385-411 0012-6667/05/0003-0385/$39.95/0  2005 Adis Data Information BV. All rights reserved.

Oral Antidiabetic Agents Current Role in Type 2 Diabetes Mellitus Andrew J. Krentz1 and Clifford J. Bailey2 1 2

Southampton University Hospitals NHS Trust, Southampton, UK Life and Health Sciences, Aston Pharmacy School, Aston University, Birmingham, UK

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386 1. Insulin Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1 Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 1.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 1.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 1.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 1.1.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 1.1.6 New Formulations of Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2 Rapid-Acting Prandial Insulin Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 1.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 1.2.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 2. α-Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 3. Insulin Sensitisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1 Biguanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 3.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 3.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 3.1.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 3.2 Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 3.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 3.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 3.2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 4. Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

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Abstract

Krentz & Bailey

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet β-cell function, usually in the presence of obesity-related insulin resistance. Today’s clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (α-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis – beyond expected effects on glycaemic control – is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated

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haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1–2% reduction in HbA1c), α-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers’ recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.

In 1998, the results of the randomised, multicentre UKPDS (United Kingdom Prospective Diabetes Study)[1] provided firm evidence of the importance of long-term glycaemic control in middle-aged patients with newly diagnosed type 2 diabetes mellitus. Compared with dietary manipulation alone, intensified therapy in the form of oral antidiabetic agents or insulin significantly reduced the development of microvascular complications (table I).[1] This knowledge drives current clinical practice, in which treatment is directed to the attainment of near-normoglycaemia, i.e. glycosylated haemoglobin (HbA1c) concentrations of 6.5–7.0%.[2-4] While such targets may be perceived as being unrealistic for many – perhaps most – patients, there is a broad consensus that chronic hyperglycaemia should be managed as well as is possible, weighing safety and quality-of-life considerations on an individual basis. It is important to bear in mind that glycaemic control is just one aspect of an overall  2005 Adis Data Information BV. All rights reserved.

management plan that encompasses effective treatment of hypertension and dyslipidaemia;[2-6] both are commonly encountered in patients with type 2 Table I. Summary of main results of UKPDS (United Kingdom Prospective Diabetes Study) glycaemic control study.[1] Relative risk (RR) reductions in clinical endpoints for patients randomised to intensive (i.e. sulphonylurea or insulin) vs conventional therapy (i.e. diet) Endpoints

RR for intensive therapy

Confidence intervala

Log-rank p-value

Diabetes-related endpoints

0.88

0.79, 0.99

0.029

Microvascular complications

0.75

0.60, 0.93

0.0099

Aggregate endpointsb

Single endpoints Sudden death

0.54

0.24, 1.21

0.047

Retinal photocoagulation

0.71

0.53, 0.96

0.0031

Cataract extraction

0.76

0.53, 1.08

0.046

a

95% Confidence interval for aggregate endpoints; 99% confidence interval for single endpoints.

b

As defined and ascertained in UKPDS 33.[1]

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Table II. Main results for intensive (n = 80) vs conventional (n = 80) treatment of patients with type 2 diabetes mellitus and microalbuminuria. Mean follow-up was 7.8 years[8] Outcomes

Intensive (%)

Conventional (%)

Adjusted HR (95% CI)

Composite endpoint

24

44

0.47 (0.22, 0.74)

nephropathy

24

47

61% (13, 83)

retinopathy

52

71

58% (14, 79)

5 (3, 35)

63% (21, 82)

4 (2, 9)

autonomic neuropathy 36 64 HR = hazard ratio; NNT = number needed to treat; RRR = relative risk reduction.

RRR (95% CI)

NNT (95% CI) 5 (3, 19) 4 (3, 14)

diabetes and are regarded as important modifiable risk factors for atherosclerosis, the principal cause of premature mortality. Thus, a combined multifactorial therapeutic approach is required to maximise the impact of lifestyle and drug therapy on chronic micro- and macrovascular complications. Since management of chronic vascular and neuropathic complications accounts for the majority of health service spending for diabetes, such an approach is likely to be cost effective.[7] The Steno-2 Study,[8] which embraced such a multifactorial approach to treatment, demonstrated impressive reductions in vascular complications. In this randomised study of only 160 patients with type 2 diabetes and microalbuminuria, half of the patients received intensive target-driven therapy based in a hospital clinic and the remaining patients were cared for in primary care according to national guidelines. The main results of the study are presented in table II. While providing evidence for effectiveness, the translation of this approach to large numbers of patients in already stretched healthcare systems presents an additional challenge.

