current role in type 2 diabetes mellitus · 2017. 6. 7. · current role in type 2 diabetes...

Drugs 2005; 65 (3): 385-411REVIEW ARTICLE 0012-6667/05/0003-0385/$39.95/0

2005 Adis Data Information BV. All rights reserved.

Oral Antidiabetic AgentsCurrent Role in Type 2 Diabetes Mellitus

Andrew J. Krentz1 and Clifford J. Bailey2

1 Southampton University Hospitals NHS Trust, Southampton, UK2 Life and Health Sciences, Aston Pharmacy School, Aston University, Birmingham, UK

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3861. Insulin Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

1.1 Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3901.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3901.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3931.1.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3931.1.6 New Formulations of Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

1.2 Rapid-Acting Prandial Insulin Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3951.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3951.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

2. α-Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3982.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3982.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

3. Insulin Sensitisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.1 Biguanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

3.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4023.1.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

3.2 Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4053.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4073.2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

4. Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

386 Krentz & Bailey

Type 2 diabetes mellitus is a progressive and complex disorder that is difficultAbstractto treat effectively in the long term. The majority of patients are overweight orobese at diagnosis and will be unable to achieve or sustain near normoglycaemiawithout oral antidiabetic agents; a sizeable proportion of patients will eventuallyrequire insulin therapy to maintain long-term glycaemic control, either as mono-therapy or in conjunction with oral antidiabetic therapy. The frequent need forescalating 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 antidiabeticdrugs for type 2 diabetes. The main classes are heterogeneous in their modes ofaction, safety profiles and tolerability. These main classes include agents thatstimulate insulin secretion (sulphonylureas and rapid-acting secretagogues),reduce hepatic glucose production (biguanides), delay digestion and absorption ofintestinal carbohydrate (α-glucosidase inhibitors) or improve insulin action (thia-zolidinediones).

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated thebenefits of intensified glycaemic control on microvascular complications in newlydiagnosed patients with type 2 diabetes. However, the picture was less clearcutwith regard to macrovascular disease, with neither sulphonylureas nor insulinsignificantly reducing cardiovascular events. The impact of oral antidiabeticagents on atherosclerosis – beyond expected effects on glycaemic control – is anincreasingly important consideration. In the UKPDS, overweight and obesepatients randomised to initial monotherapy with metformin experienced signif-icant reductions in myocardial infarction and diabetes-related deaths. Metformindoes not promote weight gain and has beneficial effects on several cardiovascularrisk factors. Accordingly, metformin is widely regarded as the drug of choice formost patients with type 2 diabetes. Concern about cardiovascular safety ofsulphonylureas has largely dissipated with generally reassuring results fromclinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Studyshowed that intensive target-driven, multifactorial approach to management,based around a sulphonylurea, reduced the risk of both micro- and macrovascularcomplications in high-risk patients. Theoretical advantages of selectively target-ing postprandial hyperglycaemia require confirmation in clinical trials of drugswith preferential effects on this facet of hyperglycaemia are currently in progress.The insulin-sensitising thiazolidinedione class of antidiabetic agents has poten-tially 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 biochemicalassessment of the patient, safety considerations being paramount. In some circum-stances, for example pregnancy or severe hepatic or renal impairment, insulin maybe the treatment of choice when nonpharmacological measures prove inadequate.Insulin is also required for metabolic decompensation, that is, incipient or actualdiabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certaincomorbidities, for example presentation with myocardial infarction during otheracute intercurrent illness, may make insulin the best option.

Oral antidiabetic agents should be initiated at a low dose and titrated upaccording to glycaemic response, as judged by measurement of glycosylated

2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)

Oral Antidiabetic Agents 387

haemoglobin (HbA1c) concentration, supplemented in some patients by selfmonitoring of capillary blood glucose. The average glucose-lowering effect of themajor classes of oral antidiabetic agents is broadly similar (averaging a 1–2%reduction in HbA1c), α-glucosidase inhibitors being rather less effective. Tailor-ing the treatment to the individual patient is an important principle. Doses aregradually titrated up according to response. However, the maximal glucose-lower-ing 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 athiazolidinedione, are logical and widely used, and combination preparations arenow available in some countries. While the benefits of metformin added to asulphonylurea were initially less favourable in the UKPDS, longer-term data haveallayed concern. When considering long-term therapy, issues such as tolerabilityand convenience are important additional considerations.

Neither sulphonylureas nor biguanides are able to appreciably alter the rate ofprogression of hyperglycaemia in patients with type 2 diabetes. Preliminary datasuggesting that thiazolidinediones may provide better long-term glycaemic stabil-ity are currently being tested in clinical trials; current evidence, while encourag-ing, is not conclusive.

Delayed progression from glucose intolerance to type 2 diabetes in high-riskindividuals with glucose intolerance has been demonstrated with troglitazone,metformin and acarbose. However, intensive lifestyle intervention can be moreeffective 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, multicen- management plan that encompasses effective treat-tre UKPDS (United Kingdom Prospective Diabetes ment of hypertension and dyslipidaemia;[2-6] bothStudy)[1] provided firm evidence of the importance are commonly encountered in patients with type 2of long-term glycaemic control in middle-aged pa-tients with newly diagnosed type 2 diabetes mel-litus. Compared with dietary manipulation alone,intensified therapy in the form of oral antidiabeticagents or insulin significantly reduced the develop-ment of microvascular complications (table I).[1]

This knowledge drives current clinical practice, inwhich treatment is directed to the attainment ofnear-normoglycaemia, i.e. glycosylated haemo-globin (HbA1c) concentrations of 6.5–7.0%.[2-4]

While such targets may be perceived as being un-realistic for many – perhaps most – patients, there isa broad consensus that chronic hyperglycaemiashould be managed as well as is possible, weighingsafety and quality-of-life considerations on an indi-vidual basis. It is important to bear in mind thatglycaemic control is just one aspect of an overall

Table I. Summary of main results of UKPDS (United KingdomProspective Diabetes Study) glycaemic control study.[1] Relativerisk (RR) reductions in clinical endpoints for patients randomised tointensive (i.e. sulphonylurea or insulin) vs conventional therapy (i.e.diet)

Endpoints RR for Confidence Log-rankintensive intervala p-valuetherapy

Aggregate endpointsb

Diabetes-related endpoints 0.88 0.79, 0.99 0.029

Microvascular complications 0.75 0.60, 0.93 0.0099

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]


388 Krentz & Bailey

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) RRR (95% CI) NNT (95% CI)

Composite endpoint 24 44 0.47 (0.22, 0.74) 5 (3, 19)

nephropathy 24 47 61% (13, 83) 4 (3, 14)

retinopathy 52 71 58% (14, 79) 5 (3, 35)

autonomic neuropathy 36 64 63% (21, 82) 4 (2, 9)

HR = hazard ratio; NNT = number needed to treat; RRR = relative risk reduction.

diabetes and are regarded as important modifiable physical activity. The objective is always to improverisk factors for atherosclerosis, the principal cause metabolic control through reductions in bodyweightof premature mortality. Thus, a combined mul- – obesity being present in the majority of patients –tifactorial therapeutic approach is required to max- and other lifestyle measures that help improve insu-imise the impact of lifestyle and drug therapy on lin sensitivity. However, it is recognised that even ifchronic micro- and macrovascular complications. diet and exercise advice is successfully implement-Since management of chronic vascular and neuro- ed, the majority of patients will require pharmaco-pathic complications accounts for the majority of logical therapy in the medium- to long term. Thus,health service spending for diabetes, such an ap- only 25% of patients in UKPDS maintained a HbA1cproach is likely to be cost effective.[7] The Steno-2 level <7.0% after 9 years without oral agents orStudy,[8] which embraced such a multifactorial ap- insulin. Not only was drug therapy usually required,proach to treatment, demonstrated impressive reduc- the need for escalating polypharmacy in the pursuittions in vascular complications. In this randomised of glycaemic targets was also amply demonstra-study of only 160 patients with type 2 diabetes and ted.[9] Continuing loss of function of islet β cells ismicroalbuminuria, half of the patients received in- held to be the major determinant of the slowlytensive target-driven therapy based in a hospital progressive hyperglycaemia that characterises typeclinic and the remaining patients were cared for in 2 diabetes,[1] although other factors such as weightprimary care according to national guidelines. The gain and/or failure of compliance with dietary pre-main results of the study are presented in table II. scriptions may also contribute. However, reiterationWhile providing evidence for effectiveness, the of lifestyle advice continues to be important eventranslation of this approach to large numbers of when pharmacotherapy has been initiated, avoid-patients in already stretched healthcare systems pre- ance of further weight gain being an important long-sents an additional challenge. term objective.

Insulin resistance and defective insulin secretion The selection of initial pharmacotherapy is basedare regarded as cardinal metabolic features of type 2 on a detailed consideration of the clinical and bio-diabetes, subtle abnormalities of both being evident chemical characteristics of the patient. Safety con-even at the earliest stages of glucose intolerance. siderations must always be carefully consideredWhile insulin resistance is highly prevalent on a since few, if any, antidiabetic agents are completelyglobal basis – closely linked to obesity and physical devoid of risk; some are appreciably more hazard-inactivity – near-normal glucose tolerance can be ous than others in certain clinical scenarios (seemaintained as long as increased insulin secretion is section 4). An assessment of the biochemical pheno-sufficient to counter the elevated requirements im- type of the patient is required. However, in practiceposed by insulin resistance.[4] Management of the it can be difficult to judge whether insulin resistanceasymptomatic or mildly symptomatic patient with or insulin deficiency is the dominant defect. As anewly diagnosed type 2 diabetes starts with one-to- rule, although it should be stressed, not invariably,one advice and/or group education about the poten- younger patients at near-normal bodyweight aretial benefits of dietary modifications and, if feasible, more likely to have greater insulin deficiency than



obese, sedentary middle-aged patients. Failure to diabetes. We consider both well established drugsrespond rapidly (i.e. within a week or two) to an oral and recent additions to the armamentarium. For eachagent in a patient thought to be complying with the class of agents we present an outline of the mode ofdietary advice usually signals the need for early use action, pharmacokinetics, indications and contrain-of insulin. If a partial response is observed, dose dications, efficacy, safety and tolerability, currentescalation is followed by step-wise addition of com- place in management and future prospects, includ-plementary drugs (figure 1). Insulin is usually re- ing role in prevention of type 2 diabetes. We haveserved for patients: (i) who fail to respond adequate- grouped the drugs according to their principal modely to a combination of oral agents; (ii) in whom of action: (i) those that increase insulin secretioncontrol deteriorates despite logical and adequate (insulin secretagogues); (ii) drugs delaying the ratedrug combinations; or (iii) for whom safety and of digestion and absorption of carbohydrates (α-efficacy considerations favour its use as the drug of glucosidase inhibitors); and (iii) those with directchoice, for example during pregnancy, or in patients effects on insulin-responsive tissues (insulin-sen-with severe hepatic or renal impairment.[10] Several sitising agents). This sequence should not be takenclasses of oral antidiabetic agents are currently to imply a hierarchy in terms of efficacy or merit.available, the range of options having enjoyed a The recognition that type 2 diabetes is usually awelcome expansion in recent years. However, the progressive disease implies that drug dosages willevidence base and clinical experience vary consider- need to be increased or therapy moved to anotherably not only between classes but also between stage in the treatment algorithm.[2,4]

drugs drawn from the same class. As a result, pre- While this article primarily reflects current prac-scribing decisions often appear to be made on rather tice in the UK, we have endeavoured to provide asubjective grounds, such as familiarity with a partic- review that acknowledges important differences inular drug; this practice may help to explain notable prescribing in other countries. A word about moni-regional differences in prescribing. toring: assessing the response to antidiabetic therapy

In the remainder of this article we focus on involves periodic – generally 3- to 6-monthly –treatment of hyperglycaemia in patients with type 2 measurement of HbA1c. This approach, which is

Aim

Relieve symptoms,improve glycaemiccontrol, enhance

quality of life

Diagnosis

Diet, exercise, weight controland health education

Oral agent monotherapy:metformin, sulphonylurea, meglitinide,

thiazolidinedione1, acarbose

Oral agent combination therapy(using two different classes)

Insulin or insulin plus an oral agent

Procedure

Move to next stageif there is inadequatecontrol of glycaemiaor inadequate relief

of symptoms

Fig. 1. An algorithm for the treatment of type 2 diabetes mellitus. The progressive hyperglycaemia in type 2 diabetes requires a stepped-care approach with treatment being modified and added over time. Rapid progression to the next stage is recommended if the glycaemictarget is not achieved. Late introduction of combinations of oral antidiabetic agents is often a prelude to insulin treatment. 1 Note that inEurope, thiazolidinediones and nateglinide have limited licenses. The α-glucosidase inhibitor miglitol is also available in some countries(reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).


