oral antidiabetic agents1

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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

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3861. Insulin Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

1.1 Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3901.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

1.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.1.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

1.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3931.1.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

1.1.6 New Formulations of Sulphonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3951.2 Rapid-Acting Prandial Insulin Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

1.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395


1.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3961.2.5 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

2. -Glucosidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3972.3 Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

2.4 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

3.1.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4023.1.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

3.2 Thiazolidinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4043.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404


3.2.4 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4073.2.5 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

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


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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 or

obese at diagnosis and will be unable to achieve or sustain near normoglycaemiawithout oral antidiabetic agents; a sizeable proportion of patients will eventually

require insulin therapy to maintain long-term glycaemic control, either as mono-

therapy or in conjunction with oral antidiabetic therapy. The frequent need for

escalating therapy is held to reflect progressive loss of islet -cell function,usually in the presence of obesity-related insulin resistance.

Todays clinicians are presented with an extensive range of oral antidiabetic

drugs for type 2 diabetes. The main classes are heterogeneous in their modes of

action, safety profiles and tolerability. These main classes include agents that

stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues),

reduce hepatic glucose production (biguanides), delay digestion and absorption of

intestinal carbohydrate (-glucosidase inhibitors) or improve insulin action (thia-zolidinediones).

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the

benefits of intensified glycaemic control on microvascular complications in newly

diagnosed patients with type 2 diabetes. However, the picture was less clearcut

with regard to macrovascular disease, with neither sulphonylureas nor insulin

significantly reducing cardiovascular events. The impact of oral antidiabetic

agents on atherosclerosis beyond expected effects on glycaemic control is an

increasingly important consideration. In the UKPDS, overweight and obese

patients randomised to initial monotherapy with metformin experienced signif-

icant reductions in myocardial infarction and diabetes-related deaths. Metformin

does not promote weight gain and has beneficial effects on several cardiovascular

risk factors. Accordingly, metformin is widely regarded as the drug of choice for

most patients with type 2 diabetes. Concern about cardiovascular safety of

sulphonylureas has largely dissipated with generally reassuring results from

clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study

showed that intensive target-driven, multifactorial approach to management,

based around a sulphonylurea, reduced the risk of both micro- and macrovascular

complications in high-risk patients. Theoretical advantages of selectively target-

ing postprandial hyperglycaemia require confirmation in clinical trials of drugs

with preferential effects on this facet of hyperglycaemia are currently in progress.

The insulin-sensitising thiazolidinedione class of antidiabetic agents has 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 biochemical

assessment of the patient, safety considerations being paramount. In some circum-

stances, for example pregnancy or severe hepatic or renal impairment, insulin may

be the treatment of choice when nonpharmacological measures prove inadequate.

Insulin is also required for metabolic decompensation, that is, incipient or actual

diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain

comorbidities, for example presentation with myocardial infarction during other

acute intercurrent illness, may make insulin the best option.

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

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


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Oral Antidiabetic Agents 387

haemoglobin (HbA1c) concentration, supplemented in some patients by self

monitoring of capillary blood glucose. The average glucose-lowering effect of the

major classes of oral antidiabetic agents is broadly similar (averaging a 12%

reduction in HbA1c), -glucosidase inhibitors being rather less effective. Tailor-ing the treatment to the individual patient is an important principle. Doses are

gradually 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 a

thiazolidinedione, are logical and widely used, and combination preparations are

now available in some countries. While the benefits of metformin added to a

sulphonylurea were initially less favourable in the UKPDS, longer-term data have

allayed concern. When considering long-term therapy, issues such as tolerability

and convenience are important additional considerations.Neither sulphonylureas nor biguanides are able to appreciably alter the rate of

progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data

suggesting that thiazolidinediones may provide better long-term glycaemic 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-risk

individuals with glucose intolerance has been demonstrated with troglitazone,

metformin and acarbose. However, intensive lifestyle intervention can be more

effective than drug therapy, at least in the setting of interventional clinical trials.

No antidiabetic drugs are presently licensed for use in prediabetic individuals.