physical activity. The objective is always to improve metabolic control through reductions in bodyweight – obesity being present in the majority of patients – and other lifestyle measures that help improve insulin sensitivity. However, it is recognised that even if diet and exercise advice is successfully implemented, the majority of patients will require pharmacological therapy in the medium- to long term. Thus, only 25% of patients in UKPDS maintained a HbA1c level 90%

Tolbutamidec

500–2000

Short

Inactive

Urine ≈100% Bile ≈50%

Sulphonylureas

Main route of elimination

First generation

Second generation Glibenclamide (glyburide)

2.5–15

Intermediate to long

Active

Glimepiride

1–6

Intermediate

Active

Urine ≈80%

Glipizide

2.5–20

Short to intermediate

Inactive

Urine ≈70%

Gliquidone

15–180

Short to intermediate

Inactive

Bile ≈95%

Gliclazide

40–320d

Intermediate

Inactive

Urine ≈65%

a

Long >24h; intermediate 12–24h; short 5 mmol/L), decreased arterial pH and/ or bicarbonate concentration with an increased anion gap ([Na+] – [Cl– + HCO3–] >15 mmol/L). Presenting symptoms are often nonspecific, but frequently include hyperventilation, malaise and abdominal discomfort. Treatment should be commenced immediately without waiting to determine whether metformin is a cause; bicarbonate remains the therapy of choice but evidence of its efficacy is scanty. The value of haemodialysis in removing accumulatDrugs 2005; 65 (3)

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ed metformin has been challenged by some authorities, but dialysis may nonetheless be helpful in optimising fluid and electrolyte balance during treatment with high-dose intravenous bicarbonates.[54] 3.2 Thiazolidinediones

Thiazolidinediones improve whole-body insulin sensitivity via multiple actions on gene regulation. These effects result from stimulation of a nuclear receptor peroxisome proliferator-activated receptorγ (PPARγ), for which thiazolidinediones are potent synthetic agonists.[55] The antidiabetic activity of thiazolidinediones was described in the early 1980s, troglitazone being the first of the class to become available for clinical use. Troglitazone was introduced in the US in 1997, only to be withdrawn in 2000 because of cases of idiosyncratic hepatotoxicity resulting in fatalities. Troglitazone was available in the UK for only for a few weeks in 1997 before being withdrawn by its distributor as reports of hepatotoxicity accumulated in other countries. To date, two other thiazolidinediones, rosiglitazone and pioglitazone, have not shown the hepatotoxicity that led to the demise of troglitazone. Rosiglitazone and pioglitazone were introduced in the US in 1999 and in Europe in 2000.[56] Combination preparations (e.g. thiazolidinedione plus metformin) are also available. 3.2.1 Mode of Action

Stimulation of PPARγ is regarded as the principal mechanism through which thiazolidinediones enhance insulin sensitivity. PPARγ is expressed at highest levels in adipose tissue, and less so in muscle and liver. PPARγ operates in association with the retinoid X receptor. The resulting heterodimer binds to nuclear response elements, thereby modulating transcription of a range of insulin-sensitive genes, in the presence of necessary cofactors (figure 4).[55,57] Many of the genes activated or suppressed by thiazolidinediones are involved in lipid and carbohydrate metabolism (table VI). Stimulation of PPARγ by a thiazolidinedione promotes differentiation of pre-adipocytes with accompanying lipogenesis, effects that promote or enhance the local effects of insulin. Thiazolidinediones increase  2005 Adis Data Information BV. All rights reserved.

Table VI. Metabolic effects of thiazolidinediones[55] Adipose tissue

Muscle

Liver

↑ Glucose uptake

↑ Glucose uptake

↓ Gluconeogenesis

↑ Fatty acid uptake ↑ Glycolysis ↑ Lipogenesis

↑ Glucose oxidation

↑ Pre-adipocyte ↑ Glycogenesisa differentiation a Inconsistent findings.

