Drugs 44 (Suppl, 3): 29-38. 1992 00 12-6667/92/0300-0029/$5 .00/0 © Adis International Limited . All rights reserved. DRSUP3197

Management of Non-Insulin-Dependent Diabetes Mellitus Pierre J. Lefebvre and Andre J. Scheen Division of Diabetes. Nutrition and Metabolic Disorders, Department of Medicine, University of Liege, Liege, Belgium

Summary

The initial management of non-insulin-dependent diabetes mellitus (NIDDM) should include patient education, dietary counselling and , when feasible, individualised physical activity. It is only when such measures fail that drug therapy should be considered. Dietary management of NIDDM includes a restriction in calories, and these should be appropriately distributed as carbohydrates, lipids and proteins. Supplementation of the diet with soluble fibre and supplementation with magnesium salts if hypomagnesaemia is demonstrated, is recommended. However , supplementation with fish oils or with fish oil-derived omega-S fatty acids is not currently recommended. Oral drug therapies used in NIDDM include sulphonylurea derivatives, which are a first-line treatment in patients who are not grossly obese, metformin, which is the treatment of choice for obese patients, and a-glucosidase inhibitors such as acarbose, which are used mainly to reduce postprandial blood glucose peaks. These types of drugs can be used alone or in combination. Insulin therapy may be required to achieve adequate control of blood glucose levels in some patients. In several instances, it is suggested that insulin therapy be combined with sulphonylureas (essentially when residual insulin secretion is present), with metformin, or with a-glucosidase inhibitors. The treatment of disorders associated with NIDDM, such as obesity, hypertension or hyperlipidaemia, requires particular attention in diabetic patients, since some drugs can adversely affect glycaemic control. Oral drugs for the treatment of NIDDM include sulphonylurea derivatives used in first-line treatment in patients who are not grossly obese, metforrnin, which is often the treatment of choice for obese patients and , more recently, the a-glucosidase inhibitors, such as acarbose, which are effective in reducing the postprandial rise in blood glucose.

Non-insulin-dependent diabetes mellitus (NIDDM or type 2 diabetes) is a common disorder; its prevalence in most countries is at least 2%. However, detection campaigns have shown that for every patient identified there is approximately I more who is missed, a finding recently confirmed in Belgium (Hortulanus-Beck et al. 1990). In some populations, such as the Pima Indians in Arizona, and the inhabitants of some Pacific islands such as

Nauru, the prevalence of NIDDM can reach 25 to 30% (Jarrett 1991). It has long been recognised that drugs represent only part of the management of NIDDM and that other interventions, such as patient education, modification of diet, and promotion of physical activity (when feasible) are useful therapeutic tools. Two concepts have emerged more recently: (a) the therapeutic approach must be tailored to the needs

Drugs 44 (Suppl. 3) 1992

30

of individual patients and must consider factors such as life expectancy and quality of life, and (b) NIDDM is often part of a syndrome that may include obesity, hypertension, hypertriglyceridaemia and hyperuricaemia (Reaven 1988) and, when this is the case, it is not satisfactory to treat each component of the syndrome independently. The best example in this respect is the recent recognition that several antihypertensive drugs decrease insulin sensitivity and consequently worsen diabetes control (Lithell 1991). Various aspects of the management ofNIDDM have been taken into consideration by the European NIDDM Policy Group, which recently summarised the primary objectives of treatment as being relief of symptoms, improvement of quality of life, prevention of acute and long term complications, reduction of mortality and treatment of accompanying disorders (Alberti & Gries 1988).

