Oral Antidiabetic Drug Use in the Elderly

DRUG THERAPY Drugs & Aging 1996 Dec; 9 (6): 418-437 11 70-229X/96/0012-0418/SIO.00/0

© AdlS Inte rno tionoll1mlfe d . All rightS reseN 9 d .

Oral Antidiabetic Drug Use in the Elderly Rubin Bressler and David G. Johnson

Departments of Medicine and Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona, USA

Contents Summary 1. Sulphonylureas

1 .1 Efficacy . 1.2 Tolerability 1.3 Drug Interactions

2. Combination Drug Therapy . 3. Metformin ..

3.1 Efficacy 3.2 Toxicity

4. Troglitazone 5. Acarbose . 6. Conclusion

418 420 423 424 425 425 426 427 428 428 429 430

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that is common in the elderly, and is characterised by insulin insufficiency and resistance. Measures such as bodyweight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, should improve blood glucose regulation in patients with NIDDM.

It has been well established that the incidence of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) increase with aging.[1 -9] NIDDM is a common disorder

characterised by defects in both insulin secretion and insulin action,[I ,IO-13] and typically occurs in

overweight patients aged 2:40 years. Both genetic and environmental factors playa

role in the pathogenesis of NIDDM, and it is not certain whether impairment of tissue sensitivity to

insulin (insulin resistance), impairment of insulin

response to glucose (insulin secretory defect) or both represent the initiating genetic abnormality in NIDDM.[I,8,11 ,12,14-26]

Studies have been carried out to ascertain the metabolic defect or defects in individuals genetically predisposed to NIDDM, Several such investigations have shown that decreased glucose-induced insulin output is a predictor of NIDDM.!II-1 3,27-30]

The exact basis of insulin resistance is not

Oral Antidiabetics in the Elderly

known, but can be contributed to by a decreased level of physical activity and increased body fat. [5,S,9,27,3 1-34] Moreover, many drugs used by eld-

erly patients may contribute to glucose intolerance. These include thiazide diuretics, glucocorticoids, adrenergic blocking agents, nicotinic acid and phenytoin. [5,35]

Whereas a deficient insulin output and insulin resistance in response to a glucose challenge are characteristic of and predictive of NIDDM, the biochemical sequence of changes involved in the transition of these metabolic abnormalities to overt disease is still unknown.[11.12,21] However, insulin

resistance increases as a function of aging, obesity, decreased physical activity and probably other unknown factors. Increased insulin resistance results in deterioration of glucose tolerance.

The increased blood glucose levels caused by both insulin resistance and a delay in the early phase of insulin secretion eventually stimulates increased insulin secretion, which limits the increased blood glucose levels. In time, the insulin secretory response declines and blood glucose

levels rise because of augmented gluconeogenesis and insulin insufficiency. [1 .8,11, I 5, 16,36-39J Hyper-

glycaemia itself is a causal factor in the decreased insulin output, and in insulin resistance.lS,40,41]

Diabetes mellitus can be viewed as an abnormal metabolic state characterised by glucose overproduction and underutilisation.ll.S, 10,12,30,36-39] These

abnormalities are the result of insufficient insulin secretion in response to glucose, and tissue insensitivity to the actions of insulin.[I,S,30,39]

Controlled studies of the effects of blood glucose regulation on the complications of NIDDM have not been carried out. The major causes of death and disability in elderly patients with NIDDM are atherosclerotic and arteriosclerotic vascular diseases .[42-45] In patients with NIDDM, coronary

artery disease is the leading cause of death regardless of the duration of the disease, gender or ethnic/racial origins.l42-44] There is a higher incidence of all clinical varieties of macrovascular disease, including peripheral and cerebral vascular

© Adis International Umited. All rights reserved.

419

disease, in patients with NIDDM compared with the general population.l42-44]

Poorly controlled blood glucose levels in NIDDM result in a dyslipidaemia, which constitutes an additional coronary artery disease risk factorJ44-46] The dyslipidaemia consists of low levels of high density lipoprotein (HDL)-cholesterol, elevated levels of low density lipoprotein (LDL)cholesterol and very low density lipoprotein (VLDL)cholesterol, and increased levels of apolipoproteins Band E.l45-47] These abnormalities are ameliorated by improved blood glucose controJ.l45,4S-50]

This discussion of the treatment of NIDDM in the elderly focuses on agents that increase in'sulin secretion, drugs that increase insulin sensitivity, and an agent that helps the dietary control of blood glucose.

1. Sulphonylureas

Patients with NIDDM have been shown to have defects in both target-tissue sensitivity to insulin and to glucose-induced insulin outputJI ,S,II,12,19,21 ,22]

The goal of drug therapy is to ameliorate or correct both of these abnormalities in the elderly patient with NIDDM.