390 Krentz & Bailey

recommended in the UK, can be usefully comple- nylureas with respect to the risks of weight gain andmented by self measurement of capillary blood glu- hypoglycaemia. Compared with older sulpho-cose in selected, empowered patients and in particu- nylureas, glimepiride is relatively expensive andlar clinical scenarios, for example in patients in clinical outcome data are not available, as they arewhom iatrogenic hypoglycaemia is a concern. for the agents used in the UKPDS. The clinical

relevance of theoretical, but much debated, effectsof glimepiride on ischaemic preconditioning –1. Insulin Secretagogueswhereby a brief episode of ischaemia protects themyocardium against the detrimental effects of sub-

1.1 Sulphonylureas sequent and more severe interruption of perfusion –remain uncertain. The issues of the importance of

Sulphonylureas have been extensively used for ischaemic preconditioning and the possible influ-the treatment of type 2 diabetes for nearly 50 years. ence of different sulphonylureas continue to be de-They lower blood glucose concentrations primarily bated (see section 1.1.5).[14]

by stimulating insulin secretion from the β cells ofthe pancreatic islets. By the 1960s several sulpho-

1.1.1 Mode of Actionnylureas were available, including tolbutamide,

Sulphonylureas have direct effects on the insulin-acetohexamide, tolazamide and chlorpropamide, of-producing islet β cells. The drugs bind to the β-cellfering a range of pharmacokinetic options. How-sulphonylurea receptor (SUR)-1, part of a trans-ever, doubts about safety were raised in the 1970s. Amembrane complex with adenosine 5′-triphosphate-large US multicentre trial of antidiabetic therapy,sensitive Kir 6.2 potassium channels (KATP chan-the UGDP (University Group Diabetes Program)[11]

nels).[14,15] Binding of the sulphonylurea closes thesereported apparent detrimental cardiovascular effectsKATP channels; this reduces cellular potassium ef-of tolbutamide. The UGDP was heavily criticised

for perceived methodological failings and its find- flux favouring membrane depolarisation. In turn,ings were far from being universally accepted. Sub- depolarisation opens voltage-dependent calciumsequent observational and randomised clinical stud- channels, resulting in an influx of calcium that acti-ies using sulphonylureas have provided mixed evi- vates calcium-dependent proteins that control thedence, but a review of the available literature release of insulin (figure 2). When sulphonylureasprovides little in the way of convincing evidence of interact with SUR1 in the β-cell plasma membranecardiovascular toxicity.[12] Indeed, some studies they cause prompt release of pre-formed insulinhave reported a decreased incidence of cardio- granules adjacent to the plasma membrane – the so-vascular events in subjects with lesser degrees of called ‘first phase’ of insulin release.[16] Sulpho-glucose intolerance who received sulphony- nylureas also increase the extended (‘second phase’)lureas.[12] The UKPDS investigators did not find any of insulin release that begins approximately 10 min-increase in risk of myocardial infarction among pa- utes later as insulin granules are translocated to thetients treated with sulphonylureas compared with membrane from within the β cell.[17] The protractedpatients randomised to insulin as monotherapy.[1] stimulation of the ‘second phase’ of insulin releaseThe Steno-2 Study,[8] has already been mentioned. involves the secretion of newly formed insulin gran-

ules. The increased release of insulin continuesA succession of more potent so-called second-while there is ongoing drug stimulation, providedgeneration sulphonylureas emerged in the 1970s andthe β cells are fully functional. Sulphonylureas can1980s, for example glibenclamide (glyburide),cause hypoglycaemia since insulin release is initiat-gliclazide and glipizide. The latest, glimepiride, wased even when glucose concentrations are below theintroduced in the late 1990s.[13] Glimepiride is anormal threshold for glucose-stimulated insulin re-once-daily drug for which claims have been madelease (approximately 5 mmol/L).that it might offer advantages over other sulpho-



Glucokinase

GLUT2

Glucose

Glucosemetabolism

Insulin

Exocytosis

ATP

Insulin

Receptors

Adrenergic

receptors

Ca2+

channel

Depolarisation

SUR1

Kir 6.2

K ATP

channel

cAMP

PDEinhibitors

GLP-1Exenatide

α2-adrenoceptorantagonists

PKA

Proinsulinbiosynthesis

Succinate esters

Ca2+-sensitiveproteins

SulphonylureasRepaglinideNateglinide

Fig. 2. The insulin-releasing effect of sulphonylureas and other agents on the pancreatic islet β cell. Sulphonylureas bind to the sulphonylu-rea receptor (SUR)-1 located within the plasma membrane. This closes Kir 6.2 potassium channels which reduces potassium efflux,depolarises the cell and opens voltage-dependent calcium influx channels. Raised intracellular calcium brings about insulin release.According to the stimulus-secretion model, metabolism of glucose generates adenosine 5′-triphosphate (ATP) leading to closure ofpotassium channels, permitting the normal β cell to link insulin secretion closely to glucose concentration. Sulphonylureas may alsoenhance nutrient-stimulated insulin secretion by other actions on the β cell. Other secretagogues, e.g. repaglinide, nateglinide, alsostimulate insulin secretion via the SUR-Kir 6.2 complex. Other agents, e.g. phosphodiesterase (PDE) inhibitors, glucagon-like peptide(GLP)-1 (7–36 amide), act via cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) to promote proinsulin synthesis(reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). GLUT2 = glucose transporter-2.

1.1.2 Pharmacokinetics liver, although metabolites and their routes of elimi-nation vary considerably between compounds.The principal distinguishing feature between dif-Since all sulphonylureas are highly bound to plasmaferent sulphonylureas relates to their pharmacokine-proteins they have the potential to interact with othertic characteristics (table III). Duration of action var-drugs sharing this binding, for example salicylates,ies from <12 hours for tolbutamide to >24 hours forsulphonamides and warfarin; displacement from cir-chlorpropamide because of differences in (i) rates ofculating proteins has been implicated in cases ofmetabolism; (ii) activity of metabolites; and (iii)severe sulphonylurea-induced hypoglycaemia (tablerates of elimination.[18] These properties have im-IV).portant implications for the risk of hypoglycaemia

associated with various sulphonylureas, an issue that 1.1.3 Indications and Contraindicationsis further complicated by retarded release prepara- Sulphonylureas remain a popular choice as first-tions of some compounds. All sulphonylureas are line oral therapy for patients with type 2 diabeteswell absorbed and most reach peak plasma concen- who have not achieved or maintained adequate gly-tration in 2–4 hours. They are metabolised in the caemic control using nonpharmacological measures.


392 Krentz & Bailey

Table III. Pharmacokinetic properties of sulphonylureas[19]

Sulphonylureas Daily dosage (mg) Duration of actiona Activity of metabolites Main route ofelimination

First generation

Chlorpropamideb 100–500 Long Active Urine >90%

Tolbutamidec 500–2000 Short Inactive Urine ≈100%

Second generation

Glibenclamide (glyburide) 2.5–15 Intermediate to long Active Bile ≈50%

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 <12h.

b No longer available in the UK.

c Should be taken immediately before meals.

d Modified (extended)-release preparation, Diamicron MR dose range 30–120mg.

Customarily they are preferred for patients who are develops (see section 1.1.5), or if a dosage incre-not overweight since weight gain is usually promot- ment produces no further improvement in glycaemiced by their use. Sulphonylureas can be used in control, it is advisable to return to the previous dose.combination with agents from other classes of an- Hypoglycaemia, whether actual or, more common-tidiabetic agents, with the exception of other insulin ly, perceived as a risk by either the patient or clini-secretagogues. Daytime sulphonylurea treatment cian, is the principal limitation to rapid dose escala-may be used in combination with bedtime insulin, tion of sulphonylureas. The latter point notwith-and can reduce insulin doses by up to 50%. This is standing, it should be borne in mind that thean increasingly accepted practice, albeit one that maximal blood glucose-lowering effect is usuallylacks firm evidence of long-term advantages over achieved at doses below the maximum recommen-insulin monotherapy.[20] As mentioned earlier, con- ded by the manufacturer. This is probably a reflec-tinued gradual loss of β-cell function is to be expec- tion of the fact that maximum stimulation of insulinted in most patients; this requires escalating insulin secretion has already been attained since β-celldoses with increasing duration of diabetes. function is significantly impaired. Improved β-cell

Sulphonylureas should be introduced at a low capacity resulting from alleviation of glucose toxici-dose, usually the lowest recommended by the manu- ty may contribute to the risk of hypoglycaemia infacturer, the blood glucose response being carefully some patients. Long-term glycaemic control shouldobserved over the first few weeks; self-monitoringof blood glucose by the patient may be helpful and,as mentioned earlier, is recommended where thereare concerns about the potential consequences ofhypoglycaemia, for example in the vulnerable elder-ly patient. In general, and intuitively, patients whohave achieved less marked degrees of fasting hyper-glycaemia after a trial of diet and exercise are morelikely to develop hypoglycaemia than those withmore marked hyperglycaemia. The dosage is in-creased at intervals of 2–4 weeks until the glycaemictarget is, hopefully, achieved. If hypoglycaemia

Table IV. Drugs that can potentiate the anti-hyperglycaemic effectof sulphonylureas

Mechanism Examples

Displacement from plasma Salicylates, sulphonamides,proteins warfarin, phenylbutazone, fibric

acid derivatives

Decreased hepatic metabolism Warfarin, monoamine oxidaseinhibitors, chloramphenicol,phenylbutazone

Decreased renal excretion Salicylates, probenecid,allopurinol

Intrinsic hypoglycaemic activity Salicylates, alcohol (ethanol),monoamine oxidase inhibitors



be monitored by periodic measurement of HbA1c (or nylurea therapy generally has modest effects onfructosamine if HbA1c is not available). blood lipid profiles, although some studies have

noted a small decrease in plasma triglyceride levels1.1.4 Efficacy – possibly linked to improved glycaemic control –The blood glucose-lowering efficacy of sulpho- and minor increments in high-density lipoprotein

nylureas has been evaluated in many retrospective (HDL)-cholesterol. When a sulphonylurea is used inand prospective studies, and from decades of collec- combination with another antidiabetic agent, thetive worldwide clinical experience. When used as glucose-lowering efficacy of the sulphonylurea ismonotherapy in patients inadequately controlled by approximately additive to the effect of the othernonpharmacological measures, sulphonylureas can agent. Once again, response is crucially dependentbe expected to reduce fasting plasma glucose by an on the presence of adequate β-cell function. Earlyaverage of 2–4 mmol/L accompanied by a decrease use of such combination therapy is indicated whenin HbA1c of 1–2%.[4,19,21] However, individual re- optimal titration of a single agent does not achievesponses are variable. Since the hypoglycaemic ef- adequate glycaemic control.fect of sulphonylureas is attributable to increased The combination of two different types of agentsinsulin secretion, the effectiveness of these drugs is is more likely to achieve glycaemic targets, albeitdependent on adequate β-cell function. The afore- for a variable period of time. If combination therapymentioned progressive β-cell failure that determines is started at a stage when hyperglycaemia is alreadythe natural history of type 2 diabetes may require an marked (after ‘failure’ of monotherapy), then β-cellincreased dosage of sulphonylureas if glycaemic depletion is likely to be advanced. Under thesecontrol deteriorates. Rapid and uncontrollable dete- circumstances, oral combination therapy is likely torioration of glycaemic control during sulphonylurea offer limited benefit and the need for an early movetherapy is sometimes termed ‘secondary sulphony- to insulin treatment is usually clear. Since there arelurea failure’. This phenomenon, which is some- occasional exceptions to this rule, a limited trial ofthing of a misnomer, occurs in approximately combination oral therapy may be worthwhile. How-5–10% of patients per annum with suggestions of ever, the temptation to procrastinate unduly ondifferences in ‘failure’ rates between some com- transferring the patient to insulin treatment shouldpounds.[21,22] The inability to maintain acceptable be firmly resisted, not least since some patientsglycaemic control is common to all sulphonylureas derive rapid symptomatic benefit from insulin ther-and is held to reflect an advanced stage of β-cell apy. Impending metabolic decompensation, with orfailure, that is, it is a reflection of disease progres- without ketosis, mandates immediate insulin treat-sion rather than a true failure of therapy. Individuals ment; more severe degrees of decompensation, forwho have greater degrees of β-cell reserve usually example obtundation, dehydration, ketosis-asso-respond well to sulphonylureas; early use of sulpho- ciated vomiting, necessitates emergency hospitalisa-nylureas as first-line monotherapy in these patients tion for treatment with intravenous insulin, fluidswill produce better blood glucose lowering than late and electrolytes.intervention in patients with severely compromisedβ-cell function. 1.1.5 Adverse Events