In 1998, the results of the randomised, multicen- management plan that encompasses effective treat-

tre UKPDS (United Kingdom Prospective Diabetes ment of hypertension and dyslipidaemia;[2-6] both

Study)[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 antidiabetic

agents or insulin significantly reduced the develop-

ment of microvascular complications (table I).[1]

This knowledge drives current clinical practice, in

which treatment is directed to the attainment of

near-normoglycaemia, i.e. glycosylated haemo-

globin (HbA1c) concentrations of 6.57.0%.[2-4]

While such targets may be perceived as being un-

realistic for many perhaps most patients, there is

a broad consensus that chronic hyperglycaemia

should be managed as well as is possible, weighing

safety and quality-of-life considerations on an 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 Kingdom

Prospective Diabetes Study) glycaemic control study.[1] Relative

risk (RR) reductions in clinical endpoints for patients randomised to

intensive (i.e. sulphonylurea or insulin) vs conventional therapy (i.e.

diet)

Endpoints RR for Confidence Log-rank

intensive intervala p-value

therapy

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]



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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 improve

risk factors for atherosclerosis, the principal cause metabolic control through reductions in bodyweight

of 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


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obese, sedentary middle-aged patients. Failure to diabetes. We consider both well established drugs

respond rapidly (i.e. within a week or two) to an oral and recent additions to the armamentarium. For each

agent in a patient thought to be complying with the class of agents we present an outline of the mode of

dietary 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, current

escalation 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 have

served for patients: (i) who fail to respond adequate- grouped the drugs according to their principal mode

ly to a combination of oral agents; (ii) in whom of action: (i) those that increase insulin secretion

control deteriorates despite logical and adequate (insulin secretagogues); (ii) drugs delaying the rate

drug combinations; or (iii) for whom safety and of digestion and absorption of carbohydrates (-efficacy considerations favour its use as the drug of glucosidase inhibitors); and (iii) those with direct

choice, 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 taken

classes 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 a

welcome expansion in recent years. However, the progressive disease implies that drug dosages will

evidence base and clinical experience vary consider- need to be increased or therapy moved to another

ably 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 rathertice in the UK, we have endeavoured to provide a

subjective grounds, such as familiarity with a partic-review that acknowledges important differences in

ular 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 glycaemic

control, enhance

quality of life

Diagnosis

Diet, exercise, weight control

and 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 inadequate

control of glycaemia

or 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 glycaemic

target is not achieved. Late introduction of combinations of oral antidiabetic agents is often a prelude to insulin treatment. 1 Note that in

Europe, thiazolidinediones and nateglinide have limited licenses. The -glucosidase inhibitor miglitol is also available in some countries(reproduced from Krentz and Bailey,[4] with permission from the Royal Society of Medicine Press).



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390 Krentz & Bailey

recommended in the UK, can be usefully comple- nylureas with respect to the risks of weight gain and

mented 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 and

lar clinical scenarios, for example in patients in clinical outcome data are not available, as they are

whom iatrogenic hypoglycaemia is a concern. for the agents used in the UKPDS. The clinical

relevance of theoretical, but much debated, effects

of glimepiride on ischaemic preconditioning 1. Insulin Secretagogueswhereby a brief episode of ischaemia protects the

myocardium against the detrimental effects of sub-1.1 Sulphonylureas sequent and more severe interruption of perfusion

remain uncertain. The issues of the importance ofSulphonylureas 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 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 cells. The drugs bind to the -cellfering a range of pharmacokinetic options. How-sulphonylurea receptor (SUR)-1, part of a trans-ever, doubts about safety were raised in the 1970s. A

membrane 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 effects

KATP channels; this reduces cellular potassium ef-of tolbutamide. The UGDP was heavily criticisedfor perceived methodological failings and its find- flux favouring membrane depolarisation. In turn,

ings were far from being universally accepted. Sub- depolarisation opens voltage-dependent calcium

sequent 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 the

dence, but a review of the available literature release of insulin (figure 2). When sulphonylureas

provides little in the way of convincing evidence of interact with SUR1 in the -cell plasma membranecardiovascular toxicity.[12] Indeed, some studies they cause prompt release of pre-formed insulin

have 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 the

tients treated with sulphonylureas compared with membrane from within the cell.[17] The protractedpatients randomised to insulin as monotherapy.[1] stimulation of the second phase of insulin release