The sulphonylureas have been the primary drug therapy of NIDDM for 4 decades. The sulphonylureas that were available at the time of this review are shown in figure 1. The chemical differences between the drugs are responsible for their differing pharmacokinetic profiles, which are shown in table P51]

Recently, glimepiride, a long-acting sulphonylurea available outside the US, was approved for use in the US. [53] This agent is similar to glipizide and glibenclamide (glyburide) in terms of its potency and duration of action, and is efficacious at daily dosages of I to 6mg, although lower dosages are recommended in the elderly and in those with renal or hepatic disease. The agent is metabolised by the liver and its principle metabolite accounts for 30% of the activity of glimepiride. Maximal activity occurs 2 to 3 hours after administration, and efficacy persists for 24 hoursJ53,54] Glimepiride is an effective drug that appears to offer no

Drugs & Aging 1996 Dec; 9 (6)

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proven advantage over currently available drugs for the treatment of NIDDM.l53,54]

The sulphonylureas stimulate insulin secretion by the pancreatic ~-cells, thereby correcting one of the 2 deficits present in NIODM. The mechanism of action is the same for all the sulphonylureas, although the potency of the second-generation drugs is greater (table 1).151 .58] The stimulatory effect of sulphonylureas has been demonstrated both in vitro and in vivo.[57·60] In many patients, control of elevated blood glucose levels by sulphonylureas may also increase the sensitivity of target tissues to insulin by removing glucose toxicity.[1,8,40,41]

The sulphonylureas have no stimulatory effect on insulin secretion in patients with insulin-de-

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pendent diabetes mellitus (IODM) or in pancreatectomised diabetic patients. [51 ,57,58.61·64]

Untreated NIDDM patients have elevated fasting and postprandial blood glucose levels and low plasma insulin levels compared with nondiabetic individuals. Sulphonylurea therapy lowers blood glucose and raises plasma insulin to above pretreatment levels. Over a period of months, the efficacy of the sulphonylurea is evidenced by improved fasting and postprandial blood glucose levels. However, the plasma insulin falls to a level that is above the pretreatment level, but below the level achieved soon after initiation of sulphonylurea therapy.[8,65] This reduction in insulin secretion reflects the improvement in blood glucose levels pro-

Tolbutamide

CH3-C0-o-S02-NH-CO-NH-D Acetohexamide

C,,-o-So,-NH-CO-NH-{]

CI--O-S02-NH-CO-NH-CH2-CH2-CH3

CH'~-=>-CO-NH-C"-CH,-o-so,-.a<-CO-NH-D CI

< )-CO-NH-CH,-C,,-o-so,-NH-CO-NH-D

CH3-o-S02-NH-CO-NH-NCD

Tolazamide

Chlorpropamide

Glipizide

Glibenclamide

Gliclazide

Fig. 1. Commonly used sulphonylurea drugs. The first generation sulphonylureas are tolbutamide, acetohexamide, tolazamide and chlorpropamide. The second generation sulphonylureas are glipizide, glibenclamide (glyburide) and gliclazide.

© Adis International Umited. All rights reserved . Drugs & Aging 1996 Dec; 9(6)


duced by the sulphonylurea therapy. If the blood glucose level is raised to pretreatment values, the insulin secretory response is greater than it was before treatment. [65-67]

To stimulate insulin secretion, sulphonylureas must bind to pancreatic ~-cells. The sulphonylurea receptor has been described and its physiological function characterised (fig. 2) .[65-68] Recently, the sulphonylurea receptor has been cloned, providing further insight into its function.[69-71] It has been

shown that the occupation by a sulphonylurea of its pancreatic ~-cell high-affinity receptor inhibits an adenosine triphosphate (ATP)-dependent potassium channel, KATP, which determines resting ~cell membrane potential. The resultant decreased potassium efflux causes ~-cell depolarisation and the activation of L-type calcium channeis.[65.66.69] The consequent calcium influx stimulates insulin secretion.[65-70]

421

The sulphonylurea receptor is situated in the KATP domain, thereby linking the sulphonylurea receptor with openers of the K+ channel functionally and anatomically.l69] Stimulation of insulin secretion by sulphonylureas and glucose is shown in figure 2.[72]

The stimulation of insulin secretion by glucose and amino acids occurs by a similar physiological mechanism to that of the sulphonylureas.l59.65.66,69,701

In the case of glucose, its metabolism produces ATP, which raises the intracellular ATP: adenosine diphosphate (ADP) ratio. This closes the ATPsensitive K+ channel, decreasing K+ efflux (fig. 2) and causing cell membrane depolarisation. As a result, the voltage-sensitive Ca++ channel opens, promoting Ca++ influx[59,67,69] and causing insulin

secretion. Thus, glucose and sulphonylureas stimulate in

sulin secretion via similar actions on ion flux and

Table I. Pharmacokinetic properties and clinical data on sulphonylureas (modified from GerichI51))

Characteristic Drug

tolbutamide tolazamide chlorpropamide glipizide glibenclamide (glyburide)

Relative potency 5 6 100 150

Duration of action (h) 6-10 16-24 24-72 16-24 18-24

Protein binding

type Ionic/non ionic lonic/nonionic Ionic/non ionic Nonionic Nonionic

extent (%) 98 98 95 98 98

Activity of hepatic Weak One active, others Weak Weak One active, others metabolites inactive inactive

Daily dosage (mg)

range 500-3000 100-1000 100-500 2.5-40' 1.25-20

average 1500 250 250 10 7.5

No. of doses per day 2-3 1-2 1-2 1-2

Usual initial daily 500 100 100 5 2.5 dosage (mg)

Dosage forms 250,500 100,250, 500 100,250 5, 10 1.25, 2.5, 5b

available (mg)

Diuretic effect? Yes Yes No No Yes

Antidiurelic effect? Yes No Yes No No

Disulfiram effect? No No Yes No No

Frequency of severe 1 1 4-6 2-4 4-6 hypoglycaemia (%)

Overall frequency of 3 4 9 6 7 adverse effects (%)

a Studies have shown that the maximum effective dosage of glipizide is 10mg daily. Dosages above this may have reduced efficacy.l521

b Glibenclamide is available worldwide as better absorbed micronised preparations. These preparations are available in 1 .5, 1.75, 3, 3.7 and 6mg tablets.