The plasma insulin concentrations achieved Hypoglycaemia, usually subclinical or minor butduring sulphonylurea therapy do not usually extend occasionally life threatening, is the most commonbeyond the range observed in the general non-diabe- and potentially most serious adverse effect of sul-tic population (including those with impaired glu- phonylurea therapy.[23] Patients receiving sulpho-cose tolerance), and suggestions that sulphonylurea- nylureas should receive instruction on the recogni-induced hyperinsulinaemia might increase the risk tion and prevention of hypoglycaemia and theof detrimental insulin-induced effects on the cardio- prompt actions they must take should warningvascular system remain unsubstantiated.[12] Sulpho- symptoms develop. Severe protracted hypogly-


394 Krentz & Bailey

caemia is more likely with longer-acting sulpho- patients receiving insulin therapy is orders of magni-nylureas such as glibenclamide, with tolbutamide tude higher. However, this does not detract from theholding the lowest place in the hierarchy of risk (see importance of sulphonylurea-induced hypogly-also section 1.1.6). Individuals with irregular eating caemia. Minor recurrent hypoglycaemia shouldhabits (see section 1.2.3) or excessive alcohol con- prompt a reassessment of the choice of agent andsumption are at higher risk of sulphonylurea-in- consideration of an alternative secretagogue, for ex-duced hypoglycaemia. As mentioned in section ample a rapid-acting insulin releaser (see section1.1.3, hypoglycaemia is also more likely to occur in 1.2). The treatment schedule, the possibility of drugpatients with satisfactory glycaemic control, as indi- interactions (table IV) and relevant features of thecated by an HbA1c concentration within, or just patient’s lifestyle, such as diet, meal patterns andabove, the non-diabetic reference range. These pa- alcohol use, should be reviewed. Severe episodes oftients should always be questioned directly about sulphonylurea-induced hypoglycaemia mandate im-recent symptoms of hypoglycaemia, although their mediate admission to hospital: treatment with a con-nonspecific nature can raise problems of over-diag- tinuous intravenous infusion of dextrose may benosis; self-monitoring of capillary blood glucose required for several days. There is a tendency forconcentrations during suggestive episodes should hypoglycaemia to recur shortly after initial resusci-help to clarify this issue, although uncertainties may tation with intravenous dextrose; the patient shouldnot be completely dispelled. If there is continuing not be prematurely discharged after emergencydoubt, a temporary reduction in dose is usually treatment. Where accumulation of chlorpropamideindicated. Estimates of the incidence of mild hypo- is suspected, renal elimination may be enhanced byglycaemia, that is, not requiring assistance from forced alkaline diuresis. The vasodilator diazoxideanother individual, are often based on symptoms and the somatostatin analogue octreotide[24] havewhich have not necessarily been confirmed by con- been used successfully to reversibly inhibit insulintemporaneous self-measurement of capillary blood secretion in severe sulphonylurea-induced hypogly-glucose. In the UKPDS, for example, about 20% of caemia, thereby reducing intravenous dextrose re-sulphonylurea-treated patients reported one or more quirements. These drugs should be regarded as po-episodes suggestive of hypoglycaemia annually; tentially useful adjuncts to intravenous glucose inother studies have suggested similar rates.[23] The some patients; octreotide avoids the adverse haemo-timing of hypoglycaemia tends to reflect the

dynamic effects of diazoxide, an obsolete antihyper-pharmacokinetics of the sulphonylurea. Thus, gli-

tensive agent that may pose a hazard in the elderlybenclamide has a propensity to cause inter-prandial

patient with compromised cardiovascular reflexes.hypoglycaemia whereas chlorpropamide tends to

Other adverse events of sulphonylureas includeinduce hypoglycaemia in the pre-breakfast period.uncommon sensitivity reactions – usually cutaneousMore severe hypoglycaemia (i.e. requiring assis-– that are usually transient; erythema multiforme istance) occurred in about 1% of sulphonylurea-treat-rare. Fever, jaundice and blood dyscrasias are veryed patients annually in the UKPDS. In general,rare; some sulphonylureas can reportedly precipitatelower rates (approximately 0.2–2.5 episodes peracute porphyria in predisposed individuals. In its1000 patient-years) have been reported from ad-heyday, chlorpropamide was notorious for causingverse event reporting to regulatory authorities orunpleasant facial flushing after consuming smallfrom physician-completed questionnaires. The mor-quantities of alcohol; photosensitivity has also beentality risk from severe sulphonylurea-induced hypo-reported. Chlorpropamide could also increase renalglycaemia has been calculated to be 0.014–0.033 persensitivity to antidiuretic hormone, occasionally1000 patient-years.[23] Predictably, longer-actingcausing water retention with hyponatraemia. In con-high-potency agents, such as glibenclamide, appeartrast, glibenclamide is credited with a mild diureticto carry the greater mortality risk. For comparison,action. Weight gain is regarded as a class effect ofthe occurrence of severe hypoglycaemia induced in



sulphonylurea therapy, typically amounting to held to be equivalent to 80mg of unmodified glicla-1–4kg and stabilising after about 6 months. This zide. In a recent 6-month comparative multicentreweight gain, which is always unwelcome, is thought study, gliclazide MR was associated with approxi-to reflect the anabolic effects of increased plasma mately 50% reduction in episodes of minor hypogly-insulin concentrations; some studies have suggested caemia compared with glimepiride, at similar levelsthat reduced loss of calories as glucose in the urine of glycaemic control; no episodes of severe hypo-may account for the majority of the weight glycaemia were observed with either agent in thisgain.[19,21] study.[26]

The saga of the questionable cardiovascular safe-1.2 Rapid-Acting Prandial Insulin Releasersty of the sulphonylureas was given a nudge by the

discovery that cardiac muscle and vascular smooth Under experimental conditions the first phase ofmuscle express isoforms of the SUR2A and SUR2B. glucose-stimulated insulin secretion is diminishedSulphonylureas that contain a benzamido group (gli- early in the natural history of type 2 diabetes. Thebenclamide, glipizide, glimepiride) can bind to prompt physiological rise in plasma insulin in res-SUR2A and SUR2B,[15] whereas those without (e.g. ponse to meals is attenuated and its peak delayed.tolbutamide, chlorpropamide and gliclazide) show An initial surge of insulin release appears to bevery little interaction with the cardiac and vascular particularly important for effective postprandialSUR receptors. The effects of the KATP channel suppression of hepatic glucose production; failure toopener nicorandil (an anti-anginal drug with cardi- suppress endogenous glucose production exacer-oprotective properties) are blocked by sulpho- bates postprandial hyperglycaemia. Because post-nylureas that have a benzamido group.[15] The clin- prandial hyperglycaemia contributes to elevatedical implications of these observations remain to be HbA1c levels it is a logical therapeutic target. Rapid-determined. Although very high concentrations of acting prandial insulin releasers are available thatsulphonylureas can cause contraction of cardiac and stimulate rapid, but short-lived, insulin secre-vascular muscle, this is regarded as being unlikely to tion.[27,28] These agents are taken orally immediatelybe clinically significant effect at therapeutic drug before a meal. Derivatives of meglitinide, such asconcentrations. Nonetheless, on the basis of adverse repaglinide and the phenylalanine derivative nateg-clinical experiences in high-risk patients, some high linide, are promoted as ‘prandial glucose regula-profile authorities continue to advocate that sulpho- tors’; in fact, fasting hyperglycaemia is also im-nylurea use be kept to a minimum in patients with proved to a lesser extent, particularly with repagli-overt coronary artery disease.[25]

nide. Clinical experience with these agents remainslimited in most countries; these drugs are appreci-

1.1.6 New Formulations of Sulphonylureasably more expensive than most sulphonylureas, the

Alterations to the formulation of some sulpho-latter also having the reassurance of outcome data

nylureas have been undertaken to modify the dura-from the UKPDS.

tion of action.[4] For example, a micronised formula-1.2.1 Mode of Actiontion of glibenclamide is available in the US that

increases the rate of gastrointestinal absorption, Benzamido prandial insulin releasers bind to thethereby enabling an earlier onset of action. A longer- SUR1 in the plasma membrane of the β cell at a siteacting (‘extended release’) formulation of glipizide distinct from the sulphonylurea binding site (figurehas also been introduced. A new (‘modified release’ 2). Since the KATP channel is closed when either the[MR]) formulation of gliclazide was launched in benzamido binding site or the sulphonylurea bind-some countries in 2002. This formulation has been ing site on the SUR1 is bound with its respectivedesigned to produce an initially rapid, followed by agonist, there is no advantage in giving a prandialsteady release of the drug to enable once-daily dos- insulin releaser in addition to a sulphonylurea. How-age. For the MR formulation of gliclazide, 30mg is ever, drugs are also in development that promote β-


396 Krentz & Bailey

cell proinsulin synthesis and act via signalling path- daily dosages is a potential disincentive. Repagli-ways distinct from the KATP channel (figure 2). The nide should ideally be taken about 15–30 minutesshort half-life of repaglinide results in enhancement before a meal. Starting with a low dose, for exampleof the first-phase and early second-phase of insulin 0.5mg before each main meal, the effect on gly-secretion that is less sustained than that observed caemic control is monitored and the dosage titratedwith sulphonylureas.[27-29] Theoretical benefits on up every 2 weeks to a maximum of 4mg before eachcardiovascular outcomes from preferentially target- main meal; if a meal is not consumed the corre-ing the postprandial period remain to be con- sponding dose of repaglinide should be omitted. Iffirmed.[28,29] It is unclear whether postprandial glycaemic targets are not met, consider early intro-hyperglycaemia per se is detrimental to the vascular duction of combination therapy (e.g. with metfor-endothelium or whether closely associated metabol- min). Unlike some sulphonylureas and metformin,ic disturbances, for example dyslipidaemia, are re- repaglinide is suitable for patients with moderatesponsible. Thus, the mechanism of the association renal impairment, although careful upward dosebetween post-challenge hyperglycaemia and mor- titration and close monitoring is still recommended.tality observed in the multicentre DECODE (Diabe- In contrast with the US, the UK license for nategli-tes Epidemiology: Collaborative analysis Of Diag- nide currently restricts use to combination therapynostic criteria in Europe) study is uncertain.[30] Ran- with metformin in patients who do not achieve gly-domised trials that are currently in progress should caemic targets with the latter drug as monother-help clarify this issue. apy.[29] In the US, nateglinide may also be used as

monotherapy or combined with a thiazolidinedione.1.2.2 Pharmacokinetics

Nateglinide should be used with caution in patientsRepaglinide is rapidly and almost completely

with hepatic disease.absorbed after oral administration, with peak plasmaconcentrations achieved in about 1 hour.[27] The