The 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 and

the cells are fully functional. Sulphonylureas can1980s, for example glibenclamide (glyburide),cause hypoglycaemia since insulin release is initiat-gliclazide and glipizide. The latest, glimepiride, was

ed even when glucose concentrations are below theintroduced in the late 1990s.[13] Glimepiride is a

normal 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-



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Glucokinase

GLUT2

Glucose

Glucose

metabolism

Insulin

Exocytosis

ATP

Insulin

Recepto

rs

Adrene

rgic

receptor

s

Ca2+

channel

Depolarisa

tion

SUR1

Kir6.2

KATP

channe

l

cAMP

PDE

inhibitors

GLP-1

Exenatide

2-adrenoceptorantagonists

PKA

Proinsulin

biosynthesis

Succinate esters

Ca2+-sensitive

proteins

SulphonylureasRepaglinide

Nateglinide

Fig. 2. The insulin-releasing effect of sulphonylureas and other agents on the pancreatic islet 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 cell to link insulin secretion closely to glucose concentration. Sulphonylureas may alsoenhance nutrient-stimulated insulin secretion by other actions on the 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 (736 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 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 Contraindications

is 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 diabetes

well absorbed and most reach peak plasma concen- who have not achieved or maintained adequate gly-tration in 24 hours. They are metabolised in the caemic control using nonpharmacological measures.



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392 Krentz & Bailey

Table III. Pharmacokinetic properties of sulphonylureas[19]

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

elimination

First generationChlorpropamideb 100500 Long Active Urine >90%

Tolbutamidec 5002000 Short Inactive Urine 100%

Second generation

Glibenclamide (glyburide) 2.515 Intermediate to long Active Bile 50%

Glimepiride 16 Intermediate Active Urine 80%

Glipizide 2.520 Short to intermediate Inactive Urine 70%

Gliquidone 15180 Short to intermediate Inactive Bile 95%

Gliclazide 40320d Intermediate Inactive Urine 65%

a Long >24h; intermediate 1224h; short


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be monitored by periodic measurement of HbA1c (or nylurea therapy generally has modest effects on

fructosamine 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 in

and prospective studies, and from decades of collec- combination with another antidiabetic agent, the

tive worldwide clinical experience. When used as glucose-lowering efficacy of the sulphonylurea is

monotherapy in patients inadequately controlled by approximately additive to the effect of the other

nonpharmacological measures, sulphonylureas can agent. Once again, response is crucially dependent

be expected to reduce fasting plasma glucose by an on the presence of adequate -cell function. Earlyaverage of 24 mmol/L accompanied by a decrease use of such combination therapy is indicated when

in HbA1c of 12%.[4,19,21] However, individual re- optimal titration of a single agent does not achieve

sponses 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 -cell function. The afore- for a variable period of time. If combination therapymentioned progressive -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 -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 are

lurea 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-510% 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 -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-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 compromised

-cell function. 1.1.5 Adverse EventsThe plasma insulin concentrations achieved Hypoglycaemia, usually subclinical or minor but

during sulphonylurea therapy do not usually extend occasionally life threatening, is the most common

beyond 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 the

of detrimental insulin-induced effects on the cardio- prompt actions they must take should warningvascular system remain unsubstantiated.[12] Sulpho- symptoms develop. Severe protracted hypogly-



10/27

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 the

holding 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 should

habits (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 patients 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 insulin

temporaneous 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 0.22.5 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 0.0140.033 per

sensitivity to antidiuretic hormone, occasionally1000 patient-years.[23] Predictably, longer-acting

causing water retention with hyponatraemia. In con-high-potency agents, such as glibenclamide, appear

trast, 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



11/27


sulphonylurea therapy, typically amounting to held to be equivalent to 80mg of unmodified glicla-

14kg and stabilising after about 6 months. This zide. In a recent 6-month comparative multicentre

weight 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 levels

that 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 this

gain.[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 smoothUnder experimental conditions the first phase of

muscle express isoforms of the SUR2A and SUR2B.glucose-stimulated insulin secretion is diminished

Sulphonylureas 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 that

sulphonylureas 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 remains

limited in most countries; these drugs are appreci-1.1.6 New Formulations of Sulphonylureas

ably more expensive than most sulphonylureas, theAlterations to the formulation of some sulpho-

latter also having the reassurance of outcome datanylureas 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 the

thereby enabling an earlier onset of action. A longer- SUR1 in the plasma membrane of the cell at a siteacting (extended release) formulation of glipizide distinct from the sulphonylurea binding site (figure

has 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 respective

designed to produce an initially rapid, followed by agonist, there is no advantage in giving a prandial

steady 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 -



12/27

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 1530 minutes

short half-life of repaglinide results in enhancement before a meal. Starting with a low dose, for example

of 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 titrated

with sulphonylureas.[27-29] Theoretical benefits on up every 2 weeks to a maximum of 4mg before each