© Adis International Lirnited. All rights reserved. Drugs & Aging 1996 Dec; 9 (6)

422 Bressler & Johnson

Depolarises ---m-'e-'m""'b-ra-ne---.~ CaH

Closes K+

channel K+

ATP/ADP

o o

o o

o ' ''''Ii' ---O vesicles o ... Insulin and C peptide

Fig. 2. Mechanism of insulin secretion by pancreatic ~-cells. In the basal state, an adenosine triphosphate (ATP)·modulated K+ channel is open, maintaining polarisation of the plasma membrane. At the same time, a voltage-dependent Ca++ channel is closed. The entry of glucose into the cell via Glut 2 transporters, and its subsequent metabolism, increases ATP production. An increase in the ATP/adenosine diphosphate (ADP) ratio causes closure of the K+ channel. The level of K+ increases at the plasma membrane, causing depolarisation, which opens the voltage-dependent Ca++ channel and allows Ca++ to enter the cell. The resultant increase in the cytosolic Ca++ level stimulates the secretion of insulin.

membrane depolarisation, but they differ metabolically.l59,69.71] Glucose stimulates proinsulin bio

synthesis, causing both phase I (the initial rapid peak) and phase 2 (later prolonged) insulin release, whereas sulphonylureas induce only phase I insulin release and do not stimulate insulin biosynthesis.[57,58,72,73]

Sulphonylureas augment insulin secretion, but have no direct effect on insulin sensitivity. In addition, they are not effective in IDDM since there is no functioning residual insulin secretory system,P4.80] A number of studies have proposed that sulphonylureas have extrapancreatic effects that contribute to their antidiabetic efficacy. These have recently been summarised.l72]

The sulphonylureas are well absorbed from the gastrointestinal tractJ57,58,81 ,82] Absorption may be

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slowed by age, diabetic gastric atony and dilatation, hyperglycaemia and the presence of food. [35,57,58,72,81,82]

All sulphonylureas are cleared by both the liver and kidneys, and some undergo hepatic transformation into weakly active or inactive metabolites. For example, one metabolite of acetohexamide is more active than the parent molecule. Because hepatic inactivation is the primary route of clearance of sulphonylureas, standard dosages can cause hypoglycaemia in older patients and those with liver disease.

Renal disease can also result in toxic levels of sulphonyJureas that have active or partially active metabolites (table I). The active metabolites of several sulphonylureas[57,58] are eliminated by renal

excretion. Although its metabolites have only weak



antidiabetic activity (table I), chlorpropamide is contraindicated in patients with renal disease. Sulphonylureas are highly bound to plasma proteins.[83-85]

The potency of sulphonylureas is based on their effects on insulin secretion. The characterisation of the sulphonylurea receptor has permitted quantification of intrinsic activity in terms of binding constants.[65,68,69,86] The second generation sulphonylureas (e.g. glipizide and glibenclamide) are up to 100 times more potent than the first generation agents (tolbutamide, tolazamide, acetohexamide and chlorpropamide). However, the maximal activity of all of the sulphonylureas is approximately the same. [51 ,55,56,86·90]

The duration of action of the sulphonylureas determines drug dosage schedules. The use of sulphonylureas in elderly patients with NIDDM is complicated by decreased renal function, decreased liver size and liver blood flow, and decreased plasma albumin levels.l35] These changes impede sulphonylurea clearance and predispose the patient to excessive drug activity. Sulphonylureas with longer durations of action (e.g. chlorpropamide) are more likely to cause hypoglycaemia. [57,58,91 ,92J

Although the sulphonylureas ameliorate the deficiency in glucose-stimulated insulin output to some degree, they are frequently not capable of restoring the NIDDM patient to a euglycaemic state. The recognition of the metabolic defects that occur in NIDDM has suggested the development of antidiabetic drugs that aid in dietary control (uglucosidase inhibitors), increase tissue sensitivity to insulin (metformin, thiazolinediones) and decrease hepatic glucose production (metformin). These drugs are being used in conjunction with sulphonylurea therapy because they act via separate mechanisms[93] that will be discussed in sections 4 to 6.

1.1 Efficacy

The efficacy of sulphonylureas in NIDDM depends to a great extent on the selection of suitable patients for such therapy. Ideal patients for


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sulphonylurea therapy are those with NIDDM whose blood glucose level cannot be regulated by dietary modification and physical activity alone.[57,58,88,94-96] The clinical efficacy of sulpho-

nylurea therapy is greatest in patients with NIDDM of 5 years' duration.[57,58,95-IOO] However,

data on the efficacy of sulphonylureas are complicated by uncertainty about patients' suitability for sulphonylurea therapy, and by the lack of suitable placebo controls in most studies.l57,58,101,102] The

apparent efficacy of sulphonylureas may be greater than in reality because of the lack of placebocontrolled crossover studies, especially in newly diagnosed patients.l57,58,101,102] Because NIDDM

responds to dietary modification, exercise and bodyweight loss, placebo effects may be prominent. [101-103]