1.2.4 Efficacydrug is rapidly metabolised in the liver to inactive

Repaglinide (0.5–4mg taken about 15–30 min-metabolites, which are mainly excreted in bile.

utes before meals) results in dose-dependent in-When taken about 15 minutes before a meal, repag-

creases in insulin secretion with reduced postprandi-linide produces a prompt insulin-releasing effect,

al hyperglycaemia; a lesser reduction in fastingwhich is limited to a period of about 3 hours, rough-

hyperglycaemia is also observed. Overall reductionsly coinciding with the duration of meal digestion.

in HbA1c are similar in magnitude to those observedNateglinide has a slightly faster onset and shorter

with sulphonylureas, that is 1–2%. Combined withduration of action, its binding to target receptors

metformin, nateglinide reduces HbA1c by up tolasting only seconds. A 60mg dose of nateglinide

1.5%.[28,29]

taken 20 minutes before an intravenous glucosetolerance test restored first-phase insulin release and

1.2.5 Adverse Eventslowered glucose concentrations.[28,29]

The overall incidence of hypoglycaemic episodes1.2.3 Indications and Contraindications is lower with repaglinide than with sulphonyureas.Repaglinide may be used as monotherapy in pa- Sensitivity reactions, usually transient, can occur.

tients inadequately controlled by nonpharmacologi- Increased plasma levels of repaglinide have beencal measures. Suitable candidates for rapid-acting reported when co-administered with gemfibrozil. Ainsulin releasers include individuals with irregular small increase in bodyweight can be expected inlifestyles wherein meals are unpredictable or patients starting repaglinide as initial monotherapy,missed. The lower risk of hypoglycaemia associated but there may be little change in weight amongwith its use makes repaglinide an attractive option patients switched from a sulphonylurea. Nateglinidefor some elderly patients, particularly if other agents appears to have little effect on bodyweight whenare contraindicated. However, the need for multiple combined with metformin.[29]



Intestinallumen

Brushborder

Starch

Maltosemaltotriose

dextrins

Sucrose

Microvillus

α-Glucosidaseenzymes

α-Amylase

Enterocyte

Villus

α-Glucosidaseinhibitor (acarbose,miglitol, voglibose)

Fig. 3. α-Glucosidase inhibitors (e.g. acarbose) competitively inhibit the activity of α-glucosidase enzymes in the brush border of smallintestinal enterocytes (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).

2. α-Glucosidase Inhibitors carbohydrate digestion until further along the intes-tinal tract, in turn causing glucose absorption to be

Inhibitors of intestinal α-glucosidase enzymes delayed. The α-glucosidase inhibitors should be tak-retard the rate of carbohydrate digestion, thereby en with meals containing digestible carbohydrates,providing an alternative means to reduce postpran- not monosaccharides; these drugs generally do notdial hyperglycaemia.[31] Acarbose, the first α-

significantly affect the absorption of glucose. Sinceglucosidase inhibitor to be marketed, was intro- α-glucosidase inhibitors move glucose absorptionduced in the early 1990s. Recently, two additional

more distally along the intestinal tract they alteragents, miglitol and voglibose, have been intro-

glucose-dependent release of intestinal hormonesduced in some countries.[4] The α-glucosidase inhib-that enhance nutrient-induced insulin secretion. Re-itors do not cause weight gain, can reduce postpran-lease of gastric inhibitory polypeptide, which occursdial hyperinsulinaemia and have lowered plasmamainly from the jejunal mucosa, may be reduced bytriglyceride concentrations in some studies.[31] Theirα-glucosidase inhibitors, whereas glucagon-likegood safety record is a further advantage, but limitedpeptide-1 (7–36 amide) secretion (mostly from thegastrointestinal tolerability has substantially limitedileal mucosa) is increased. Overall, α-glucosidasetheir use. The relatively high cost of α-glucosidaseinhibitors reduce postprandial insulin concentrationsinhibitors is another consideration that has influ-through the attenuated rise in postprandial glucoseenced prescribing. In the UK, acarbose use remainslevels.[31]low.

2.1 Mode of Action 2.2 Pharmacokinetics

The α-glucosidase inhibitors competitively in-Acarbose is absorbed only to a trivial degreehibit the activity of α-glucosidase enzymes in the

(<2%).[31] The drug is degraded by amylases in thebrush border of enterocytes lining the intestinal villismall intestine and by intestinal bacteria; some of(figure 3). High affinity binding prevents these en-these degradation products are systemically ab-zymes from cleaving their normal disaccharide andsorbed, subsequently to be eliminated in the urineoligosaccharide substrates into monosaccharidesover about 24 hours.prior to absorption. This defers the completion of


398 Krentz & Bailey

2.3 Indications and Contraindications breast-feeding are traditionally regarded to be con-traindications for all oral antidiabetic drugs, mainly

An α-glucosidase inhibitor may be used as because of a lack of safety data rather than evidencemonotherapy for patients with type 2 diabetes that is of detrimental effects.inadequately controlled by nonpharmacological

2.4 Efficacymeasures. Because α-glucosidase inhibitors targetpostprandial hyperglycaemia, they can be a useful

An α-glucosidase inhibitor can reduce peak con-first-line treatment in patients who have a combina-

centrations of blood glucose and reduce interprandi-tion of only slightly raised basal glucose concentra-

al troughs. Used as monotherapy to patients whotions and more marked postprandial hypergly-

comply appropriately with dietary advice, an α-caemia. A recent multicentre clinical trial (STOP-

glucosidase inhibitor will typically reduce postpran-NIDDM [Study TO Prevent NonInsulin-Dependent

dial glucose concentrations by 1–4 mmol/L. TheDiabetes Mellitus]) confirmed the utility of acarbose

incremental area under the postprandial plasma glu-in preventing the transition from impaired glucose

cose curve can be more than halved in some individ-tolerance to diabetes[32] (see section 2.4). Acarbose

uals. There seems to be a ‘carry-over’ effect thatcan be used in combination with other antidiabetic

may produce a reduction in basal glycaemia up toagents. When starting therapy with an α-glucosidase

1 mmol/L. The decrease in HbA1c is usually aboutinhibitor it is said to be important to ensure that the

0.5–1.0%, provided that a high dose of the drug ispatient is taking a diet rich in complex carbohy-

tolerated and dietary compliance is maintained.[33]

drates, as opposed to simple sugars. AcarboseThere may be a trivial alteration in the gastrointesti-

should be taken with meals, starting with a low dose,nal absorption of other oral antidiabetic agents when

for example 50 mg/day, and slowly titrating up overused in combination therapy. In general, the extra

several weeks. Monitoring of glycaemic control,benefit to glycaemic control achieved by addition of

particularly postprandially, may be helpful. Thean α-glucosidase inhibitor to another antidiabetic

postprandial action of these agents would not beagent is additive. In the recently published multicen-

expected to induce hypoglycaemia, at least whentre STOP-NIDDM trial acarbose reduced the risk of

they are used as monotherapy. The maximum dos-progression from impaired glucose tolerance to type

age of α-glucosidase inhibitors may be limited by2 diabetes (relative hazard 0.75; 95% CI 0.63, 0.90;

gastrointestinal symptoms; this is certainly our ex-p = 0.0015).[32] This study randomised 1429 patients

perience with acarbose (see section 2.5). Intuitively,with impaired glucose tolerance to acarbose 100mg

patients experiencing gastrointestinal adverse ef-three times daily or placebo, of whom data were

fects with metformin may not be the best candidatesavailable for a modified intention-to-treat analysis

in whom to add an α-glucosidase inhibitor. A his-in 1368 patients. Glucose tolerance was determined

tory of chronic intestinal disease serves as a – large-using a 75g oral glucose tolerance test. Intriguingly,

ly theoretical – contraindication to acarbose andnew cases of hypertension and major cardiac events,

other agents in this class. High dosages of acarboseincluding overt and clinically silent myocardial in-

can occasionally increase liver enzyme concentra-farction, were also reduced by acarbose therapy.[34]

tions, and it is recommended that transaminase con-The latter were not primary endpoints of the study, a

centrations are measured at intervals in patients re-limitation acknowledged by the investigators.[34]

ceiving the maximum dosage (200mg three timesThe results of ongoing trials using acarbose and

daily in the UK, a dosage rarely attained in practiceother agents in this class are awaited.[35]

for the aforementioned reasons). If liver enzymesare raised, the dosage of acarbose should be reduced 2.5 Adverse Effectsto a level at which normal enzyme concentrationsare re-established. Alternative causes of hepatic dys- The most common problems with α-glucosidasefunction should be considered. Pregnancy and inhibitors are gastrointestinal adverse effects. In the



STOP-NIDDM trial 31% of acarbose-treated pa- guanidine derivatives in the 1920s. These earlytients compared with 19% on placebo discontinued antidiabetic agents were all but forgotten as insulintreatment early.[32] If the dosage is too high (relative became widely available and it was not until the lateto the amount of complex carbohydrate in the meal), 1950s that three antidiabetic biguanides were report-undigested oligosaccharides pass into the large bow- ed: metformin, phenformin and buformin. Phen-el.[23] Carbohydrates fermented by the flora of the formin was withdrawn in many countries in thelarge bowel cause flatulence, abdominal discomfort 1970s because of a high incidence of lactic acidosis;and sometimes diarrhoea. This is most likely to buformin received limited use in a few countries,occur during the initial titration of the drug and can leaving metformin as the main biguanide on a globalsometimes be minimised by slow titration and by basis. Metformin is the only biguanide available inensuring dietary compliance with meals rich in com- the UK and, since 1995, the US.[23,40] Extensiveplex carbohydrate. In some patients the gastrointes- clinical experience with metformin has been com-tinal symptoms may gradually subside with time, plemented by favourable results from the UKPDS.suggesting an adaptive response within the gastroin- Metformin also enjoys the accolade of being amongtestinal tract. Hypoglycaemia is only likely to be the least expensive of the oral antidiabetic agents.encountered when an α-glucosidase inhibitor is used

3.1.1 Mode of Actionin combination with a sulphonylurea or insulin.[23]

Metformin has a variety of metabolic effects,No clinically significant drug interations have beensome of which may confer clinical benefits thatreported. However, agents affecting gut motility canextend beyond glucose lowering (table V). How-potentially influence the efficacy and gastrointesti-ever, the molecular mechanisms of metformin havenal effects of acarbose; cholestyramine may in-yet to be fully identified. At the cellular level, met-crease the glucose-lowering effect of acarbose.formin improves insulin sensitivity to some extent,an action mediated via post-receptor signalling path-3. Insulin Sensitisersways for insulin.[41,42] Recent data have suggested

Insulin resistance is a prominent metabolic defect that adenosine 5′-monophosphate-activated proteinin most patients with type 2 diabetes.[36,37] Defectiveinsulin action is not confined to glucose metabolism,subtle defects also being demonstrable in the regula-tion of other aspects of intermediary metabolism(e.g. lipolysis), using appropriate investigative tech-niques. Many cross-sectional and prospective stud-ies have implicated insulin resistance in the patho-genesis of type 2 diabetes and the related metabolicsyndrome of cardiovascular risk.[38] Therefore, de-fective insulin action at target tissue level is anattractive therapeutic target in type 2 diabetes.[39]

The biguanides and, in particular, the thiazolidinedi-ones act directly against insulin resistance, and soare regarded as insulin sensitising drugs.

3.1 Biguanides

The finding that Galega officinalis (goat’s rue orFrench lilac), historically used as a traditional treat-ment for diabetes in Europe, was rich in guanidineled to the introduction of several glucose-lowering

Table V. Metabolic and vascular effects of metformin

Anti-hyperglycaemic action

suppresses hepatic glucose output

increases insulin-mediated glucose utilisation

decreases fatty acid oxidation

increases splanchnic glucose turnover

Weight stabilisation or reduction

Improves lipid profile

reduces hypertriglyceridaemia

lowers plasma fatty acids and LDL-cholesterol; raises HDL-cholesterol in some patients

No risk of serious hypoglycaemia

Counters insulin resistance

decreases endogenous or exogenous insulin requirements

reduces basal plasma insulin concentrations

Vascular effects

increased fibrinolysis

decreases PAI-1 levels

improved endothelial functionHDL = high-density lipoprotein; LDL = low-density lipoprotein;PAI-1 = plasminogen activator inhibitor-1.