1. Nonpharmacological Management ofNIDDM 1.1 Diet

1.1.1 Caloric Content Most patients with NIDDM are overweight or obese, and it is now well recognised that this is a major factor in insulin resistance. Consequently, reduction of excess weight is a primary component in the management of NIDDM. A dietary interview (ideally with a dietician) is needed to evaluate the daily caloric intake of the patient, and to ascertain dietary habits. Together with information regarding the level of physical activity (see below), the dietary interview will be the basis on which the caloric content of the prescribed diet will be calculated . When extreme caloric restriction and/or rapid weight loss seem desirable, a very low calorie diet or protein-sparing modified fast may be considered. 1.1.2 Macronutrients The ideal balance of carbohydrate, protein or fat intake in patients with NIDDM is still a matter of discussion. The European Consensus recommends that carbohydrates should provide 50 to

60%, proteins no more than 15%, and total fat some 30 to 35%, of total energy. It has recently been recognised that a diet containing 60% carbohydrate, even if not including sugars, may predispose to the development of dyslipidaemia (Garg et al. 1988). Consequently, Reaven (1990) recently advocated the 'Stanford diet' for type 2 diabetes, in which carbohydrates, proteins and lipids provide 45%, 15% and 40%, respectively, of the daily energy intake. Carbohydrates should be predominantly complex and high in soluble fibre; foods with a low glycaemic index (Jenkins et al. 1989) are preferred, although moderate intake of simple sugars such as sucrose does not seem to be detrimental (Slama 1990). Protein intake should not exceed daily requirements , since high protein intake appears to have a detrimental effect on renal function (Brenner et al. 1982). Whatever the daily lipid allowance (30, 35 or 40% of daily total energy), there is general agreement that approximately one-third should be polyunsaturated, one-third monounsaturated and one-third saturated.

1.1.3 Dietary Fibre Numerous studies recently reviewed by Horwitz (1990) have shown that addition of certain types of soluble fibre, particularly guar gum and pectin, may result in significant reduction of postprandial glucose and insulin levels in patients with NIDDM. Tables offood fibre content are available to assist in making dietary recommendations (Anderson & Bridges 1988; Del Tomma et al. 1988). 1.1.4 Fish Oils There is some evidence that fish oils or fish oilderived omega-3 fatty acids may play some role in preventing atherosclerotic vascular disease, by reducing plasma triglyceride and lipoprotein levels (see review by Axelrod 1989). However, there is also evidence that in NIDDM the decrease in plasma triglyceride levels is counterbalanced by adverse effects on blood glucose or low density lipoprotein (LDL)-cholesterol (Hendra et al. 1990; Mori et al. 1990; Vessby & Boberg 1990). At pre-

Management of Non -Insulin-Dependent Diabetes Mellitus

sent , omega-3 fatty acid supplementation is not recommended in patients with NIDDM (Axelrod 1989).

1.1.5 Magnesium Low plasma and erythrocyte concentrations of magnesium are frequently found in patients with NIDDM (Paolisso et al. 1990). It has been suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance . Furthermore, there are some indications that decreased intracellular magnesium content might contribute to the impaired insulin response and activity that are seen in NIDDM (Paolisso et al. 1990). Recent observations suggest that long term magnesium supplementation can contribute to an improvement in both islet J3-cell response (Paolisso et al. 1989a) and insulin activity (Paolisso et al. 1989b) in patients with NIDDM . 1.2 Physical Activity

Recent clinical investigations have shed further light on the mechanisms by which exercise may help in controlling excessive blood glucose levels (Berger et al. 1982). Furthermore, there is good evidence that regular exercise has a positive influence on various cardiovascular risk factors that worsen prognosis in patients with type 2 diabetes (ADA Position Statement 1990). However, in a small proportion of patients, exercise may be harmful and , therefore, should not be prescribed .

1.2.1 Metabolic Effects of Training Regular exercise improves insulin sensmvity and, as a consequence, may improve glucose tolerance (Horton 1986). Such effects result partly from enzymatic adaptation in skeletal muscles (considered to be responsible for improvement in maximal oxygen uptake), and partly from a de.crease in bodyweight , body fat, and possibly also fat cell size. Such effects are beneficial in patients with type 2 diabetes since they enhance work capacity and quality of life, and may also help to reduce the requirement for insulin or oral hypoglycaemic agents.