↓ Glycogenolysis ↑ Lipogenesis ↑ Glucose uptakea

↑ indicates increase; ↓ indicates decrease.

glucose uptake via glucose transporter-4 in skeletal muscle, and some reports indicate that rates of gluconeogenesis in the liver are reduced. Stimulation of lipogenesis via PPARγ reduces circulating non-esterified fatty acid (NEFA) concentrations through cellular uptake and triglyceride synthesis (figure 5). The reduction in plasma NEFA concentrations is associated with increased glucose utilisation and reducing gluconeogenesis by reducing operation of the glucose-fatty acid cycle; reductions in ectopic lipid deposition in muscle and liver may contribute to the improvements on glucose metabolism. Thiazolidinediones also reduce the production and activity of the adipocyte-derived cytokine tumour necrosis factor (TNF)-α.[55] The latter has been implicated in the development of impaired insulin action in muscle,[58] although the precise role of TNFα in human states of insulin resistance remains unclear. Reductions in plasma insulin concentrations and lowering of circulating triglycerides are additional indirect mechanisms that may help to improve whole-body insulin sensitivity. Thiazolidinediones, like metformin, are anti-hyperglycaemic agents and require the presence of sufficient insulin to generate a significant blood glucose-lowering effect. 3.2.2 Pharmacokinetics

Rosiglitazone and pioglitazone are rapidly, and nearly completely absorbed (1–2 hours to peak concentration), although absorption is slightly delayed when taken with food. Both agents are extensively metabolised by the liver. Rosiglitazone is metabolised mainly to very weakly active metabolites with lesser activity that are excreted predominantly in the urine. The metabolites of pioglitazone are more active and excreted mainly in the bile. Metabolism of rosiglitazone is undertaken mainly by cytoDrugs 2005; 65 (3)

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chrome P450 (CYP) 2C8, which is not a widely activated isoform of CYP.[59] Thus, rosiglitazone does not interfere with the metabolism of other drugs. Pioglitazone is metabolised in part by CYP3A4 but, to date, no clinically significant reductions in plasma concentrations of other drugs (e.g. oral contraceptives) has been reported. Although both thiazolidinediones are almost completely bound to plasma proteins, their concentrations are low and have not been reported to interfere with other protein-bound drugs. 3.2.3 Indications and Contraindications

In the US, rosiglitazone and pioglitazone are available for use as monotherapy in non-obese and obese patients with type 2 diabetes in whom diabetes is not adequately controlled by nonpharmacological measures. They can also be used in combination with various other antidiabetic drugs and in combination with insulin. In Europe, rosiglitazone and pioglitazone can be used as monotherapy if the patient is contraindicated for or intolerant of metformin. Thiazolidinediones can be used in combination with metformin or a sulphonylurea. In Europe, combination with insulin remains a contraindication to Thiazolidinedione

PPARγ

thiazolidinediones.[60] Substituting a thiazolidinedione for either a sulphonylurea or metformin in patients with inadequate glycaemic control is generally of limited value and risks a temporary deterioration in glycaemic control because of the slow onset of action of thiazolidinediones. Having been disappointed with this experience, some UK diabetologists have elected to use thiazolidinediones in combination with both a sulphonylurea and metformin.[60] The former strategy has met with variable success: some patients respond well, others show little response, requiring transfer to insulin. The combination of thiazolidinedione plus insulin can improve glycaemic control while reducing insulin dosages in obese patients, although peripheral oedema has been reported.[61] The main cautions to using thiazolidinediones are listed in table VII. Rosiglitazone and pioglitazone can cause fluid retention with increased plasma volume, a reduced haematocrit and a decrease in haemoglobin concentration. Therefore, the risk of oedema and anaemia should be taken into account, and in Europe, use of thiazolidinediones in patients with any evidence of congestive heart disease or

Glucose

Fatty acids

GLUT-4

FATP

Glucose uptake and utilisation

aP2, acylCoA synthase

RXR

Transcription of certain insulin-sensitive genes

Lipogenesis and adipocyte differentiation

Lipoprotein lipase

↑ Hydrolysis of circulating triglycerides in chylomicrons and VLDL

Adipocyte Fig. 5. Mechanism of action of a thiazolidinedione on an adipocyte (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). aP2 = adipocyte fatty acid binding protein; CoA = coenzyme A; FATP = fatty acid transporter protein; GLUT-4 = glucose transporter-4; PPARγ = peroxisome proliferator-activated receptor-γ; RXR = retinoid X receptor; VLDL = very low-density lipoproteins; ↑ indicates increase.