400 Krentz & Bailey

Metformin

↑ Anaerobic glucosemetabolism

↑ Glucose uptakeand oxidation

↑ Glucoseuptake andoxidation

↑ Glycogenesis

↓ Oxidationof FA

↓ Fatty acids

Intestine Fat

↓ Glyconeogenesis

↓ Glycogenesis

↓ Oxidation of FA

Liver Muscle

↑ Lactate

↓ Hepatic glucoseproduction

↑ Insulin-mediatedglucose disposal

↓ Blood glucoseconcentration

Fig. 4. Actions of metformin. Inhibition of hepatic glucose production is regarded as the principal mechanism through which metforminlowers blood glucose (reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press). FA = fatty acids;↑ indicates increase; ↓ indicates decrease.

kinase (AMPK) is a possible intracellular target of nant glucose-lowering mechanism of action of met-metformin.[43] Through phosphorylation of key pro- formin is to reduce excessive rates of hepatic glu-teins, AMPK acts as a regulator of glucose and lipid cose production. Metformin reduces gluconeogene-metabolism and cellular energy regulation.[44] Since sis by increasing hepatic sensitivity to insulin (figuremetformin lowers blood glucose concentrations 4) and decreasing the hepatic extraction of certainwithout causing overt hypoglycaemia it is most ap- gluconeogenic substrates (e.g. lactate). Hepaticpropriately classed as an anti-hyperglycaemic – as glycogenolysis is also decreased by metformin. In-distinct from hypoglycaemic – agent. The clinical sulin-stimulated glucose uptake in skeletal muscle isefficacy of metformin in patients with type 2 diabe- enhanced by metformin. This involves an increasetes requires the presence of insulin. The drug does in the movement of insulin-sensitive glucose trans-not stimulate insulin release and a small decrease in porter molecules to the cell membrane; an increasefasting insulin concentrations is typically observed in the activity of the enzyme glycogen synthasein patients with hyperinsulinaemia.[21] The predomi- promotes synthesis of glycogen. Metformin also



acts in an insulin-independent manner to suppress other class of oral antidiabetic agent or with insulin.oxidation of fatty acids and to reduce triglyceride The drug is contraindicated in patients with im-levels in patients with hypertriglyceridaemia.[19] paired renal function (i.e. serum creatinineThis reduces the energy supply for hepatic gluco- >120–130 µmol/L, depending on lean body mass),neogenesis and has favourable effects on the glu- as a precaution against drug accumulation. Cardiaccose-fatty acid (Randle) cycle (in which fatty acids or respiratory insufficiency, or any other conditionare held to compete with glucose as a cellular energy predisposing to hypoxia or reduced perfusion (e.g.source).[37] Glucose metabolism in the splanchnic

hypotension, septicaemia) are further contraindica-bed is increased by metformin through insulin-inde-

tions, as well as liver disease, alcohol abuse and apendent mechanisms. This may contribute to the

history of metabolic acidosis. Metformin can beblood glucose-lowering effect of the drug, and inused in the elderly, provided that renal insufficiencyturn may help to prevent gains in bodyweight. Col-and other exclusions are not present. A difficulty inlectively, the cellular effects of metformin serve topractice is that significant renal dysfunction may becounter insulin resistance and to reduce the putativepresent without the aforementioned elevation of se-toxic metabolic effects of hyperglycaemia (glucoserum creatinine.toxicity) and fatty acids (lipotoxicity) in type 2

diabetes. The improvement in insulin sensitivity can causeovulation to resume in cases of anovulatory polycys-

3.1.2 Pharmacokinetics tic ovary syndrome (PCOS) [an unlicensed applica-Metformin is a stable hydrophilic biguanide that tion of the drug in the absence of diabetes].[45]

is quickly absorbed and eliminated unchanged in theMetformin should be taken with meals or immed-

urine. It is imperative that metformin is only pre-iately before meals to minimise possible gastrointes-scribed to patients with renal function that is suffi-tinal adverse effects. Treatment should be startedcient to avoid accumulation of the drug. Renal clear-with 500 or 850mg once daily, or 500mg twice dailyance of metformin is achieved more by tubular(one tablet with the morning and evening meals).secretion than glomerular filtration, the only signif-The dosage is increased slowly – one tablet at a timeicant drug interaction being competition with cime-– at intervals of about 2 weeks until the target leveltidine, which can increase plasma metformin con-of glycaemic control is attained. If the target is notcentrations. There is little binding of metformin to

plasma proteins. Metformin is not metabolised, and attained and an additional dose produces no greaterso does not interfere with the metabolism of co- effect, return to the previous dose and, in the case ofadministered drugs. Metformin is widely distribut- monotherapy, consider combination therapy by ad-ed, high concentrations being retained in the walls of ding in another agent (e.g. a sulphonylurea, prandialthe gastrointestinal tract; this provides a reservoir insulin releaser or thiazolidinedione). The maximalfrom which plasma concentrations are maintained. effective dosage appears to be about 2000 mg/day,Nevertheless, peak plasma metformin concentra- given in divided doses with meals, the absolutetions are short-lived: in patients with normal renal

maximum being 2550 or 3000 mg/day in differentfunction the plasma half-life (t1/2) for metformin is

countries. Several single tablet combinations of a2–5 hours, and almost 90% of an absorbed dosage issulphonylurea (usually glibenclamide) with a bigua-eliminated within 12 hours.[40]

nide (metformin or phenformin) have been availablein some European countries and elsewhere for more3.1.3 Indications and Contraindicationsthan a decade. A slow-release formulation of met-Metformin is the therapy of choice for over-formin and a fixed-dose combination of metforminweight and obese patients with type 2 diabetes.[42] Itwith glibenclamide is available in the UScan be equally effective in normal weight patients.(Glucovance, Bristol-Myers Squibb Company,Metformin can also be used in combination with any


402 Krentz & Bailey

Princeton, NJ, USA)1 and elsewhere (although not secretion. Indeed, the reduction of basal insulin con-in the UK). A combined rosiglitazone/metformin centrations, notably in hyperinsulinaemic patients,(Avandamet, GlaxoSmithKline, Philadelphia, PA, should itself improve insulin sensitivity by relievingUSA) [see section 3.2] preparation is also available the insulin-induced downregulation of insulin recep-in some parts of the world. tor number and suppression of post-receptor insulin

pathways.[35] Bodyweight tends to stabilise or de-During long-term treatment with metformin it iscrease slightly during metformin therapy. Small im-advisable to check (e.g. annually) for the develop-provements in the blood lipid profile may be observ-ment of contraindications, particularly an elevateded in hyperlipidaemic patients; plasma concentra-serum creatinine concentration (yearly measurementtions of triglycerides, fatty acids and low-densityof creatinine clearance posing practical difficulties).lipoprotein (LDL)-cholesterol tend to fall, whereasMetformin can reduce gastrointestinal absorption ofcardioprotective HDL-cholesterol tends to rise.cyanocobalamin (vitamin B12). While anaemia isThese effects appear to be independent of the anti-very rare, an annual haemoglobin measurement ishyperglycaemic effect, although a lowering of trig-prudent in patients at risk of nutritional deficiencies.lyceride and free fatty acids is likely to help improveIt is advised to stop metformin treatment temporari-insulin sensitivity and benefit the glucose-fatty acidly during use of intravenous radiographic contrastcycle.media, surgery and any other intercurrent situation

in which the exclusion criteria could be invoked.[46] In the UKPDS, overweight patients who startedSubstitution with insulin may be appropriate at such oral antidiabetic therapy with metformin showed atimes. Metformin alone is unlikely to cause serious statistically significant 39% reduced risk of myocar-hypoglycaemia, but hypoglycaemia becomes an is- dial infarction compared with conventional treat-sue when metformin is used in combination with an ment (p = 0.01).[47] No clear relationship is evidentinsulin-releasing agent or insulin. between metformin dosage and decreased coronary

artery events. This suggests that patients who can3.1.4 Efficacy only tolerate a low dosage of metformin may benefitThe long-term blood glucose-lowering efficacy from continuing the drug, even when other agents

of metformin is broadly similar to sulphonylureas. have to be added to optimise glycaemic control. TheAs monotherapy in patients who are not adequately decrease in myocardial infarction observed withcontrolled on nonpharmacological therapy, optimal- metformin therapy in the UKPDS was not attributa-ly titrated metformin therapy typically reduces fast- ble to more effective lowering of HbA1c or majoring plasma glucose by 2–4 mmol/L, corresponding effects on classic cardiovascular risk factors such asto a decrease in HbA1c by approximately 1–2%.[40] plasma lipids. Consequently, other potentiallyThe effect is dependent upon the presence of some vasoprotective effects of metformin have been in-endogenous β-cell function, and is largely indepen- voked. Reported benefits of metformin on non-clas-dent of bodyweight, age and duration of diabetes. sic cardiovascular risk factors (table V) include in-However, given the progressive nature of type 2 creased fibrinolysis and a reduced concentration ofdiabetes, re-assessment of dosage and consideration the anti-thrombolytic factor plasminogen activatorof additional therapy are required to maintain gly- inhibitor-1 (PAI-1).[41,46] The mechanism of thecaemic control in the long term.[4,21] Metformin has cardioprotective effects of metformin remains un-several features that mark it out as a good choice for certain. Detracting somewhat from this generallyfirst-line monotherapy. The anti-hyperglycaemic ac- favourable view was evidence of an initially greatertion of metformin means that it is unlikely to cause mortality when metformin was added to a sulphony-severe hypoglycaemia. This may be explained in lurea in a UKPDS substudy,[47] but longer-term fol-part because metformin does not stimulate insulin low-up has shown the benefits of metformin to be

1 The use of trade names is for product identification purposes only and does not imply endorsement.



sustained.[48] The explanation may have been, at by 33% overall. This compares with an intensiveregimen of diet and exercise, which reduced the riskleast in part, a spuriously low mortality rate in theby 58%.[51] Younger, more obese individuals show-comparator sulphonylurea monotherapy group.[47,49]

ed the most response to the preventive effects ofThe small number of events in this substudy adds tometformin.the uncertainty.