31

1.2.2 Physical Training and Cardiovascular Disease in NIDDM As analysed by Kemmer and Berger (1986), when measured by objective criteria such as mortality rate, incidence of coronary heart disease, or concurrence of coronary risk factors, there is little doubt about the overall beneficial effect of chronic physical activity in patients with NIDDM. In several prospective studies analysed by Kemmer and Berger (1986), physical training has reduced plasma concentrations of triglycerides and cholesterol, and increased high dens ity lipoprotein (HDL)-cholesterol, effects which are associated with a decreased risk of coronary heart disease. In trained subjects with normal glucose tolerance, plasma insulin levels are particularly low, and a physical training programme has been shown to lower plasma insulin concentrations in nondiabetic patients. Hyperinsulinaemia has been implicated as a coronary risk factor (Ducimetiere et al. 1980; Py6riilii 1979). Thus , training, by improving insulin sensitivity and lowering plasma insulin levels, may contribute to a reduction in coronary risk. Finally, physical training can help to reduce bodyweight and hypertension and may min imise, or even prevent, the development of atherosclerosis. 1.2.3 Prescription of Exercise in Patients with NIDDM It is generally agreed that the intensity and duration of physical exercise should be adjusted to the general health and physical training of the patient (Schneider & Ruderman 1990). Before prescribing an exercise programme, the physician should estimate with the patient their usual daily level of physical activity. Encouraging walking and using staircases instead of elevators, etc., are simple ways of increasing daily caloric expenditure. The use of a cheap pedometer may be helpful; inactive patients can be advised to progressively increase the number of steps to at least 5000 to 6000 per day. Before prescribing a programme of more intense exercise, a detailed medical evaluation, including cardiovascular examination (pulse, blood pressure, ECG at rest and during exercise), chest x-ray and eye fundus examination, is mandatory. Needless to say,

32

Drugs 44 (Suppl. 3) /992

Table I. Drug therapies used in non-insuiin-dependent diabetes Drug class Sulphonylureas

Biguanides a-Glucosidase inhibitors

Chlorpropamide Tolbutamide Glibenclamide Glibornuride Gliclazide Glipizide Acetohexamide Tolazamide Metformin Acarbose

heavy exercise is contraindicated in patients with severe diabetic retinopathy or cardiopathy. Furthermore, in patients with diabetic peripheral neuropathy, adequate footwear (soft cushioned footwear with sufficient support) is mandatory . Exercise involving feet affected by neurotrophic ulcerations is contraindicated. Exercise should always start at low intensity and gradually increase. Regular medical supervision and re-evaluation are recommended. Hazardous sports such as deep sea diving, parachuting, etc. are not recommended for patients at risk of hypoglycaemia.

2. Drug Therapy 0/ NIDDM Drug therapy of NIDDM should be considered when diet, patient education and increased physical activity have failed to achieve individual treatment goals. Table I lists the types of drugs most commonly used in NIDDM. 2.1 Sulphonylureas Iii. a recent review, Melander et al. (1990) stated that 'although controversies remain as to the usefulness of sulfonylureas, most evidence is in favour of their use in many if not most patients with noninsulin-dependent diabetes mellitus'. Sulphonylureas are widely considered as first-line drug treatment in NIDDM patients who are not grossly obese. The main pharmacological effect of sul-