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Table VII. Cautions in the use of thiazolidinediones Active liver disease This remains a contraindication to the use of thiazolidinediones even though neither rosiglitazone nor pioglitazone have been associated with troglitazone-like hepatotoxicity. In fact, the latter drugs are under investigation as a potential treatment for nonalcoholic steatohepatitis. In 2004, the US FDA recommendation for 2-monthly monitoring of biochemical liver function tests was relaxed. Instead, periodic biochemical monitoring is now left to the supervising clinician’s discretion Heart failure The precise contraindications differ between countries. In Europe, current heart failure or a history of heart failure are contraindications to thiazolidinediones Insulin treatment Although rosiglitazone and pioglitazone are licensed in the US for use in combination with insulin, caution is required. Concerns about higher rates of heart failure underlie this concern. The European Agency for the Evaluation of Medicinal Products considers insulin therapy a contraindication to the use of thiazolidinediones Pregnancy and breast-feeding Thiazolidinediones are classified as pregnancy category C because of growth retardation in mid-to-late gestation in animal models. These drugs should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Polycystic ovary syndrome Thiazolidinediones can cause ovulation to recommence in women with hyperandrogenism and chronic anovulation; risk of pregnancy

heart failure is contraindicated. The choice of which patients to exclude on the basis of cardiac status varies between the product labelling sheets in the US and Europe. Consensus guidelines from the American Heart Association and the American Diabetes Association have recently been published.[62] Patients treated with a combination of insulin plus thiazolidinedione appear to be at highest risk of oedema, although the absolute rate of cardiac failure is low despite the fact the diabetes is a major risk factor for this complication.[62] The guidelines urge a cautious approach and careful clinical monitoring, especially for patients likely to be at higher risk of cardiac failure. The haemogloblin concentration should be checked before starting a thiazolidinedione, bearing in mind that reductions of up to 1 g/ dL in haemoglobin concentration may occur during therapy. No adverse effects on blood pressure have been noted with the thiazolidinediones, even with the increase in plasma volume; on the contrary, there  2005 Adis Data Information BV. All rights reserved.

Krentz & Bailey

is some evidence for a modest blood pressure-lowering effect.[63] As a precautionary measure, liver function should be assessed by measuring serum ALT before starting therapy and subsequently at 2-monthly intervals (or, in the US, as judged necessary by the prescribing clinician) during the first year of treatment; thereafter, periodic monitoring of liver function is prudent. Pre-existing liver disease, the development of clinical hepatic dysfunction or elevated ALT levels >2.5 times the upper limit for the laboratory serve as contraindications to thiazolidinediones. However, as mentioned earlier, hepatotoxicity has not been a concern with either rosiglitazone or pioglitazone. Isolated cases of nonfatal hepatocellular damage have been reported; however, the issue is clouded by reports suggesting an intrinsically higher risk of liver failure in patients with type 2 diabetes. Nevertheless, precautionary monitoring of liver function remains advisable. When initiating therapy with rosiglitazone or pioglitazone, blood glucose monitoring and titration of drug dosage should be undertaken while bearing in mind that thiazolidinediones exert a slowly generated anti-hyperglycaemic effect that usually requires 2–3 months to reach maximum effect. According to the EU license, rosiglitazone can be given at a dosage of 4 mg/day in combination with a sulphonylurea, increasing to 8 mg/day (either once daily or in divided doses) in combination with metformin. Pioglitazone can be given as a once-daily dosage of 15mg, increasing to 30mg if necessary (maximum 45mg in the US and Europe). The therapeutic response varies markedly between patients and it can be difficult to predict those most likely to respond. If no effect is observed after 3 months it is appropriate to consider the patient as a nonresponder and to stop the treatment. Rosiglitazone and pioglitazone can be used in the elderly, provided there are no contraindications. Both drugs may be used in patients with mild-to-moderate renal impairment, although the potential for oedema is a concern. In women with anovulatory PCOS the improvement in insulin sensitivity may cause ovulation to resume during thiazolidinedione therapy. A combination Drugs 2005; 65 (3)

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preparation containing rosiglitazone plus metformin (Avandamet; combining rosiglitazone/metformin in strengths 1mg/500mg, 2mg/500mg, 4mg/500mg, 2mg/1000mg, although not all strengths are available in all countries). 3.2.4 Efficacy