Sulphonylurea plus metformin is a commonly3.1.5 Adverse Effectsused combination and it would be reassuring to haveAbdominal discomfort and other gastrointestinaldefinitive safety data. Since each class as monother-

adverse effects, including diarrhoea, are encoun-apy appears safe from the cardiovascular perspec-tered fairly commonly during the introduction oftive, alternative explanations have been postulatedmetformin. Symptoms may remit if the dose is re-to explain similar findings seen in observationalduced and re-titrated slowly, but about 10% of pa-studies.[49] One plausible confounder might be great-tients cannot tolerate the drug at any dose. The moster cardiovascular risk attributable to more severeserious feared adverse event associated with metfor-metabolic derangements in patients treated with themin is lactic acidosis; the occurrence is rare (aboutcombination. Results from US trials and various0.03 cases per 1000 patient-years), but the mortalitylarge databases of follow-up with sulphonylurearate is high.[14,38] Since the background incidence of

plus metformin combination therapy have been re-lactic acidosis amongst type 2 diabetic patients has

assuring.[21,49,50] Additional well designed compara-not been established, it is possible that a proportion

tive studies of appropriate statistical power would beof cases that have been attributed to the drug were

required to quantify the risk to benefit equation forcaused by other factors; this remains an area of

combination treatment with sulphonylurea plus met-controversy. Most cases of lactic acidosis in patients

formin. However, recent results from the 5-yearreceiving metformin are due to inappropriate pre-

follow-up of UKPDS – with no further attempt toscription of the drug.[23,40,46,52] The leading contrain-

continue in randomised groups – show that the ad-dication is renal insufficiency.[52] Metformin in-

verse impact of sulphonylurea plus metformin com-creases glycolysis to lactate, particularly in the

bination seen initially is no longer evident.[48] At this splanchnic bed. The situation will be aggravated bypoint, the aforementioned benefits observed on mor- any hypoxic condition or impaired liver function.[53]

tality and cardiovascular disease in overweight pa- Hyperlactataemia occurs in cardiogenic shock andtients initially randomised to metformin monother- other illnesses that decrease tissue perfusion, andapy, while diminished, remained significant. metformin is often only an incidental factor in these

Consistent with the action of metformin on insu- cases.[54] In the absence of reliable data to the con-lin sensitivity, addition of metformin to patients trary, metformin treatment should be stopped im-receiving insulin therapy may necessitate a reduc- mediately in all cases of suspected or proven lactiction of insulin dosage. Some patients also show an acidosis, regardless of cause. Lactic acidosis is typi-improvement in glycaemic control, although this is cally characterised by a raised blood lactate concen-not always impressive. Metformin reduces the tration (e.g. >5 mmol/L), decreased arterial pH and/weight gain associated with insulin therapy and, by or bicarbonate concentration with an increased ani-decreasing the insulin dosage, there may be a de- on gap ([Na+] – [Cl– + HCO3–] >15 mmol/L).crease in hypoglycaemic episodes. The regimen has Presenting symptoms are often nonspecific, but fre-usually involved once-daily bedtime long-acting quently include hyperventilation, malaise and abdo-(lente) insulin or twice-daily insulin suspension iso- minal discomfort. Treatment should be commencedphane with metformin at mealtimes. In the US Dia- immediately without waiting to determine whetherbetes Prevention Program, metformin reduced the metformin is a cause; bicarbonate remains the ther-incidence of new cases of diabetes in overweight apy of choice but evidence of its efficacy is scanty.and obese patients with impaired glucose tolerance The value of haemodialysis in removing accumulat-


404 Krentz & Bailey

ed metformin has been challenged by some authori-ties, but dialysis may nonetheless be helpful in op-timising fluid and electrolyte balance during treat-ment with high-dose intravenous bicarbonates.[54]

3.2 Thiazolidinediones

Thiazolidinediones improve whole-body insulin

Table VI. Metabolic effects of thiazolidinediones[55]

Adipose tissue Muscle Liver

↑ Glucose uptake ↑ Glucose uptake ↓ Gluconeogenesis

↑ Fatty acid uptake ↑ Glycolysis ↓ Glycogenolysis

↑ Lipogenesis ↑ Glucose oxidation ↑ Lipogenesis

↑ Pre-adipocyte ↑ Glycogenesisa ↑ Glucose uptakea

differentiation

a Inconsistent findings.

↑ indicates increase; ↓ indicates decrease.sensitivity via multiple actions on gene regulation.These effects result from stimulation of a nuclear

glucose uptake via glucose transporter-4 in skeletalreceptor peroxisome proliferator-activated receptor-muscle, and some reports indicate that rates of glu-γ (PPARγ), for which thiazolidinediones are potentconeogenesis in the liver are reduced. Stimulation ofsynthetic agonists.[55] The antidiabetic activity oflipogenesis via PPARγ reduces circulating non-es-thiazolidinediones was described in the early 1980s,terified fatty acid (NEFA) concentrations throughtroglitazone being the first of the class to becomecellular uptake and triglyceride synthesis (figure 5).available for clinical use. Troglitazone was intro-The reduction in plasma NEFA concentrations isduced in the US in 1997, only to be withdrawn inassociated with increased glucose utilisation and2000 because of cases of idiosyncratic hepato-reducing gluconeogenesis by reducing operation oftoxicity resulting in fatalities. Troglitazone wasthe glucose-fatty acid cycle; reductions in ectopicavailable in the UK for only for a few weeks in 1997lipid deposition in muscle and liver may contributebefore being withdrawn by its distributor as reportsto the improvements on glucose metabolism. Thia-of hepatotoxicity accumulated in other countries. Tozolidinediones also reduce the production and ac-date, two other thiazolidinediones, rosiglitazone andtivity of the adipocyte-derived cytokine tumour ne-pioglitazone, have not shown the hepatotoxicity thatcrosis factor (TNF)-α.[55] The latter has been impli-led to the demise of troglitazone. Rosiglitazone andcated in the development of impaired insulin actionpioglitazone were introduced in the US in 1999 andin muscle,[58] although the precise role of TNFα inin Europe in 2000.[56] Combination preparationshuman states of insulin resistance remains unclear.(e.g. thiazolidinedione plus metformin) are alsoReductions in plasma insulin concentrations andavailable.lowering of circulating triglycerides are additional

3.2.1 Mode of Action indirect mechanisms that may help to improveStimulation of PPARγ is regarded as the principal whole-body insulin sensitivity. Thiazolidinediones,

mechanism through which thiazolidinediones en- like metformin, are anti-hyperglycaemic agents andhance insulin sensitivity. PPARγ is expressed at require the presence of sufficient insulin to generatehighest levels in adipose tissue, and less so in a significant blood glucose-lowering effect.muscle and liver. PPARγ operates in association

3.2.2 Pharmacokineticswith the retinoid X receptor. The resulting heter-odimer binds to nuclear response elements, thereby Rosiglitazone and pioglitazone are rapidly, andmodulating transcription of a range of insulin-sensi- nearly completely absorbed (1–2 hours to peak con-tive genes, in the presence of necessary cofactors centration), although absorption is slightly delayed(figure 4).[55,57] Many of the genes activated or sup- when taken with food. Both agents are extensivelypressed by thiazolidinediones are involved in lipid metabolised by the liver. Rosiglitazone is metabol-and carbohydrate metabolism (table VI). Stimula- ised mainly to very weakly active metabolites withtion of PPARγ by a thiazolidinedione promotes lesser activity that are excreted predominantly in thedifferentiation of pre-adipocytes with accompany- urine. The metabolites of pioglitazone are moreing lipogenesis, effects that promote or enhance the active and excreted mainly in the bile. Metabolismlocal effects of insulin. Thiazolidinediones increase of rosiglitazone is undertaken mainly by cyto-



chrome P450 (CYP) 2C8, which is not a widely thiazolidinediones.[60] Substituting a thiazolidine-activated isoform of CYP.[59] Thus, rosiglitazone dione for either a sulphonylurea or metformin indoes not interfere with the metabolism of other patients with inadequate glycaemic control is gener-drugs. Pioglitazone is metabolised in part by ally of limited value and risks a temporary deteriora-CYP3A4 but, to date, no clinically significant reduction in glycaemic control because of the slow onsettions in plasma concentrations of other drugs (e.g. of action of thiazolidinediones. Having been disap-oral contraceptives) has been reported. Although pointed with this experience, some UK diabetolo-both thiazolidinediones are almost completely gists have elected to use thiazolidinediones in com-bound to plasma proteins, their concentrations are bination with both a sulphonylurea and metfor-low and have not been reported to interfere with min.[60] The former strategy has met with variableother protein-bound drugs. success: some patients respond well, others show

little response, requiring transfer to insulin. The3.2.3 Indications and Contraindications

combination of thiazolidinedione plus insulin canIn the US, rosiglitazone and pioglitazone are

improve glycaemic control while reducing insulinavailable for use as monotherapy in non-obese anddosages in obese patients, although peripheral oede-obese patients with type 2 diabetes in whom diabe-ma has been reported.[61]

tes is not adequately controlled by nonpharmacolo-The main cautions to using thiazolidinediones aregical measures. They can also be used in combina-

listed in table VII. Rosiglitazone and pioglitazonetion with various other antidiabetic drugs and incan cause fluid retention with increased plasma vol-combination with insulin. In Europe, rosiglitazoneume, a reduced haematocrit and a decrease inand pioglitazone can be used as monotherapy if thehaemoglobin concentration. Therefore, the risk ofpatient is contraindicated for or intolerant of metfor-oedema and anaemia should be taken into account,min. Thiazolidinediones can be used in combinationand in Europe, use of thiazolidinediones in patientswith metformin or a sulphonylurea. In Europe, com-

bination with insulin remains a contraindication to with any evidence of congestive heart disease or

Thiazolidinedione Glucose Fatty acids

GLUT-4

Glucose uptakeand utilisation

aP2, acyl-CoA synthase

Lipogenesisand adipocytedifferentiation

Lipoproteinlipase

Transcription of certaininsulin-sensitive genes

PPARγ RXR

Adipocyte

↑ Hydrolysis ofcirculating triglyceridesin chylomicrons and VLDL

FATP

Fig. 5. Mechanism of action of a thiazolidinedione on an adipocyte (reproduced from Krentz and Bailey,[4] with permission from the RoyalSociety 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 lipopro-teins; ↑ indicates increase.


406 Krentz & Bailey

is some evidence for a modest blood pressure-lower-ing effect.[63]

As a precautionary measure, liver functionshould be assessed by measuring serum ALT beforestarting therapy and subsequently at 2-monthly in-tervals (or, in the US, as judged necessary by theprescribing clinician) during the first year of treat-ment; thereafter, periodic monitoring of liver func-tion is prudent. Pre-existing liver disease, the devel-opment of clinical hepatic dysfunction or elevatedALT levels >2.5 times the upper limit for the labora-tory serve as contraindications to thiazolidinedi-ones. However, as mentioned earlier, hepatotoxicityhas not been a concern with either rosiglitazone orpioglitazone. Isolated cases of nonfatal hepatocellu-lar damage have been reported; however, the issue isclouded by reports suggesting an intrinsically higherrisk of liver failure in patients with type 2 diabetes.Nevertheless, precautionary monitoring of liverfunction remains advisable. When initiating therapywith rosiglitazone or pioglitazone, blood glucosemonitoring and titration of drug dosage should beundertaken while bearing in mind that thiazolidine-diones exert a slowly generated anti-hypergly-

Table VII. Cautions in the use of thiazolidinediones

Active liver disease

This remains a contraindication to the use of thiazolidinedioneseven though neither rosiglitazone nor pioglitazone have beenassociated with troglitazone-like hepatotoxicity. In fact, the latterdrugs are under investigation as a potential treatment for non-alcoholic steatohepatitis. In 2004, the US FDA recommendationfor 2-monthly monitoring of biochemical liver function tests wasrelaxed. Instead, periodic biochemical monitoring is now left tothe supervising clinician’s discretion

Heart failure

The precise contraindications differ between countries. In Europe,current heart failure or a history of heart failure arecontraindications to thiazolidinediones

Insulin treatment

Although rosiglitazone and pioglitazone are licensed in the US foruse in combination with insulin, caution is required. Concernsabout higher rates of heart failure underlie this concern. TheEuropean Agency for the Evaluation of Medicinal Productsconsiders insulin therapy a contraindication to the use ofthiazolidinediones

Pregnancy and breast-feeding

Thiazolidinediones are classified as pregnancy category Cbecause of growth retardation in mid-to-late gestation in animalmodels. These drugs should only be used during pregnancy if thepotential benefit justifies the potential risk to the fetus