phonylureas is to stimulate insulin release but extrapancreatic effects of these drugs, including reduction of hepatic insulin clearance, have also been suggested (Almer et al. 1982; Gerich 1989; Groop et al. 1987; Melander et al. 1989; Scheen et al. 1984, 1988). Rate of onset and duration of action of the various drugs available are important parameters to consider (Gerich 1989). Rapid onset drugs reduce the delay in acute insulin release and, consequently, reduce the magnitude and duration of postprandial hyperglycaemia. A long duration of action increases the risk of delayed hypoglycaemia and, probably, loss of response to sulphonylureas. The use of rapid onset short-acting sulphonylureas may also minimise the risk of chronic hyperinsulinaemia, which is implicated as a major risk factor for atherosclerosis (Ducirnetiere et al. 1980; Pyorala 1979). The major acute problem associated with sulphonylureas is hypoglycaemia, the risk of which is markedly increased in the elderly and those patients with renal insufficiency. Sulphonylureainduced hypoglycaemia can be exacerbated by interaction with numerous drugs, including alcohol (ethanol), aspirin (acetylsalicylic acid) sulphonamides, phenylbutazone, dicoumarol, clofibrate, monoamine oxidase inhibitors and tricylic antidepressants. 2.2 Biguanides Because of the associated risk of lactic acidosis, 2 biguanide compounds that were widely used in the treatment of NIDDM, phenformin and buformin, have been withdrawn in most countries. The only remaining compound, metformin (dimethylbiguanide), is unavailable in several countries, including the USA, but is widely used in Europe. The mechanism of action of metformin is still under debate (Bailey 1988; Jackson et al. 1987; Shafer 1983) and may include decreased glucose absorption by the gut, increased peripheral glucose uptake, and decreased liver glucose output. Metformin is considered to be a first-line drug treatment in the obese NIDDM patient. It should be taken with food, and the maximum daily dose is 500mg

Management of Non-Insulin-Dependent Diabetes Mellitus

administered 3 times daily or 850mg administered twice daily. Interestingly, metformin improves blood glucose control, despite decreasing plasma insulin levels, and tends to decrease bodyweight, or not to be associated with weight gain as are insulin and sulphonylureas. Contraindications to metformin include renal insufficiency and major liver or cardiovascular disease. Kidney function and plasma lactate levels should be checked regularly during metformin therapy. 2.3 Acarbose and Other a-Glucosidase Inhibitors Acarbose and related compounds, such as miglitol, delay the intraluminal production of monosaccharides, particularly glucose, by competitively inhibiting the o-glucosidasesthat are associated with the brush-border membrane of the small intestine and are responsible for the digestion of complex polysaccharides and sucrose (Creutzfeldt 1982, 1988). Several noncomparative multicentre and placebo-controlled studies performed in patients with NIDDM have shown that acarbose reduces postprandial blood glucose peaks and postprandial plasma insulin levels and improves indices of blood glucose stability (Clissold & Edwards 1988). HbAlc concentrations were decreased by around 0.5 to 3% in the majority of studies in which this parameter was adequately monitored. Innerfield and Connif (1990) recently presented (in abstract form) preliminary results of a multicentre, double-blind, placebo-controlled study of the long term efficacy and safety of acarbose in the treatment of 212 patients with NIDDM managed by diet alone; 107 patients were randomised to placebo and 105 to acarbose 50 to 300mg 3 times daily for 24 weeks. Treatment started after a 6-week run-in period and was followed by a 6-week wash-out period. Acarbose was superior to placebo in all variables studied, producing decreases in HbAlc (0.59%), fasting blood glucose (0.858 mrnol/L), 60-minute postprandial blood glucose (3.28 mrnol/L), 120-minute postprandial blood glucose (2.77 mmol/L) and maximum blood glucose (3.02 mmol/L) levels.

33

As emphasised by Toeller (199I), it is extremely important that diabetic patients receiving acarbose follow dietary guidelines that recommend the ingestion of complex carbohydrates rather than simple sugars. Other potential side effects are discussed by Hollander on page 49 of this issue. 2.4 Combined Oral Therapy In patients whose condition is not adequately controlled by diet and single-drug hypoglycaemic therapy, it may be necessary to consider combination therapy. 2.4.1 Sulphonylureas and Biguanides This combination therapy has been used for more than 30 years. As already discussed, sulphonylureas are considered to be first-line drugs in nonobese patients not controlled by diet alone. In patients in whom sulphonylurea therapy is inadequate , the addition of metformin may provide satisfactory control for several years, while addition of a sulphonylurea to metformin monotherapy is used more rarely (Hermann 1990). Obviously, the well-known contraindications for both types of drugs (see above) must be taken into consideration when using combination therapy. As discussed by Hermann (1990), this type of oral combination therapy has not yet been assessed as primary drug treatment in formal clinical studies, and more data are needed to evaluate the full clinical potential and the mechanism ofaction ofthecombination ofsuiphonylureas and biguanides in patients with NIDDM . 2.4.2 Sulphonylureas and Acarbose As reviewed by Clissold and Edwards (1988), several placebo-controlled studies have demonstrated improvement in diabetic control in patients with NIDDM treated with a sulphonylurea compound and acarbose. For instance, in the study performed by Uttenthal et al. (1988), 17 NIDDM patients who were poorly controlled by diet and sulphonylureas were treated for 20 to 52 weeks with acarbose 100mg 3 times daily. Addition of acarbose reduced integrated postprandial increases in plasma glucose to 58 ± 10% (p < 0.00 I), insulin