Sulphonylurea therapy is ineffective in inducing a significant decrease in blood glucose levels in between 15 and 20% of patients with recent-onset (i.e. within the previous 12 months) NIDDM.l57,58,97,99,101,102,104] This is termed 'pri-

mary failure'. About 50% of sulphonylurea-treated patients achieve normal or near-normal blood glucose levels, and the remainder have lesser, varying degrees of blood glucose controP57,58,97-106] In a proportion of NIDDM patients who have an initial clinical response to sulphonylureas, treatment failure occurs after months to years. This has been designated 'secondary failure' .[76,97,101,102,107,108]

The attribution of lack of efficacy to the drug alone is complicated by inadequate selection of suitable candidates for sulphonylurea therapy, patient noncompliance with dietary modifications and prescribed drugs, the use of inadequate drug dosages, and other confounding factors.l57,58,107]

The annual secondary failure rate has been reported to be as high as 3 to 5%.[76,97,107,108]

An effective response to a sulphonylurea is characterised by a reduction in the fasting and postprandial blood glucose levels. These changes in blood glucose are brought about by an increase in ~-cell insulin output; the insulin is transported to the liver, where it decreases hepatic glucose output, and to the periphery, where it stimulates glucose


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uptake and utilisation. The resulting lower blood glucose level sensitises peripheral target tissues to insulin, leading to glucose uptake and utilisation, and the p-cells to glucose, leading to insulin secretion. [1,8,37,39-41, I 09-111]

There is a lack of evidence that successful regulation of blood glucose with sulphonylureas decreases the retinal, renal and neurological complications associated with NIDDM. A large prospective study is ongoing in the UK to ascertain whether better blood glucose control decreases the morbidity and mortality of NIDDM, and to determine whether insulin or oral antidiabetic drugs are more effective.l I04,105] Interim data from the study, collated at I year, showed that dietary modification failed to control blood glucose in 83% of patients, and that sulphonylureas and insulin were about equally effective in reducing fasting blood glucose and glycated haemoglobin (HbAlc) levels.l 104,105]

Follow-up studies at 3 to 6 years revealed that 85% of sulphonylurea-treated NIDDM patients had good diabetic control (mean fasting blood glucose level 7.2 mmoIlL), although 10% also required metformin and 5% were switched to insulin.l 112] The average nonfasting blood glucose level in the insulin-treated group (i.e. those initially treated with insulin, as opposed to a sulphonylurea) was the same as that in the sulphonylurea-treated group (7.2 mmoI/L), whereas the level in the placebo group was 9.1 mmol/L.

By the sixth year of the study, 20% of the patients who were initially treated with sulphonylureas required the addition of metformin to their regimen, and 12% had been changed to insulin therapy.! I 13] The efficacy of sulphonylurea therapy was found to diminish progressively with time. The percentage of sulphonylurea-treated patients with a fasting blood glucose of >7.0 mmollL was 50% at 3 years and 65% at 6 years. The investigators noted that the likelihood of sulphonylurea failure at 6 years was correlated with higher blood glucose levels at the start of the study. [113]

The main reason for primary failure in sulphonylurea therapy is probably insulin insufficiency. [75,108] There are a number of reversible causes


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of secondary failure,[107,114] including obesity, lack of physical activity, underdosage and poor compliance with sulphonylureas.[51,55,57,58,72]

1.2 Tolerability

The frequency of adverse effects of sulphonylureas is low. The most common adverse effects are gastrointestinal disorders and skin rashes.!57,58,86, 114, 115] Infrequent cases of haemato-

logical , liver and immunological abnormalities have been reported.!57,58,101] Water retention and hyponatraemia occur with the use of chlorpropamide (6.3% ).[116,117] The cause of this hyponatraemia is the increased secretion and activity of antidiuretic hormone,[118] which is unique to chlorpropamide among the sulphonylurea agents. Risk factors for this adverse effect are old age and the coadministration of thiazide diuretics. [I 19]

Some patients receiving chlorpropamide experience an intense flushing after alcohol (ethanol) consumption.!120] The flushing reaction is of uncertain aetiology and is not seen with the secondgeneration sulphonylurea agents. However, the effect is dose-dependent, and patients who are not affected may experience flushing if their dosage is increased'! 120]

1.2.1 Hypoglycaemia Hypoglycaemia is the most frequent and serious

adverse effect of sulphonylurea therapy.[91 ,92] The frequency of this effect is unknown because most episodes are treated at home, and the incidence from primary and hospital care data is therefore an underestimate. Moreover, many NIDDM patients are elderly, and the signs and symptoms of hypoglycaemia may not be recognised by these patients. Symptoms of weakness, tiredness, confusion, light-headedness and tachycardia may not be recognised as hypoglycaemia.

Symptomatic hypoglycaemia occurred in 20.2% of 40- to 65-year-old NIDDM patients who were treated with sulphonylureas over a 6-month surveillance period.[121] The risk of sulphonylureainduced hypoglycaemia is increased in elderly patients with multiple medical problems, such as poor renal function and inadequate nutrition,



and in those who are being treated with multiple drugs. [35,57,58,91,92,122,123] Chlorpropamide and

glibenclamide are more frequently associated

with prolonged hypoglycaemia than tolbutamide and gIipizideJI21-125] Glibenciamide has

been identified as the most frequent cause of

sulphonylurea-induced coma and death in Western Europe.[I22,1 24-1 26] However, it is also the most

commonly used sulphonylurea in Western Europe.