Polycystic ovary syndrome

Thiazolidinediones can cause ovulation to recommence in womenwith hyperandrogenism and chronic anovulation; risk ofpregnancy

caemic effect that usually requires 2–3 months toreach maximum effect.heart failure is contraindicated. The choice of which

patients to exclude on the basis of cardiac status According to the EU license, rosiglitazone can bevaries between the product labelling sheets in the given at a dosage of 4 mg/day in combination with aUS and Europe. Consensus guidelines from the sulphonylurea, increasing to 8 mg/day (either onceAmerican Heart Association and the American Dia- daily or in divided doses) in combination with met-betes Association have recently been published.[62]

formin. Pioglitazone can be given as a once-dailyPatients treated with a combination of insulin plus dosage of 15mg, increasing to 30mg if necessarythiazolidinedione appear to be at highest risk of (maximum 45mg in the US and Europe). The thera-oedema, although the absolute rate of cardiac failure peutic response varies markedly between patientsis low despite the fact the diabetes is a major risk and it can be difficult to predict those most likely tofactor for this complication.[62] The guidelines urge a respond. If no effect is observed after 3 months it iscautious approach and careful clinical monitoring, appropriate to consider the patient as a nonresponderespecially for patients likely to be at higher risk of and to stop the treatment. Rosiglitazone and piog-cardiac failure. The haemogloblin concentration litazone can be used in the elderly, provided thereshould be checked before starting a thiazolidine- are no contraindications. Both drugs may be used indione, bearing in mind that reductions of up to 1 g/ patients with mild-to-moderate renal impairment,dL in haemoglobin concentration may occur during although the potential for oedema is a concern. Intherapy. No adverse effects on blood pressure have women with anovulatory PCOS the improvement inbeen noted with the thiazolidinediones, even with insulin sensitivity may cause ovulation to resume

during thiazolidinedione therapy. A combinationthe increase in plasma volume; on the contrary, there



preparation containing rosiglitazone plus metformin subcutaneous depots increase as new small, insulin-(Avandamet; combining rosiglitazone/metformin sensitive adipocytes are formed. There are provi-in strengths 1mg/500mg, 2mg/500mg, 4mg/500mg, sional data to suggest that thiazolidinediones exert a2mg/1000mg, although not all strengths are avail- range of effects on aspects of the metabolic syn-able in all countries). drome that might reduce the risk of atherosclerotic

cardiovascular disease.[63,65] For example, thiazoli-3.2.4 Efficacy dinediones have been reported to downregulateAddition of rosiglitazone or pioglitazone to the PAI-1 expression. Thiazolidinediones have also

treatment schedule of patients whose glycaemic been reported to decrease urinary albumin excretioncontrol with a sulphonylurea or metformin is subop- to a greater extent than expected for the improve-timal has consistently resulted in significant reduc- ment in glycaemic control and to reduce circulatingtions in HbA1c. As judged by the available literature, markers of chronic low-grade inflammation.these agents have similar glucose-lowering effects, Preclinical studies suggesting that treatment of glu-reducing HbA1c by around 0.5–1.5%.[64] However, cose-intolerant animals with a thiazolidinedionethe participants in these clinical trials had known preserved β-cell function have yet to be confirmeddiabetes of several years’ duration, the effects of in human studies. In insulin-resistant women with athiazolidinediones being more apparent when β-cell history of gestational diabetes at high risk of type 2function is less impaired. While earlier use of thia- diabetes troglitazone reduced the incidence of new-zolidinediones may be advantageous, the longer- onset diabetes.[66] Whether thiazolidinediones willterm picture requires clarification. Estimates of in- prove more effective than conventional antidiabeticsulin sensitivity and β-cell function (based on ana- agents in reducing the decline in β-cell function inlysis of fasting glucose and insulin concentrations) patients with established type 2 diabetes remains tohave indicated that both defects can be improved by be determined, although preliminary data in patientsthe addition of a thiazolidinedione.[64] The effects on who respond to the drugs have been encouraging.[67]

plasma lipids and apoproteins have been the subject Also of considerable interest are the clinical impli-of debate. Rosiglitazone can cause a small rise in the cations of the aforementioned effects of thiazolidi-total cholesterol concentration, which stabilises nediones on risk factors for cardiovascular disease.within about 3 months. This is accounted for by a These effects, allied to direct anti-atherogenic ac-rise in both the LDL-cholesterol and the HDL-cho- tions reported in animal studies, are presently beinglesterol, leaving the LDL : HDL-cholesterol ratio studied in clinical trials with cardiovascular end-and the total : HDL-cholesterol ratio little changed points.[68]

or slightly raised. Pioglitazone generally appears tohave little effect on total cholesterol, and has been 3.2.5 Adverse Effectsshown to reduce triglyceride concentrations in sev- Rosiglitazone and pioglitazone are generally welleral studies. Both thiazolidinediones reduce the pro- tolerated. As noted in section 3.2.3, caution is ad-portion of the smaller, more dense (more atherogen- vised in heart disease; in the UK this includes aic) LDL particles.[64] To date, no prospective com- history of cardiac failure, oedema, anaemia and liverparative studies of the two drugs have been reported function requiring intermittent monitoring in accor-and the clinical implications of these changes are dance with the package labelling. If contraindica-uncertain.[63] tions arise during treatment, monitoring should be

Weight gain, similar in magnitude to sulphonylu- intensified and, if necessary, treatment discontin-rea therapy (typically 1–4kg) and stabilising over ued. Hypoglycaemia may occur several weeks after6–12 months, has been observed during thiazo- adding a thiazolidinedione to a sulphonylurea; self-lidinedione therapy. There is some evidence that the monitoring of blood glucose can be helpful in identi-distribution of body fat is altered such that visceral fying the point at which the dosage of the sulphony-adipose depots are little changed or reduced, while lurea should be reduced. Since PPARγ is expressed


408 Krentz & Bailey

by many tissues, albeit at a low level, we must await id improvement in glycaemic control (withinthe verdict of time for any unforeseen effects of days), whereas the maximal response to thiazoli-long-term stimulation with thiazolidinediones. For dinediones may take several weeks to becomeexample, PPARγ activation in macrophages can re- apparent. Maximal glucose-lowering effects areduce the production of some inflammatory cyto- usually obtained at doses lower than the manu-kines and might increase transformation of mono- facturer’s recommendations, e.g. 5–10 mg/daycytes to macrophages in the vascular wall. Stimula- for glibenclamide.tion of PPARγ in colon cells has been variously • If the glycaemic target is not achieved considerreported to increase and decrease division and adding another class of agent at an early stage.differentiation of these cells in different animals and Undertake the same evaluation and titration pro-cell models;[69] thus, familial polyposis coli is a cedure for the second agent. If a combination ofcontraindication to thiazolidinediones on theoretical two oral agents does not give adequate control,grounds. there may be some patients who will benefit from

addition of a third differently acting oral therapy.4. Summary and Conclusion Compliance generally deteriorates as the daily

number of doses increases.The management of patients with type 2 diabetes• Inability to achieve adequate glycaemic controlhas been given a firm evidence base in recent years

with a logical combination of oral therapies isthrough the results of randomised clinical trials,likely to indicate that the natural history of thenotably the UKPDS. An improved understanding ofdisease has progressed to a state of severe β-cellthe pathogenesis and natural history of this complexfailure. In this situation it is usually necessary tometabolic disorder has facilitated the application ofswitch to insulin therapy. Similarly, failure tonew therapeutic agents. Attainment and mainten-respond to an oral agent (so-called primary fail-ance of near-normal glycaemic control, whileure) or loss of control (secondary failure) usuallyminimising the risk of iatrogenic hypoglycaemia, isreflects a severe degree of insulin deficiency anda central long-term objective of therapy; however,early need for insulin. All oral antidiabetic agentsthis is often difficult to achieve in practice.are contraindicated in type 1 diabetes and inThe following general principles should be ap-major metabolic decompensation. Insulin may beplied while using oral antidiabetic drugs.required temporarily during intercurrent severe• Antidiabetic drug therapy must be consideredillness.carefully within the context of the overall care

plan. This includes an assessment of which agent Clinicians have a greater range of antidiabeticis most likely to achieve the therapeutic goals of treatments to choose from than ever, but this hasthe care plan, taking account of the accompany- brought a new level of complexity to management.ing medical and lifestyle circumstances and com- In addition, polypharmacy has become the norm formitments of the patient. many patients with type 2 diabetes in recognition of

• Always check for contraindications. the importance of treating hypertension and dys-• For some classes of agents, e.g. sulphonylureas, lipidaemia, both commonly encountered and modi-

duration of action and route of elimination will be fiable cardiovascular risk factors. The main classesimportant considerations if hypoglycaemia is of oral antidiabetic drugs are broadly similar in theirlikely, or if renal or liver disease raises concerns. glucose-lowering capacity, at least in the short- toShorter-acting preparations are preferred for medium term.[70] Accordingly, the most appropriatethose at risk of hypoglycaemia and in the elderly. therapy should be selected according to the clinical

and biochemical characteristics of the patient, safety• Start with the lowest recommended dose andconsiderations always being a major consideration.monitor response taking the mode of action intoThe UKPDS has influenced prescribing in the UKaccount. Sulphonylureas generally produce a rap-



since its publication (table VIII), with metformin geneity of type 2 diabetes, any single therapeuticapproach inevitably being of limited value. Thenow being the most commonly prescribed oral an-thiazolidinediones are appreciably more expensivetidiabetic drug. Not only did metformin reduce thethan metformin and sulphonylureas, which mayrisk of myocardial infarction and all-cause mortalitycontribute to their lesser use in many countries.in the UKPDS, it has the added advantages of de-Recent evidence suggesting that these agents maycades of clinical experience and it is inexpensivepreserve β-cell function suggests a unique propertyand weight-neutral (table V).that might usefully be exploited.[66] If the putativeOn theoretical grounds, the thiazolidinedionesanti-atherogenic benefits of the thiazolidinedionesappear promising, particularly with respect to poss-are confirmed this might dramatically alter theible preservation of β-cell function and the potentialapplication of these agents in clinical medicine.for cardiovascular disease prevention. However,

Some authorities argue the case for early use ofthese agents have perhaps not entirely fulfilled earlyinsulin-sensitising agents in combination therapy.[73]

expectations of success, at least if judged in terms ofThe realisation that the majority of type 2 diabetictheir glucose-lowering abilities, which are no betterpatients will require a combination of differentlythan the conventional drugs. Part of this shortfallacting oral antidiabetic agents to achieve and main-may be attributable to the complexity and hetero-tain glycaemic control in the long term has expand-ed interest in single tablet combinations. For pa-tients with newly diagnosed type 2 diabetes it seemslogical to introduce effective and safe pharmacolog-ical agents at an early stage, when responses to drugtreatment are likely to be optimal. Identifying indi-viduals with asymptomatic glucose intolerancewould permit the early application of lifestyle mea-sures; this might be followed by pharmacologicalintervention with metformin or acarbose. Furtherstudies are required to clarify this issue as none ofthe currently available drug is licensed for use inprediabetic individuals. The emerging epidemic oftype 2 diabetes in younger adults and children[74]

poses particular challenges for clinicians all tooaware of the limitations of current therapeutic op-tions. The lifetime risk of vascular complicationswill be high in these individuals and nonadherenceto therapy may be an even greater issue than inadults. In addition, despite exceptions,[75] lingeringconcerns over cardiovascular safety of sulpho-nylureas are largely dissipated by accumulatingdata. Until more data emerge, a cautious approach tothe use of new drugs in young patients seems pru-dent.

Acknowledgements

No sources of funding were used to assist in the prepara-tion of this manuscript. The authors have no conflicts ofinterest that are directly relevant to the content of this review.

Table VIII. Relative costs and frequency of prescriptions for oralantidiabetic 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 Repaglinide, nateglinidereleasers

Thiazolidinediones Rosiglitazone, pioglitazone

a This classification attempts to take average effectivemaintenance dosages into account and may be regarded asan approximate guide to relative UK Drug Tariff prices.

b Use of metformin has increased in recent years, this drugnow being the most widely prescribed oral antidiabetic agentin the UK (49%); sulphonylureas lie close behind, gliclazidebeing the most popular agent accounting for 31% of spendingon oral antidiabetic agents. Thiazolidinediones account foronly 5% of all prescriptions but for 32% of the cost of all oralantidiabetic agents in the UK; these figures predate the 2003license amendment permitting limited prescription ofthiazolidinediones as monotherapy in selected patients.Acarbose, the only α-glucosidase inhibitor in the UK, and therapid-acting prandial insulin releasers repaglinide andnateglinide account for a small percentage (<5%) ofprescribing or oral antidiabetic agents.

c In the UK the least expensive sulphonylureas are generictolbutamide and glibenclamide. At the maximumrecommended doses there is approximately a 5-folddifference between the least and most expensivesulphonylureas.