Drugs 44 (Suppl. 3) 1992

34

to 61 ± 10%(p < 0.01) and gastric inhibitory peptide to 45 ± 8% (p < 0.001) of control values. The effect of acarbose remained approximately constant throughout the trial period and values returned to pretreatment levels within 2 days of stopping treatment. In another study performed by Gerard et aI. (1984), a single dose of glibenclamide (glyburide) 5mg was administered to 6 NIDDM patients immediately before a standardised breakfast , following one week's treatment with placebo or acarbose 100mg 3 times daily, in randomised crossover sequence. Acarbose induced a significant improvement in the blood glucose profile (area under the plasma concentration-time curve [AUC] decreased by 18%; p < 0.05), together with a significant decrease in plasma insulin levels (AUC decreased by 15%; p < 0.005). Interestingly, acarbose had no significant effect on the pharmacokinetics of glibenclamide. Reaven et aI. (1990) also demonstrated significant reductions in fasting and postprandial blood glucose, HbAl c and plasma triglyceride levels following addition of acarbose in 12 patients with NIDDM poorly controlled by diet plus sulphonylureas. 2.4.3 Biguanides and Acarbose To date, there is only I published report of a controlled study investigating the effects of combination therapy with a biguanide and acarbose, probably because of the risk of gastrointestinal effects associated with these 2 types of drugs. A preliminary report of the I-year Multicenter Canadian Trial (Ross et aI. 1992)stated that HbAI levels were significantly reduced in patients treated with metformin plus acarbose. If such a combination is used, it is necessary to recognise that acarbose has been reported to significantly modify the pharmacokinetics of metformin (Scheen et aI. 1989). 2.5 Other Oral Drugs That Improve .G lycaem ic Control

2.5.1 Fenfluramine and Dexfenfluramine Fenfluramine and its dextrostereoisomer, dexfenfluramine, are widely used in the pharmacological treatment of obesity (Guy-Grand et al. 1989).

Fenfluramine has been shown to improve glycaemic control in patients with NIDDM, independently of its effects on food intake and bodyweight (Verdy et al. 1983). Improved glycaemic control was attributed to an increase in insulin sensitivity, an effect confirmed more recently in sulphonylurea-treated NIDDM patients (Pestell et aI. 1989). Using the euglycaemic hyperinsulinaemic glucose clamp technique, performed at 3 insulin levels and combined with 3-3H-glucose turnover measurements, a recent study showed that I week's treatment with dexfenfluramine improved glycaemic control and insulin-mediated glucose disposal in obese patients with NIDDM managed by diet, independently of any significant weight reduction (Scheen et al. 1991). Although not used as hypoglycaemic medications, some studies suggest that fenfluramine, dexfenfluramine and quinine derivatives may contribute to improving metabolic control in patients with NIDDM. 2.5.2 Quinine Derivatives Recent studies have indicated that hydroxychloroquine 600 mg/day improves blood glucose control in patients with NIDDM refractory to sulfonylureas (Quatraro et aI. 1990). Further studies are needed to confirm the long term safety and usefulness of hydroxychloroquine or chloroquine (Quatraro et aI. 1988;Smith et al. 1987)in NIDDM.