Other studies have shown that sulphonylureas are

the major cause of drug-induced hypoglycaemia

requiring hospitalisation (59% of 840 cases), with

9% resulting in death or permanent neurological injury.[9I ,92] Sulphonamide-induced hypoglycae

mic episodes may occur even at standard dosagesJ124,125] In elderly patients with NIDDM, it is

prudent to increase the dosage of sulphonylurea slowly, since these patients may have multiple

other conditions for which drug therapy has been

prescribed.

7.2.2 Cardiofoxicity The University Group Diabetes Program

(UGDP) was a large study that was designed to ascertain whether control of blood glucose could

decrease vascular complications in patients with NIDDM. The study was discontinued because of a

perception that there was a higher incidence of death from cardiovascular causes among patients receiving tolbutamide.[I27,128] However, the study

was criticised on a number of grounds, including

the use of fixed dosages of sulphonylureas, inappropriate selection of patients,[129.130] and poor

study design. Controversy has continued over the

study and the cardiovascular issue for many years.[I02,129,130] The supposed increase in cardio

vascular risk associated with sulphonylureas has

not been substantiated by other studies. In a 1979 policy publication,[1 31] the American Diabetes As

sociation stated that the decision not to use sul

phonylureas based on the UGDP findings should be 'held in abeyance' .[1 31] Thus, evidence that sul

phonylureas are cardiotoxic is lacking.

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425

Table II. Clinically important drug interactions with sulphonylureas (from Lebovitz & Melander,ll'll with permission)

Interacting drug(s)

Increase in hypoglycaemia Aspirin (acetylsalicylic acid), fibrates, trimethoprim

Alcohol (ethanol), histamine H2 receptor antagonists, anticoagulants

Probenecid, allopurinol

Alcohol, aspirin

Nature of interaction

Displacement of sulphonylurea from albumin binding sites

Competitive inhibition of sulphonylurea metabolism

Inhibition of urinary sulphonylurea excretion

Concomitant use of drugs with hypoglycaemic activity

~-Blockers, sympatholytic drugs Antagonism of counter-regulatory hormones

Worsening of glycaemic control Barbiturates, rifampiCin (rifampin)

Thiazide and loop diuretics, ~-blockers, phenytoin

Corticosteroids, growth hormone, estrogens, catecholamines

1 .3 Drug Interactions

Stimulation of sulphonylurea metabolism

Inhibition of insulin secretion

Inhibition of insulin action

Elderly patients with NIDDM are likely to have other chronic diseases that require drug therapy.[35] NIDDM patients treated with sulphonylureas may be exposed to both pharmacokinetic and pharmacodynamic drug interactions. [35,5 I ,57,58,72,10 I ,132,133]

Sulphonylureas can interact with a number of drugs, resulting in an alteration of the effect of either the sulphonylurea or the interacting drug.[35,5I,57,58,72,IOI ,132,133] Table II lists the mech-

anisms by which some sulphonylureas interact with other drugs.[57,58, 134,135] There have been

many reports of drug interactions between sulphonylureas and drugs commonly used by elderly patients. [57 ,58, I 33-14 I]

2. Combination Drug Therapy

The use of sulphonylureas plus subcutaneous insulin in patients with NIDDM has been studied by several investigators using various regimens. This therapy, although it did not achieve euglycaemia in patients with NIDDM, improved blood glucose control in many patients, including those with sulphonylurea failure .[142-148]


426

The 'dawn phenomenon' is characterised by an increase in blood glucose levels in the early morning hours in the absence of a preceding hypoglycaemic episode. It has been described in patients with IDDM and those with NIDDM.l149.15I) A combination of daytime sulphonylurea therapy and intermediate-acting insulin at night has become commonly used to improve fasting blood glucose levels through better control of nocturnal glycogenolysis and gluconeogenesis.[1O,36,37.152,153) Sim-

ilarly, combination therapy with sulphonylureas and metformin has been used to improve blood glucose control. [154·157]

Acarbose is an a-glucosidase inhibitor that limits and delays the postprandial hyperglycaemia resulting from orally ingested sucrose and starch in patients with NIDDM.[93] Acarbose is effective in both NIDDM and IDDM, since its effects are not dependent on insulin secretion.1158.159) Acarbose is rarely used alone; it is usually combined with insulin, sulphonylureas or metformin.

3. Metformin

Metformin (fig. 3) is a biguanide that has been used worldwide for the treatment of NIDDM since 1957, but has only recently been approved for use in the US. This antihyperglycaemic drug has several unique characteristics that are suited to the therapy of NIDDM in elderly patients.l156.16o.163] The efficacy of metformin monotherapy in the treatment of NIDDM has been well documented, as has its augmentation of the blood glucose lowering effects of sulphonylureas when they are used together. I 154, 155, 157,161 -164)

Metformin is an amphoteric compound (pKa of 2.8 and 11 .5) that is protonated at physiological pH and therefore has a low degree of lipid solubility.[161-163) The oral bioavailability of metformin is

Fig. 3. Structural formula of metformin (1 , 1-dimethylbiguanide).


Bressler & Johnson

around 50 to 60%.[162,163) After oral administration, most of the drug is absorbed within 6 hours of ingestion, with peak plasma concentrations being reached after 2 to 3 hours. The proportion of a dose that is absorbed is lower at higher doses.l165-169) Metformin is not protein bound, nor is it metabolised. 1156,160,165,166,169] It has an elimination half-

life of 1.5 to 5h, and is primarily eliminated via renal tubular secretion.[166.168,169) Because of the risk of drug accumulation, metformin is contraindicated in patients with renal insufficiency.