410 Krentz & Bailey

23. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerabilityReferencesprofiles of oral antidiabetic agents. Drug Saf 1994; 11: 223-41

1. UK Prospective Diabetes Study Group. Intensive blood-glucose24. Krentz AJ, Boyle PJ, Justice K, et al. Successful treatment ofcontrol with sulphonylureas or insulin compared with conven-

severe refractory sulfonylurea-induced hypoglycemia with oc-tional treatment and risk of complications in patients with typetreotide. Diabetes Care 1993; 16: 184-62 diabetes (UKPDS 33). Lancet 1998; 352: 837-53

25. Wilson SH, Kennedy FP, Garratt KN. Optimisation of the2. European Diabetes Policy Group. A desktop guide to type 2management of patients with coronary heart disease and type 2diabetes mellitus. Diabetic Med 1999; 16: 716-30diabetes mellitus. Drugs Aging 2001; 18: 325-333. Tuomilheto J. Controlling glucose and blood pressure in type 2

26. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study:diabetes. BMJ 2000; 321: 394-6double-blind comparison of once-daily gliclazide MR and4. Krentz AJ, Bailey CJ. Type 2 diabetes in practice. London:glimepiride in type 2 diabetic patients. Eur J Clin Invest 2004;Royal Society of Medicine Press, 200134: 535-42

5. Adler AI. Cardiovascular risk reduction in diabetes: under-27. Landgraf R. Meglitinide analogues in the treatment of type 2emphasized and overdue: messages from major trials. Clin

diabetes mellitus. Drugs Aging 2000; 17 (5): 411-25Med 2001; 1: 472-728. Dornhorst A. Insulotropic meglitinide analogues. Lancet 2001;6. Beckman JA, Creager MA, Libby P. Diabetes and atherosclero-

358: 1709-15sis: epidemiology, pathophysiology and management. JAMA29. Davies M. Nateglinide: better post-prandial glucose control.2002; 287: 2570-81

Prescriber 2002; 13: 17-277. Gray A, Clarke P, Farmer A, et al. Implementing intensive30. Qiao Q, Tuomilehto J, Borch-Johnsen K. Post-challenge hyper-control of blood glucose concentration and blood pressure in

glycaemia is associated with premature death and macrovascu-type 2 diabetes in England: cost analysis. United Kingdomlar complications. Diabetologia 2002; 46 Suppl. 1: M17-21Prospective Diabetes Study (UKPDS) Group. BMJ 2002; 325:

31. Lebovitz HE. α-Glucosidase inhibitors as agents in the treat-860-3ment of diabetes. Diabetes Revs 1998; 6: 132-458. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention

32. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for theand cardiovascular disease in patients with type 2 diabetes. Nprevention of diabetes mellitus: the STOP-NIDDM random-Engl J Med 2003; 348: 383-93ised trial. STOP-NIDDM Trial Research Group. Lancet 2002;9. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet,359: 2072-7sulfonylurea, metformin, or insulin in patients with type 2

33. Holman RR, Cull CA, Turner RC. A randomised double-blinddiabetes mellitus: progressive requirements for multiple thera-trial of acarbose in type 2 diabetes shows improved glycemicpies. JAMA 1999; 281: 2005-12control over 3 years (UK Prospective Diabetes Study 44).10. Evans AJ, Krentz AJ. Benefits and risks of transfer from oralDiabetes Care 1999; 22: 960-4antidiabetic agents to insulin in type 2 diabetes. In: Krentz AJ,

34. Chiasson J-L, Josse RG, Gomis R, et al. Acarbose treatment andeditor. Drug treatment of type 2 diabetes. Auckland: Adisthe risk of cardiovascular disease and hypertension in patientsBooks, 2000: 85-101with impaired glucose tolerance: the STOP-NIDDM trial. The11. Seltzer HS. A summary of criticisms of the findings and conclu-STOP-NIDDM Trial Research Group. JAMA 2003; 290:sions of the University Group Diabetes Program. Diabetes486-941972; 21: 976-9

35. Scheen A. Is there a role for alpha-glucosidase inhibitors in the12. Krentz AJ. Sulfonylureas in the prevention of vascular compli-prevention of type 2 diabetes mellitus? Drugs 2003; 63 (10):cations: from UKPDS to the ADVANCE study. Proceedings933-51of the VIIIth European symposium on metabolism. Amster-

36. Reaven GM. Role of insulin resistance in human disease. Diabe-dam: Elsevier Science International Congress Series 1253;tes 1988; 37: 1595-6072003: 261-77

37. Krentz AJ. Insulin resistance. Oxford: Blackwell Science, 200213. Evans AJ, Krentz AJ. Glimepiride: a new sulphonylurea. Pre-scriber 1999; 10: 51-8 38. Ginsberg HN. Insulin resistance and cardiovascular disease. J

Clin Invest 2000; 106: 453-814. Ashcroft FM, Gribble FM. ATP-sensitive K+ channels andinsulin secretion: their role in health and disease. Diabetologia 39. Campbell IW. Antidiabetic drugs past and future: will improv-1999; 42: 903-19 ing insulin resistance benefit cardiovascular risk in type 2

diabetes mellitus? Drugs 2000; 60 (5): 1017-2815. Gribble FM, Reimann F. Pharmacological modulation of KATPchannels. Biochem Soc Trans 2002; 30: 333-9 40. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:

16. Rorsman P, Renstrom E. Insulin granule dynamics in pancreatic 574-9beta cells. Diabetologica 2003; 46: 1029-45 41. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an up-

17. Groop LC. Sulfonylureas in NIDDM. Diabetes Care 1992; 15: date. Ann Intern Med 2002; 137: 25-331737-54 42. Cusi K, DeFronzo RA. Metformin: a review of its metabolic

18. Rendell M. The role of sulfonylureas in the management of type effects. Diabetes Rev 1998; 6: 89-1312 diabetes. Drugs 2004; 64 (12): 1339-58 43. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein

19. Bailey CJ, Day C. Antidiabetic drugs. Br J Cardiol 2003; 10: kinase in the mechanism of action of metformin. J Clin Invest128-36 2001; 108: 1167-74

20. Yki-Jarvinen H. Combination therapies with insulin in type 2 44. Winder WW, Hardie DG. AMP-activated protein kinase, adiabetes. Diabetes Care 2001; 24: 758-67 metabolic master switch: possible roles in type 2 diabetes. Am

J Physiol 1999; 277: E1-E1021. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mel-litus. Ann Intern Med 1999; 131: 281-303 45. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic

22. Lebovitz HE. Insulin secretagogues: old and new. Diabetes ovary syndrome: systematic review and meta-analysis. BMJRevs 1999; 7: 139-53 2003; 327: 951-5



46. Howlett HCS, Bailey CJ. A risk-benefit assessment of metfor- 62. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use,min in type 2 diabetes mellitus. In: Krentz AJ, editor. Drug fluid retention, and congestive heart failure: a consensus state-treatment of type 2 diabetes. Auckland: Adis Books, 2000: ment from the American Heart Association and the American61-76

Diabetes Association. Circulation 2003; 108: 2941-847. UK Prospective Diabetes Study Group. Effect of intensive 63. Parulkar AA, Pendergrass ML, Granda-Ayala R, et al. Nonhy-

blood-glucose control with metformin on complications inpoglycemic effects of thiazolidinediones. Ann Intern Medoverweight patients with type 2 diabetes (UKPDS 34). Lancet2001; 134: 61-711998; 352: 854-65

64. Yki-Jarvinen H. Thiazolidinedions. N Engl J Med 2004; 351:48. The Oxford Centre for Diabetes, Endocrinology and Metabol-1106-18ism: Diabetes Trials Unit. UK Prospective Diabetes Study

[online]. Available from URL: http://www.dtu.ox.ac.uk/ 65. Marten FMAC, Visseren FLJ, Lemay J, et al. Metabolic andukpds/index.html [Accessed 2004 Nov 23] additional vascular effects of thiazolidinediones. Drugs 2002;

49. Hermann LS, Lindberg G, Lindblad U, et al. Efficacy, effec- 62 (10): 1463-80tiveness and safety of sulphonylurea-metformin combination 66. Buchanan TA, Xiang AH, Peters RK, et al. Preservation oftherapy in patients with type 2 diabetes. Diabetes Obes Metab

pancreatic beta-cell function and prevention of type 2 diabetes2002; 4: 296-304by pharmacological treatment of insulin resistance in high-risk

50. Johnson JA, Majumdar SR, Simpson SH, et al. Decreasedhispanic women. Diabetes 2002; 51: 2796-803mortality associated with sulfonylurea monotherapy in type 2

67. Bell DSH. B-cell rejuvenation with thiazolidinediones. Am Jdiabetes. Diabetes Care 2002; 25: 2244-8Med 2003; 115 (8A): 20-23S51. Diabetes Prevention Program Research Group. Reduction of the

68. Roberts AW, Thomas A, Rees A, et al. Peroxisome proliferatorincidence of type 2 diabetes with lifestyle intervention ormetformin. N Engl J Med 2002; 346: 393-403 activated receptor-γ agonists in atherosclerosis: current evi-

dence and future directions. Curr Opin Lipidol 2003; 14:52. Sulkin T, Bosman D, Krentz AJ. Contraindications to metfor-min therapy in patients with NIDDM. Diabetes Care 1997; 20: 567-73925-8 69. Schoonjans K, Auwerx J. Thiazolidinediones: an update. Lancet

53. Holt HB, Krentz AJ. Metabolic emergencies in type 2 diabetes. 2000; 355: 1008-10In: Goldstein B, Muller-Wieland D, editors. Textbook of type 70. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabe-2 diabetes. London: Martin Dunitz, 2003: 183-98

tes. JAMA 2002; 287: 360-7254. Lalau J-D, Race J-M. Metformin and lactic acidosis in diabetic

71. Kendall H. Trends in prescribing of drugs used to treat diabetes.humans. Diabetes Obes Metab 2000; 2: 131-7

Prescriber 2003; 14 (24): 38-955. Day C. Thiazolidinediones: a new class of antidiabetic drugs.

72. Cuthbertson D, Leese G. Managing type 2 diabetes: oral an-Diabetic Med 1999; 16: 1-14tidiabetic drugs. Prescriber 2003; 14 (13): 47-53

56. Krentz AJ, Bailey CJ, Melander A. Thiazolidinediones for type73. Bell DSH. Type 2 diabetes mellitus: what is the optimal treat-2 diabetes. BMJ 2000; 321: 252-3

ment regimen? Am J Med 2004; 116 (5A): 23S-9S57. Rosen ED, Spiegelman BM. PPAR-γ: a nuclear regulator of

74. Kaufman FR. Type 2 diabetes mellitus in children and youth: ametabolism, differentiation, and cell growth. J Biol Chemnew epidemic. J Pediatr Endocrinol Metab 2002; 15 Suppl. 2:2001; 276: 37731-4737-44

58. Fasshauer M, Paschke R. Regulation of adipocytokines and75. Huizar JF, Gonzalez LA, Alderman J, et al. Sulfonylureasinsulin resistance. Diabetologia 2003; 46: 1594-1603

attenuate electrocardiographic ST-segment elevation during a59. Baldwin SJ, Clarke SE, Chenery RJ. Characterisation of the

myocardial infarction. J Am Coll Cardiol 2003; 42: 1017-21cytochrome P450 enzymes involved in the in vitro metabolismof rosiglitazone. Br J Clin Pharmacol 1999; 48: 424-32

60. Bailey CJ, Day C, Krentz AJ. Nice timing for glitazones. Br J Correspondence and offprints: Dr Andrew J. Krentz,Diabetes Vasc Dis 2003; 3: 366-7

Mailpoint 47, Southampton General Hospital, Tremona61. Buch HN, Baskar V, Barton DM, et al. Combination of insulin

Road, Southampton SO16 6YD, UK.and thiazolidinedione therapy in massively obese patients withtype 2 diabetes. Diabetic Med 2002; 19: 572-4 E-mail: [email protected]


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