3. Insulin Therapy of NIDDM When diet and oral drug therapy (either monotherapy or combined therapy) have failed to achieve adequate glycaemic control in patients with NIDDM, it is usual practice to initiate insulin therapy . It is beyond the scope of the present paper to review the use of insulin in NIDDM; the reader is referred to recent reviews on this topic (Galloway 1990; Genuth 1990; Turner & Hollman 1990). However, the potential benefits of combining insulin and various oral antidiabetic drugs in this type of patient are briefly reviewed.

Management of Non-Insulin-Dependent Diabetes Mellitus

3.I Insulin and Sulphonylureas A number of reviews on the effectiveness of combined insulin and sulphonylurea therapy in NIDDM patient s have been published recently (Bailey & Mezitis 1990; Groop et al. 1990; Lebovitz & Pasmantier 1990; Scheen & Lefebvre 1989). Several recent well designed controlled studies reviewed by Scheen and Lefebvre (1989), have clearly shown that some patients can indeed benefit from this type of combination therapy. Most of the studies investigating the mechanism of action have shown that the beneficial effects (improved blood glucose control, reduction in HbAlc levels, reduction in daily insulin requirements) are mainly due to stimulation of residual insulin secretion, with minimal or no effect on insulin sensitivity (Castillo et al. 1987). However, some investigators have suggested that sulphonylureas may also decrease the metabolic clearance rate of insulin (Scheen et al. 1988). We use combination therapy in patients with NIDDM proven to have residual insulin secretion by plasma C-peptide determination when satisfactory metabolic control is not achieved by insulin or sulphonylureas alone. 3.2 Insulin and Biguanides As already discussed, biguanides improve diabetes control, despite reducing circulating insulin levels, in obese patients with NIDDM (reviewed by Shafer 1983). Several studies have shown that metformin improves both peripheral (Hother-Nielsen et al. 1989; Nosadini et al. 1987; Prager et al. 1986) and hepatic (Jackson et al. 1987; Nosadini et al. 1987) insulin sensitivity in patients with NIDDM. However, no studies appear to have provided data clearly showing the advantages of the combination of insulin and biguanides during chronic treatment in obese patients with type 2 diabetes. 3.3 Insulin Plus Acarbose In many studies performed in patients with type I (insulin-dependent diabetes mellitus) diabetes, insulin requirements decreased during acarbose

35

treatment (Clissold & Edwards 1988). This has also been observed in NIDDM patients. Of the 32 patients studied by Gerard et al. (1981), 10 had residual insulin secretion. Improved metabolic control was obtained during acarbose treament, with a small but significant reduction in insulin requirements. Addition of acarbose to insulin should be considered in insulin-requiring NIDDM patients when an excessive postprandial rise in blood glucose cannot be adequately controlled by rapid acting insulin given before meals.

4. Treatment of Associated Disorders As already stated, NIDDM is often associated with other disorders and, when treating these, care should be taken to avoid drugs that may adversely affect glycaemic control. 4.1 Obesity Any treatment (diet, behaviour modifications, exercise) that may favour weight loss is desirable in obese NIDDM patients. Significant weight loss will often permit a reduction of the dose of oral antidiabetic agents, or of insulin. A number of drugs used for the treatment of obesity (e.g. amphetamine) should not be used in patients with diabetes. Other drugs such as rnetformin, dexfenfluramine (Scheen et al. 1991) or acarbose (Sjostrom & William-Olsson 1988) may improve the control of diabetes (see review by Carpenter & Bodansky 1990). 4.2 Hypertension As recently reviewed by DeFronzo and Ferrannini (1991) and by Reaven (1991), new information indicates that resistance to the action of insulin on glucose metabolism in peripheral tissues is a common underlying mechanism in hypertension and diabetes. As reviewed by Lithell (1991), the effects of antihypertensive agents on insulin sensitivity and lipoprotein metabolism have recently been evaluated . It has been shown that both (j-blockers and thiazide diuretics worsen insulin resistance and adversely affect lipoprotein metabol-