Addition of rosiglitazone or pioglitazone to the treatment schedule of patients whose glycaemic control with a sulphonylurea or metformin is suboptimal has consistently resulted in significant reductions in HbA1c. As judged by the available literature, these agents have similar glucose-lowering effects, reducing HbA1c by around 0.5–1.5%.[64] However, the participants in these clinical trials had known diabetes of several years’ duration, the effects of thiazolidinediones being more apparent when β-cell function is less impaired. While earlier use of thiazolidinediones may be advantageous, the longerterm picture requires clarification. Estimates of insulin sensitivity and β-cell function (based on analysis of fasting glucose and insulin concentrations) have indicated that both defects can be improved by the addition of a thiazolidinedione.[64] The effects on plasma lipids and apoproteins have been the subject of debate. Rosiglitazone can cause a small rise in the total cholesterol concentration, which stabilises within about 3 months. This is accounted for by a rise in both the LDL-cholesterol and the HDL-cholesterol, leaving the LDL : HDL-cholesterol ratio and the total : HDL-cholesterol ratio little changed or slightly raised. Pioglitazone generally appears to have little effect on total cholesterol, and has been shown to reduce triglyceride concentrations in several studies. Both thiazolidinediones reduce the proportion of the smaller, more dense (more atherogenic) LDL particles.[64] To date, no prospective comparative studies of the two drugs have been reported and the clinical implications of these changes are uncertain.[63] Weight gain, similar in magnitude to sulphonylurea therapy (typically 1–4kg) and stabilising over 6–12 months, has been observed during thiazolidinedione therapy. There is some evidence that the distribution of body fat is altered such that visceral adipose depots are little changed or reduced, while  2005 Adis Data Information BV. All rights reserved.

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subcutaneous depots increase as new small, insulinsensitive adipocytes are formed. There are provisional data to suggest that thiazolidinediones exert a range of effects on aspects of the metabolic syndrome that might reduce the risk of atherosclerotic cardiovascular disease.[63,65] For example, thiazolidinediones have been reported to downregulate PAI-1 expression. Thiazolidinediones have also been reported to decrease urinary albumin excretion to a greater extent than expected for the improvement in glycaemic control and to reduce circulating markers of chronic low-grade inflammation. Preclinical studies suggesting that treatment of glucose-intolerant animals with a thiazolidinedione preserved β-cell function have yet to be confirmed in human studies. In insulin-resistant women with a history of gestational diabetes at high risk of type 2 diabetes troglitazone reduced the incidence of newonset diabetes.[66] Whether thiazolidinediones will prove more effective than conventional antidiabetic agents in reducing the decline in β-cell function in patients with established type 2 diabetes remains to be determined, although preliminary data in patients who respond to the drugs have been encouraging.[67] Also of considerable interest are the clinical implications of the aforementioned effects of thiazolidinediones on risk factors for cardiovascular disease. These effects, allied to direct anti-atherogenic actions reported in animal studies, are presently being studied in clinical trials with cardiovascular endpoints.[68] 3.2.5 Adverse Effects

Rosiglitazone and pioglitazone are generally well tolerated. As noted in section 3.2.3, caution is advised in heart disease; in the UK this includes a history of cardiac failure, oedema, anaemia and liver function requiring intermittent monitoring in accordance with the package labelling. If contraindications arise during treatment, monitoring should be intensified and, if necessary, treatment discontinued. Hypoglycaemia may occur several weeks after adding a thiazolidinedione to a sulphonylurea; selfmonitoring of blood glucose can be helpful in identifying the point at which the dosage of the sulphonylurea should be reduced. Since PPARγ is expressed Drugs 2005; 65 (3)

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by many tissues, albeit at a low level, we must await the verdict of time for any unforeseen effects of long-term stimulation with thiazolidinediones. For example, PPARγ activation in macrophages can reduce the production of some inflammatory cytokines and might increase transformation of monocytes to macrophages in the vascular wall. Stimulation of PPARγ in colon cells has been variously reported to increase and decrease division and differentiation of these cells in different animals and cell models;[69] thus, familial polyposis coli is a contraindication to thiazolidinediones on theoretical grounds.

id improvement in glycaemic control (within days), whereas the maximal response to thiazolidinediones may take several weeks to become apparent. Maximal glucose-lowering effects are usually obtained at doses lower than the manufacturer’s recommendations, e.g. 5–10 mg/day for glibenclamide.