cardiovascular 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. If

firmed.[28,29] It is unclear whether postprandial glycaemic targets are not met, consider early intro-

hyperglycaemiaper 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 moderate

sponsible. Thus, the mechanism of the association renal impairment, although careful upward dose

between 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 therapy

nostic 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 plasma

concentrations achieved in about 1 hour.[27] The1.2.4 Efficacydrug is rapidly metabolised in the liver to inactiveRepaglinide (0.54mg taken about 1530 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 fasting

which is limited to a period of about 3 hours, rough-hyperglycaemia is also observed. Overall reductions

ly coinciding with the duration of meal digestion.in HbA1c are similar in magnitude to those observed

Nateglinide has a slightly faster onset and shorterwith sulphonylureas, that is 12%. Combined with

duration of action, its binding to target receptorsmetformin, nateglinide reduces HbA1c by up to

lasting only seconds. A 60mg dose of nateglinide1.5%.[28,29]

taken 20 minutes before an intravenous glucose

tolerance test restored first-phase insulin release and 1.2.5 Adverse Eventslowered glucose concentrations.[28,29]

The overall incidence of hypoglycaemic episodes

1.2.3 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 been

cal measures. Suitable candidates for rapid-acting reported when co-administered with gemfibrozil. A

insulin releasers include individuals with irregular small increase in bodyweight can be expected in

lifestyles 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 among

with its use makes repaglinide an attractive option patients switched from a sulphonylurea. Nateglinide

for 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]



13/27


Intestinal

lumen

Brush

border

Starch

Maltose

maltotriosedextrins

Sucrose

Microvillus

-Glucosidaseenzymes

-Amylase

Enterocyte

Villus

-Glucosidaseinhibitor (acarbose,miglitol, voglibose)

Fig. 3. -Glucosidase inhibitors (e.g. acarbose) competitively inhibit the activity of -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. -Glucosidase Inhibitors carbohydrate digestion until further along the intes-tinal tract, in turn causing glucose absorption to be

Inhibitors of intestinal -glucosidase enzymes delayed. The -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 -

significantly affect the absorption of glucose. Sinceglucosidase inhibitor to be marketed, was intro- -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 -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] Their-glucosidase inhibitors, whereas glucagon-likegood safety record is a further advantage, but limitedpeptide-1 (736 amide) secretion (mostly from thegastrointestinal tolerability has substantially limitedileal mucosa) is increased. Overall, -glucosidasetheir use. The relatively high cost of-glucosidase

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

(


14/27

398 Krentz & Bailey

2.3 Indications and Contraindications breast-feeding are traditionally regarded to be con-

traindications for all oral antidiabetic drugs, mainly

An -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 nonpharmacological2.4 Efficacymeasures. Because -glucosidase inhibitors target

postprandial hyperglycaemia, they can be a usefulAn -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 who

tions and more marked postprandial hypergly-comply appropriately with dietary advice, an -

caemia. A recent multicentre clinical trial (STOP-glucosidase inhibitor will typically reduce postpran-

NIDDM [Study TO Prevent NonInsulin-Dependentdial glucose concentrations by 14 mmol/L. The

Diabetes 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 -glucosidase

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

0.51.0%, 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. Acarbose

There 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 whenfor example 50 mg/day, and slowly titrating up over

used in combination therapy. In general, the extraseveral weeks. Monitoring of glycaemic control,

benefit to glycaemic control achieved by addition of

particularly postprandially, may be helpful. The an -glucosidase inhibitor to another antidiabeticpostprandial 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-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 -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 enzymes

are raised, the dosage of acarbose should be reduced 2.5 Adverse Effectsto a level at which normal enzyme concentrations

are re-established. Alternative causes of hepatic dys- The most common problems with -glucosidasefunction should be considered. Pregnancy and inhibitors are gastrointestinal adverse effects. In the



15/27


STOP-NIDDM trial 31% of acarbose-treated pa- guanidine derivatives in the 1920s. These early

tients compared with 19% on placebo discontinued antidiabetic agents were all but forgotten as insulin

treatment early.[32] If the dosage is too high (relative became widely available and it was not until the late

to 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 the

large 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 global

sometimes be minimised by slow titration and by basis. Metformin is the only biguanide available in

ensuring dietary compliance with meals rich in com- the UK and, since 1995, the US.[23,40] Extensive

plex 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 -glucosidase inhibitor is used3.1.1 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 Sensitisers ways for insulin.[41,42] Recent data have suggestedInsulin resistance is a prominent metabolic defect that adenosine 5-monophosphate-activated protein

in most patients with type 2 diabetes.[36,37] Defective

insulin 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 metabolic

syndrome of cardiovascular risk.[38] Therefore, de-fective insulin action at target tissue level is an

attractive therapeutic target in type 2 diabetes.[39]

The biguanides and, in particular, the thiazolidinedi-

ones act directly against insulin resistance, and so

are regarded as insulin sensitising drugs.