36

Drugs 44 (Suppl. 3) 1992

ism. In contrast, other antihypertensive agents such as angiotensin converting enzyme (ACE) inhibitors, Catr-channel blockers and a-blockers are neutral, or improve these factors. Improvement in insulin sensitivity has recently been confirmed in NIDDM patients receiving ACE inhibitors by Torlone et al. (1991). Obviously, these factors must be taken into consideration when selecting antihypertensive therapy in a patient with NIDDM. 4.3 Hyperlipidaemia Type 2 diabetes is a major risk factor for coronary heart disease, and the lipoprotein abnormalities frequently associated with NIDDM probably contribute to this increased risk. For most NIDDM patients, lipid-lowering drugs should be considered only if a combination of diet, exercise and hypoglycaemic therapy for 3 to 6 months fails to achieve desirable plasma lipid levels. As recently stated (Garg & Grundy 1990), the therapeutic target for cholesterol lowering in patients with NIDDM should be a reduction in non-HDL-cholesterol levels, i.e. low density lipoprotein (LDL)and very low density lipoprotein (VLDL)-cholesterol rather than LDL-cholesterol alone . To minimise the risk of coronary heart disease in NIDDM, the guidelines given by the Expert Panel of the National Cholesterol Education Program (1988) for the general population should probably be adapted for the diabetic population; Garg and Grundy (1990) proposed that a minimum goal of therapy for non-HDL-cholesterol should be < 4.1 mmol/ L, and the ideal goal 3.4 mmol/L, Particular emphasis should be given to weight reduction, and in some NIDDM patients mono-unsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates (Garg & Grundy 1990). To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. As suggested by Garg and Grundy (1990), HMG CoA reductase inhibitors (e.g. lovastatin, simvastatin, pravastatin) may be the drugs of choice for NIDDM patients with elevated LDL-cholesterol and borderline hypertriglyceridaemia, whereas fibric acid derivatives (e.g. fenofibrate , bezafibrate,

gemfibrozil) appear preferable for NIDDM patients with severe hypertriglyceridaemia. Finally, some studies have shown that a reduction in serum lipid parameters can improve blood glucose control in patients with type 2 diabetes , probably via increased insulin sensitivity (Paolisso et al. 1991).

5. Conclusions The management of NIDDM requires an integrated approach, including dietary modification, recommendation to increase physical activity (if feasible) and , if these measures fail to produce adequate improvement, drug therapy. It is important to consider the needs and capabilities of individual patients, as well as factors such as life expectancy and quality of life.

Acknowledgement We acknowledge the expert secretarial help of E. Vaessen-Petit.

References A.D.A. Position Statement: diabetes mellitus and exercise. Diabetes Care 13: 804-805 , 1990 Alberti KGMM. Gries A. Management of non- insulin dependent diabetes mellitus in Europe : a consensus view. Diabetic Medicine 5: 275·281. 1988 Almer LO. Johansson E, Melander A, WAhlin·Boll E. Influence of sulfon ylureas on the secretion, disposal and effect of insulin . European Journal of Clinical Pharmacology 22: 27.32 , 1982 Anderson JW. Bridges SK. Dietary fiber content of selected foods. American Journal of Clinical Nutrition 47: 440-447 , 1988 Axelrod L. Ornega-J fatt y acids in diabetes mellitus. Gift from the sea? Diabetes 38: 539-543, 1989 Bailey CJ. Metformin revisited : its actions and indications for use. Diabetic Medicine 5: 315-320, 1988 Bailey TS, Mezitis NHE . Combination therapy with insulin and sulfon ylureas for type II diabetes. Diabetes Care 13: 687-695, 1990 Berger M, Christacopoulos P, Wahren J (Eds). Diabetes and exercise. Hans Huber Publishers, Stuttgart, 1982 Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease. New England Journal of Medicine 307: 652-660, 1982 Carpenter MA, Bodansky HJ. Drug treatment of obesity in type 2 diabetes mellitus . Diabetic Medicine 7: 99-104, 1990 Castillo M, Scheen AJ, Paolisso G, Lefebvre PJ. The addition of glipizide to insulin therapy in type II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of significant residual insulin secretion . Acta Endocrinologica 116: 364-372 , 1987 Clissold SP, Edwards C. Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 35: 214-243, 1988·