Because of the potential for lactic acidosis with biguanides, metformin should not be used in patients with renal or hepatic disease.l156.170-172] Renal disease results in the elevation of blood lactate levels, and cases of lactic acidosis have occurred in patients with NIDDM and renal insufficiency who were treated with metforminJI56,17o,173,174]

Metformin causes small, postprandial increases in plasma lactate levels.1164,175] Metformin accumulates in the intestine, resulting in the production of lactate from ingested carbohydrateJI63,176.I77) In individuals with normal hepatic function, the liver efficiently extracts and metabolises the lactate produced by the intestines.l161.176.177] However, in patients with severe liver disease, the liver may not extract the intestinal lactate and peripheral plasma levels may rise.l 156,171,178)

Metformin does not increase lactate production by muscle or other peripheral tissues.1156,16I) Diseases that predispose to decreased tissue perfusion cause hypoxia, resulting in increased lactate production, but renal impairment is the most frequent underlying complication in metformin-induced lactic acidosis.1156.171-174] Overdoses of metformin can be treated using haemodialysis, which has been used in patients with lactic acidosisJI79)

In patients with normal renal function, metformin is absorbed more slowly than it is eliminated, and accumulation does not occurJI60.162.163.168]

3.1 Efficacy

Metformin has demonstrated antihyperglycaemic effects in the therapy of obese and lean NIDDM patients whose diabetes has not been con-



trolled with diet modification alone.fI56.172,173,ISO-IS5]

The efficacy of metformin as an antihyperglycaemic agent has been confirmed by a number of double-blind, placebo-controlled randomised trials,1161 -164,IS6] and is about equal to that of the

sulphonylureas in newly diagnosed NIDDM patients. fISI ,ls4,IS7-190] When used in combination,

metformin and sulphonylureas exhibit synergistic antihyperglycaemic effects. f 154, 157, 164.191-196]

The mechanisms of action of metformin are unknown at the molecular level, and there is controversy about the quantitative importance of its various physiological and biochemical antihyperglycaemic actions.[161 ,164] Metformin has been

studied extensively in patients with NIDDM in whom acceptable blood glucose control has not been achieved with diet modification alone. The efficacy of metformin as monotherapy has been attributed to several effects,f I61 ,164,197.200] in-

cluding: (a) a reduction in the rate of gastrointestinal glu

cose absorption, reducing the intensity of the glucose challenge to insulin secretion;

(b) a decreased rate of hepatic glucose production, attributed by many investigators to a decrease in hepatic gluconeogenesis; f 161,156,164,199,200]

(c) increased peripheral glucose utilisation with a concomitant decrease in the plasma insulin level. Although it has been claimed that metformin sensitises peripheral tissues to insulin,fI61 ,200,201 ,202]

other studies have shown that metformin sensitises the peripheral tissues to glucose- rather than insulin-mediated glucose uptake.f 161 ,199,197,19S] In a

recent studyfl99] performed with the use of a 6.9 mmollL (blood glucose level) hyperglycaemic clamp, peripheral glucose uptake was increased in metformin-treated obese or lean NIDDM patients. In contrast, in a euglycaemic insulin clamp studyl199] increased glucose uptake was seen only in obese patients;

(d) a decrease in plasma total cholesterol, LDL-cholesterol and triglyceride levels, and a slight increase in the HDL-cholesterol leveJ.l156,164,172,201,203-205] These changes may be

separate from the effect of metformin on blood glu-

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427

cose, but are consonant with the bodyweight loss associated with metformin use;[156,161 ,164,ISS,IS9,200]

(e) a decrease in fasting and postprandial blood glucose and HbA lc levels in around 80% of newly diagnosed patients.l 162, 163]

Primary failure rates with metformin are around 12%, and secondary failure rates range from 5 to 10% per year.l 162, 163,206,207] Decreases in the blood

glucose level on initiating therapy are around 20%, and are accompanied by an improvement in oral glucose tolerance.[l60, 164, lSI ,200,201]

Metformin is suitable as the sole antihyperglycaemic agent for elderly NIDDM patients because it does not cause hypoglycaemia and results in some bodyweight loss. Moreover, patients with NIDDM often have elevated blood lipids and lowered HDL-cholesterol levels, which are risk factors for arteriosclerotic heart disease. f20S] These dyslipidaemias are often improved by metformin therapy.

Sulphonylureas and metformin have similar efficacy as monotherapy in NIDDM. Combination therapy is often used in patients with NIDDM in whom satisfactory control of blood glucose levels is not achieved with either drug alone. In studies in which maximal dosages of sulphonylureas failed to control blood glucose adequately, the addition of metformin (850 to 2500 mg/day) decreased mean fasting and postprandial blood glucose levels, HbA lc levels, serum lipid levels and bodyweight. f ISS, 191 -193,209]

Two randomised, parallel-group, double-blind studies of 29 weeks' durationfl64] have compared: (i) metformin 2500mg versus placebo; and (ii) metformin 2500mg or glibenclamide 20mg versus the combination. At 29 weeks, patients in the glibenclamide group had an increase in both fasting plasma glucose (0.8 ± 0.2 mmoIlL) and HbA lc (0.2 ± 0.1 %) levels. Patients who had received metformin had slight decreases in both fasting plasma glucose (0.1 ± 0.3 mmollL) and HbA lc (0.4 ± 0.1 %) levels . Patients who received both drugs showed a large decrease in fasting blood glucose (from 14.6 ± 0.2 to 10.5 ± 0.2 mmol/L) and HbA lc (8.7 ± 0.1 to 7.1 ± 0.1 %) levels compared with