3.1 Biguanides

The finding that Galega officinalis (goats rue or

French 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 profilereduces 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 function

HDL = high-density lipoprotein; LDL = low-density lipoprotein;PAI-1 = plasminogen activator inhibitor-1.



16/27

400 Krentz & Bailey

Metformin

Anaerobic glucosemetabolism

Glucose uptakeand oxidation

Glucoseuptake and

oxidation

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 metformin

lowers 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 (figure

metformin lowers blood glucose concentrations 4) and decreasing the hepatic extraction of certain

without causing overt hypoglycaemia it is most ap- gluconeogenic substrates (e.g. lactate). Hepatic

propriately 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 is

efficacy of metformin in patients with type 2 diabe- enhanced by metformin. This involves an increase

tes 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 increase

fasting 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



17/27


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- >120130 mol/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 in

used 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 to

practice 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 cause

ovulation 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 the

Metformin 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 greater

so 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 a25 hours, and almost 90% of an absorbed dosage is

sulphonylurea (usually glibenclamide) with a bigua-eliminated within 12 hours.[40]

nide (metformin or phenformin) have been available

in 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] It

with 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



18/27

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 relieving

USA) [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 is

crease 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 elevated

ed in hyperlipidaemic patients; plasma concentra-serum creatinine concentration (yearly measurement

tions of triglycerides, fatty acids and low-densityof creatinine clearance posing practical difficulties).

lipoprotein (LDL)-cholesterol tend to fall, whereasMetformin can reduce gastrointestinal absorption of

cardioprotective HDL-cholesterol tends to rise.cyanocobalamin (vitamin B12). While anaemia is

These effects appear to be independent of the anti-very rare, an annual haemoglobin measurement is

hyperglycaemic 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 contrast

cycle.media, surgery and any other intercurrent situation

in which the exclusion criteria could be invoked.[46] In the UKPDS, overweight patients who started

Substitution with insulin may be appropriate at such oral antidiabetic therapy with metformin showed a

times. 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 evident

insulin-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 benefit

The 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. The

As monotherapy in patients who are not adequately decrease in myocardial infarction observed with

controlled 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 major

ing plasma glucose by 24 mmol/L, corresponding effects on classic cardiovascular risk factors such as

to a decrease in HbA1c by approximately 12%.[40] plasma lipids. Consequently, other potentially

The effect is dependent upon the presence of some vasoprotective effects of metformin have been in-

endogenous -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 of

diabetes, re-assessment of dosage and consideration the anti-thrombolytic factor plasminogen activator

of additional therapy are required to maintain gly- inhibitor-1 (PAI-1).[41,46] The mechanism of the

caemic 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 generally

first-line monotherapy. The anti-hyperglycaemic ac- favourable view was evidence of an initially greater

tion 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.



19/27


20/27

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 nuclearglucose uptake via glucose transporter-4 in skeletalreceptor peroxisome proliferator-activated receptor-muscle, and some reports indicate that rates of glu-(PPAR), for which thiazolidinediones are potentconeogenesis in the liver are reduced. Stimulation ofsynthetic agonists.[55] The antidiabetic activity oflipogenesis via PPAR 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 that

crosis factor (TNF)-.[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 TNF 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 PPARis regarded as the principal whole-body insulin sensitivity. Thiazolidinediones,

mechanism through which thiazolidinediones en- like metformin, are anti-hyperglycaemic agents andhance insulin sensitivity. PPAR 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. PPAR operates in association3.2.2 Pharmacokineticswith the retinoid X receptor. The resulting heter-

odimer binds to nuclear response elements, thereby Rosiglitazone and pioglitazone are rapidly, and

modulating transcription of a range of insulin-sensi- nearly completely absorbed (12 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 extensively

pressed 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 with

tion of PPAR by a thiazolidinedione promotes lesser activity that are excreted predominantly in thedifferentiation of pre-adipocytes with accompany- urine. The metabolites of pioglitazone are more