•

If the glycaemic target is not achieved consider adding another class of agent at an early stage. Undertake the same evaluation and titration procedure for the second agent. If a combination of two oral agents does not give adequate control, there may be some patients who will benefit from addition of a third differently acting oral therapy. Compliance generally deteriorates as the daily number of doses increases.

•

Inability to achieve adequate glycaemic control with a logical combination of oral therapies is likely to indicate that the natural history of the disease has progressed to a state of severe β-cell failure. In this situation it is usually necessary to switch to insulin therapy. Similarly, failure to respond to an oral agent (so-called primary failure) or loss of control (secondary failure) usually reflects a severe degree of insulin deficiency and early need for insulin. All oral antidiabetic agents are contraindicated in type 1 diabetes and in major metabolic decompensation. Insulin may be required temporarily during intercurrent severe illness.

4. Summary and Conclusion The management of patients with type 2 diabetes has been given a firm evidence base in recent years through the results of randomised clinical trials, notably the UKPDS. An improved understanding of the pathogenesis and natural history of this complex metabolic disorder has facilitated the application of new therapeutic agents. Attainment and maintenance of near-normal glycaemic control, while minimising the risk of iatrogenic hypoglycaemia, is a central long-term objective of therapy; however, this is often difficult to achieve in practice. The following general principles should be applied while using oral antidiabetic drugs. • Antidiabetic drug therapy must be considered carefully within the context of the overall care plan. This includes an assessment of which agent is most likely to achieve the therapeutic goals of the care plan, taking account of the accompanying medical and lifestyle circumstances and commitments of the patient. • Always check for contraindications. • For some classes of agents, e.g. sulphonylureas, duration of action and route of elimination will be important considerations if hypoglycaemia is likely, or if renal or liver disease raises concerns. Shorter-acting preparations are preferred for those at risk of hypoglycaemia and in the elderly. • Start with the lowest recommended dose and monitor response taking the mode of action into account. Sulphonylureas generally produce a rap 2005 Adis Data Information BV. All rights reserved.

Clinicians have a greater range of antidiabetic treatments to choose from than ever, but this has brought a new level of complexity to management. In addition, polypharmacy has become the norm for many patients with type 2 diabetes in recognition of the importance of treating hypertension and dyslipidaemia, both commonly encountered and modifiable cardiovascular risk factors. The main classes of oral antidiabetic drugs are broadly similar in their glucose-lowering capacity, at least in the short- to medium term.[70] Accordingly, the most appropriate therapy should be selected according to the clinical and biochemical characteristics of the patient, safety considerations always being a major consideration. The UKPDS has influenced prescribing in the UK Drugs 2005; 65 (3)

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since its publication (table VIII), with metformin now being the most commonly prescribed oral antidiabetic drug. Not only did metformin reduce the risk of myocardial infarction and all-cause mortality in the UKPDS, it has the added advantages of decades of clinical experience and it is inexpensive and weight-neutral (table V). On theoretical grounds, the thiazolidinediones appear promising, particularly with respect to possible preservation of β-cell function and the potential for cardiovascular disease prevention. However, these agents have perhaps not entirely fulfilled early expectations of success, at least if judged in terms of their glucose-lowering abilities, which are no better than the conventional drugs. Part of this shortfall may be attributable to the complexity and heteroTable VIII. Relative costs and frequency of prescriptions for oral antidiabetic drugs in the UK[71,72]a Drug

Frequency of prescriptions

Relatively inexpensive Biguanides

Only metforminb in UK

Sulphonylureasc Moderate α-Glucosidase inhibitors

Only acarbose in UK

Sulphonylureasc Relatively expensive Rapid-acting prandial insulin releasers

Repaglinide, nateglinide

Thiazolidinediones

Rosiglitazone, pioglitazone

a

This classification attempts to take average effective maintenance dosages into account and may be regarded as an approximate guide to relative UK Drug Tariff prices.

b

Use of metformin has increased in recent years, this drug now being the most widely prescribed oral antidiabetic agent in the UK (49%); sulphonylureas lie close behind, gliclazide being the most popular agent accounting for 31% of spending on oral antidiabetic agents. Thiazolidinediones account for only 5% of all prescriptions but for 32% of the cost of all oral antidiabetic agents in the UK; these figures predate the 2003 license amendment permitting limited prescription of thiazolidinediones as monotherapy in selected patients. Acarbose, the only α-glucosidase inhibitor in the UK, and the rapid-acting prandial insulin releasers repaglinide and nateglinide account for a small percentage (