Table III. Reductions in plasma lipid levels following treatment with metformin 2500 mg/day, either as monotherapy or in combination with glibenclamide (glyburide) 20 mg/day. Data are from a 29-week study in patients with non-in sui in-dependent diabetes mellitus"641

Lipid Metformin Metformin plus glibenclamide

reduction in mg/dl reduction in mmollL reduction in mg/dl reduction in mmollL

Total cholesterol

Low density lipoprotein cholesterol

Triglycerides

4 ±2'

6±2"

16±r

0.10 ± 0.05'

0.16±0.OS··

0.1S ± O.OS·

10 ± 2'

S ± 2'

20±r

0.25 ± 0.05'

0.21 ±O.OS·

0.23 ±O.OS·

Symbols: • p < 0.001 ; •• p < 0.019.

baseline. Metformin used as monotherapy or in combination with a sulphonylurea reduced plasma lipids significantly (table III). In contrast, glibenclamide monotherapy had no beneficial effect on plasma lipids. [1M] Bodyweight decreased by 3.8 ± 0.2kg in the metformin group, and increased by 0.4 ± 0.2kg in the glibenclamide group (p < 0.001).[164] There was no significant decrease

in fasting plasma insulin levels in the metformin group.

3.2 Toxicity

The adverse effects of metformin are mainly gastrointestinal in nature. Around 5 to 20% of patients started on the drug experience transient nausea, diarrhoea and anorexia.[181,1 82,210-212] These

effects can be avoided in part by slowly increasing the metformin dosage, and by taking the drug with food . Around 4.2% of patients who begin therapy with metformin discontinue taking it because of adverse gastrointestinal effects. [ 173.21 3.214] In addi

tion, the drug decreases the absorption of vitamin BI2 (cyanocobalamin),lI56.173.212,215,216] but this is

seldom of clinical importance. As discussed on page 426, lactic acidosis is an exceedingly rare

CH, 0-CH, 0

CH'WO CH,o CH'r-( SyNH HO

o CH,

Fig. 4. Structural formula of troglitazone, (±)-all-rac-5-{p-((6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy)benzyl)-2, 4-thiazolidinedione.

© Adis International Limited. All rights reserved .

event that may occur in susceptible patients (e.g. those with renal failure) .

Drug interactions with metformin, a number of which are pharmacodynamic in nature, are infrequent. ~-Blockers may cause dyslipidaemia and decrease glucose tolerance on their own, thereby possibly overcoming the triglyceride-lowering effects of metformin. These effects are more pronounced with the nonselective agents (e.g. propranolol).[1 34,2171 They may also delay recovery from hypoglycaemia, and tachycardia deriving from hypoglycaemia,lI34,2171 in patients treated with metformin plus sulphonylureas or insulin. When given as monotherapy, metformin does not cause hypoglycaemia.

Cimetidine has been shown to cause an elevation of plasma metformin levels, probably via competition for renal tubular secretion. l351

Sulphonylureas and metformin have additive blood glucose-lowering effects. Thus, their concomitant use increases the potential for hypoglycaemia to occur.

4. Troglitazone

The thiazolinediones have been studied as antidiabetic agents for over a decade.l218-2201 During the past 5 years, studies in insulin-resistant individuals with NIDDM and/or obesity have proven the efficacy of this class of drugs. At present, troglitazone (fig. 4) is the thiazolinedione that has undergone most clinical investigation in the US.

Thiazolinediones have been tested in a number of animal models of insulin resistance. These include the KK mouse and db/db mouse, which are spontaneously diabetic obese models, and the ob/ob mouse and the Wi star and Zucker fatty rats, which are insulin-resistant obese models.l218-2231



These animals models respond to oral thiazolinediones with a fall in blood glucose, an increase in glucose tolerance and decreases in plasma insulin and triglyceride levels.1218-223] The agents are

efficacious in insulin-resistant, but not insulindeficient, animals.[218-223] The thiazolinediones

have not been shown to cause hypoglycaemia in normal animals.1218-223]

In vitro, troglitazone has been shown to increase glucose utilisation in muscle and decrease glucose production by liver tissue.[218,221,224]

The animal studies suggest that thiazolinediones increase tissue sensitivity to insulin, which would enhance glucose utilisation by adipose tissue and skeletal muscle. The drugs produce a decrease in plasma insulin levels, causing a decrease in insulin resistance.[2 1 8,224.225] The initial response

is a fall in blood glucose levels, followed by a decrease in plasma insulin.

Studies of the effect of thiazolinediones on gluconeogenesis have had conflicting results.l226-2281 In studies where gluconeogenesis inhibition was shown, the changes were small and are unlikely to be the major factor in the antihyperglycaemic action of the drugsP291

The molecular mechanism of action of the thiazolinediones is unknown, but some studies have suggested that these drugs act at an intracellular site subsequent to the binding of insulin to its receptor.[21 8,22I] The decrease in blood glucose appears to be a consequence of increased glucose utilisation rather than decreased hepatic glucose production. [218,230,231]

Troglitazone has been studied in both NIDDM and in nondiabetic obese insulin-resistant patients.l222,225,232,2331 In a placebo-controlled study

in II patients with NIDDM,[2221 troglitazone 400

mg/day lowered the fasting blood glucose level in 8 patients, with an improvement in the 7-hour meal tolerance test in the entire group. Interestingly, the fall in fasting blood glucose level occurred after 2 to 3 weeks of therapy, with maximal responses usually occurring 2 weeks after the initial response.