ing 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-



21/27


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 in

does not interfere with the metabolism of otherpatients 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 insulin

available 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 combination

and 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 uptake

and utilisation

aP2, acyl-

CoA synthase

Lipogenesis

and adipocyte

differentiation

Lipoprotein

lipase

Transcription of cer tain

insulin-sensitive genes

PPAR RXR

Adipocyte

Hydrolysis ofcirculating triglycerides

in 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 Royal

Society of Medicine Press). aP2 = adipocyte fatty acid binding protein; CoA = coenzyme A; FATP = fatty acid transporter protein; GLUT-4 =

glucose transporter-4; PPAR= peroxisome proliferator-activated receptor-; RXR = retinoid X receptor; VLDL = very low-density lipopro-teins; indicates increase.



22/27

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 before

starting therapy and subsequently at 2-monthly in-

tervals (or, in the US, as judged necessary by the

prescribing 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 elevated

ALT 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 or

pioglitazone. Isolated cases of nonfatal hepatocellu-

lar damage have been reported; however, the issue is

clouded by reports suggesting an intrinsically higher

risk of liver failure in patients with type 2 diabetes.

Nevertheless, precautionary monitoring of liver

function remains advisable. When initiating therapy

with rosiglitazone or pioglitazone, blood glucose

monitoring and titration of drug dosage should be

undertaken while bearing in mind that 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 thiazolidinediones

even though neither rosiglitazone nor pioglitazone have beenassociated with troglitazone-like hepatotoxicity. In fact, the latter

drugs are under investigation as a potential treatment for non-

alcoholic steatohepatitis. In 2004, the US FDA recommendation

for 2-monthly monitoring of biochemical liver function tests was

relaxed. Instead, periodic biochemical monitoring is now left to

the supervising clinicians discretion

Heart failure

The precise contraindications differ between countries. In Europe,

current heart failure or a history of heart failure are

contraindications to thiazolidinediones

Insulin treatment

Although rosiglitazone and pioglitazone are licensed in the US for

use in combination with insulin, caution is required. Concernsabout higher rates of heart failure underlie this concern. The

European Agency for the Evaluation of Medicinal Products

considers insulin therapy a contraindication to the use of

thiazolidinediones

Pregnancy and breast-feeding

Thiazolidinediones are classified as pregnancy category C

because of growth retardation in mid-to-late gestation in animal

models. These drugs should only be used during pregnancy if the

potential benefit justifies the potential risk to the fetus

Polycystic ovary syndrome

Thiazolidinediones can cause ovulation to recommence in women

with hyperandrogenism and chronic anovulation; risk of

pregnancy

caemic effect that usually requires 23 months to

reach 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. In

therapy. No adverse effects on blood pressure have women with anovulatory PCOS the improvement in

been noted with the thiazolidinediones, even with insulin sensitivity may cause ovulation to resumeduring thiazolidinedione therapy. A combinationthe increase in plasma volume; on the contrary, there



23/27


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 a

2mg/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 downregulate

Addition of rosiglitazone or pioglitazone to the PAI-1 expression. Thiazolidinediones have also

treatment schedule of patients whose glycaemic been reported to decrease urinary albumin excretion

control 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 circulating

tions 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 0.51.5%.[64] However, cose-intolerant animals with a thiazolidinedionethe participants in these clinical trials had known preserved -cell function have yet to be confirmeddiabetes of several years duration, the effects of in human studies. In insulin-resistant women with a

thiazolidinediones being more apparent when -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 will

term picture requires clarification. Estimates of in- prove more effective than conventional antidiabetic

sulin sensitivity and -cell function (based on ana- agents in reducing the decline in -cell function inlysis of fasting glucose and insulin concentrations) patients with established type 2 diabetes remains to

have indicated that both defects can be improved by be determined, although preliminary data in patients

the 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 being

lesterol, 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 to

have little effect on total cholesterol, and has been 3.2.5 Adverse Effects

shown to reduce triglyceride concentrations in sev- Rosiglitazone and pioglitazone are generally well

eral 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 a

ic) LDL particles.[64] To date, no prospective com- history of cardiac failure, oedema, anaemia and liver

parative 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 14kg) and stabilising over ued. Hypoglycaemia may occur several weeks after

612 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 PPARis expressed

2005 Adis Data Information BV. All rights reserved. D

oral antidiabetic agents1

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