429

In a study in 18 nondiabetic obese individuals, 9 of whom had impaired glucose tolerance, 12 weeks' treatment with troglitazone 200mg twice daily decreased insulin resistance and improved glucose tolerance to oral glucose and to mixed meals.l222,233]

5. Acarbose

Dietary control of blood glucose is considered an essential part of therapy in patients with NIDDM. Studies in which multiple small meals were compared with fewer, larger meals showed that the former were associated with better blood glucose control in diabetic patients.[234,235] Pharmacological approaches to delaying the digestion and absorption of complex carbohydrates have been made over the past several decades.1236] The development of acarbose and its sister compound miglitol (fig. 5) was the culmination of successful attempts to regulate the activity of the intestinal enzymes involved in the digestion of carbohydrates such as starch, sucrose and maltose.[237-241] Delayed digestion of complex carbohydrates leads to the delayed absorption of end-product monosaccharides throughout the small intestineP42] The absorption of dietary monosaccharides, such as glucose, is not affected by acarbose or miglitoI. 1236,242] Acarbose inhibits intestinal brush border a-glucosidases and, when administered orally, is effective in attenuating postprandial rises in blood glucose in diabetic patients.1236-239,242-244]

Chemically, acarbose is an oligosaccharide produced by cultured strains of actinomycetes. It is a competitive inhibitor that has a high affinity for sucrase and a lower affinity for glucoamylase and pancreatic amylase.l236,237] Acarbose is administered with food intake, therefore it must be taken 3 or more times a day. When a meal containing sucrose or starches is ingested, acarbose decreases the postprandial rise in blood glucose through inhibition of intestinal disaccharidases. [236,238,245,246]

Clinical studies with acarbose in both IDDM and NIDDM patients have shown that the drug attenuates the postprandial rise in blood glucose levels and reduces urinary glucose excretion.[245-247]



HO""'7=\,. CH, HO~N--\--\--O\

Ho~a~CH20H 0

o la CH20H

HO OH 0+\----0,

Acarbose LJr\~OH HO OH

HO

H

Miglitol

Fig. 5. Structural formulae of the a-glucosidase inhibitors acarbose and miglitol.

However, the overall improvement in blood glucose control is modest. [244.248.249] Acarbose does not decrease hepatic glucose outpUt.[236]

The dosages of acarbose that have been used in most clinical studies are 50 to 250mg with each large meal, and correspondingly smaller doses with snacks. The most common adverse effects are increased flatulence, abdominal bloating and, less commonly, diarrhoea.[244.250] The combined use of low-dose acarbose with guar gum crispbread was reported to decrease postprandial glycaemia with fewer adverse effects.[251] Because its mechanism of action differs from that of other antidiabetic agents, acarbose can be combined with them to produce addi ti ve efficacy. [252]

6. Conclusion

NIDDM has a high incidence in elderly people. It is a disease conditioned by hereditary factors and confounded by age, obesity and decreased physical activity. NIDDM is characterised by both insulin


resistance and, in its fully expressed stages, by insulin insufficiency.[1.8.9] If untreated or inadequately treated, NIDDM is associated with a number of organ and tissue impairments resulting from nerve, renal, retinal and cardiovascular damage.

In this review of the oral antidiabetic drugs currently available for the treatment of NIDDM, we have focused on the place of drug therapy in dealing with disease pathophysiology. The available drugs remedy, to some extent, the insulin insufficiency and the insulin resistance found in NIDDM.

The oral sulphonylureas stimulate pancreatic phase I output of insulin. The consequent lowering of blood glucose levels relieves the insulin resistance engendered by glucose toxicity; thus, stimulation of insulin output indirectly decreases insulin resistance.

Metformin decreases blood glucose levels in patients with NIDDM in several ways. It delays glucose absorption, thereby decreasing the intensity of the challenge to endogenous insulin. It sensitises



peripheral tissues to glucose-induced glucose uptake, thereby reducing blood glucose and plasma lipid levels, and decreases hepatic glucose production (via glycogenolysis and/or gluconeogenesis). Most recent clinical studies suggest that decreased hepatic glucose output, rather than the enhancement of peripheral glucose uptake, is the dominant effect of metformin in humans.

Troglitazone sensitises tissues to the actions of insulin. It stimulates insulin-induced glucose removal in skeletal muscle and adipose tissue by magnifying the insulin effect. It also has some effect in decreasing hepatic gluconeogenesis. The (X

glucosidase inhibitors serve as an aid to the dietary control of blood glucose levels by delaying the digestion of complex dietary carbohydrates. This decreases the physiological rise in blood glucose levels, thereby reducing the need for insulin. The absorption of dietary glucose and other monosaccharides is not affected.

Metformin, troglitazone and acarbose all have proven efficacy in NIDDM patients, but require endogenous insulin because they do not stimulate its secretion. They are well tolerated in elderly patients with NIDDM, partly because of the lack of hypoglycaemia that occurs with the use of these drugs.

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Correspondence and reprints: Dr Rubin Bressler, Department of Medicine, Arizona Health Sciences Center, University of Arizona, PO Box 245031, Tucson, AZ 85724-5031, USA.


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