Management of Non-Insulin-Dependent Diabetes Mellitus

Creutzfeldt W. Proceedings of the First International Symposium on Acarbose , Excerpta Medica , Amsterdam, 1982 Creutzfeldt W. Proceeding s of the Second International Symposium on Acarbose , Springer Verlag, Berlin, 1988 DeFronzo RA, Ferrannini E. Insulin resistance : a multifaceted syndrome responsible for NIDDM , obesit y, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease . Diabetes Care 14: 173-194, 1991 Del Tomma E, Clementi A, Maracelli M, Cappelloni M, Lintas C. Food fiber choices for diabetic diets . American Journal of Clinical Nutrition 47: 243-246, 1988 Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR , et al. Relationsh ip of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 19: 205-210, 1980 Expert Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Archives oflnternal Medicine 148: 36-69, 1988 Galloway JA. Treatment ofNIDDM with insulin agonists or substitutes. Diabetes Care 13: 1209-1239, 1990 Garg A, Bonanome A, Grundy SM, Zhang S-J, Unger RH . Comparison of a high-carbohydrate diet with a high monounsaturated-fat-diet in patients with non-insulin-dependent diabetes mellitus. New England Journal of Medicine 319: 829-834, 1988 Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 13: 153-169, 1990 Genuth S. Insulin use in NIDDM. Diabetes Care 13: 1240-1264, 1990 Gerard J, Lefebvre PJ, Luyckx AS. Glibenclamide pharmacokinet ics in acarbose-treated type 2 diabetics. European Journal of Clinical Pharmacology 27: 233-236, 1984 Gerard J, Luyckx AS, Lefebvre PJ. Improvement of metabolic control in insulin dependent diabetics treated with the a-glucosidase inhibitor acarbose for two months. Diabetologia 21: 446-451, 1981 Gerich JE. Oral hypoglycemic agents. New England Journal of Medicine 321: 1231-1245, 1989 Groop LC, Groop P-H, Stenman S. Combined insulin-sulfonylurea therapy in treatment ofNIDDM. Diabetes Care 13 (Suppl. 3): 47-52, 1990 Groop LC, Groop P-H, Stenman S, Salaranta C, Totterman K-J, et al. Comparison of pharmacokinetics, metabolic effects and mechanisms of act ion of g1yburide and glipizide during longterm treatment. Diabetes Care 10: 671-678, 1987 Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, et al. International trial of long-term dexfentluramine in obesity. Lancet 2: 1142-1145, 1989 Hendra TJ , Britton ME, Roper DR , Wagaine-Twabwe D, Jeremy JY , et al. Effects of fish oil supplements in NIDDM subjects. Controlled study . Diabetes Care 13: 821-829, 1990 Hermann LS. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care 13 (Suppl, 3): 37-41, 1990 Horton ES. Exercise and physical training: effects on insulin sensitivity and glucose metabolism. Diabetes-Metabolism Reviews 2: 1-17, 1986 Hortulanus-Beck D, Lefebvre PJ, Jeanjean MF. Le diabete dans la province beige de Luxembourg: frequence , importance de l'epreuve de surchage glucosee orale et d'une glycemie a jeun discreternent accrue. Diabete et Metabolisme 16: 311-317, 1990 Horwitz DL. Dietary adjuncts: efficacy and inadequacy. In Bailey . et al. (Eds) New antidiabetic drugs , pp. 53-63, Smith-Gordon, London, 1990 Hother-Nielsen 0, Schmitz 0 , Andersen PH, Beck-Nielsen H, Pedersen O. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinologica 120: 257-265, 1989 Innerfield RJ, Coniff RF. A multi-center, double-blind , placebocontrolled study of the long-term efficacy and safety of acar-

37

bose (BAY g 5421) in the Rx of obese patients with NIDDM Rxed by diet alone . Diabetes 39 (Suppl. I): Abstract no. 829, p, 211A, 1990 Jackson RA, Hawa MI, Jaspan JB, Sim BS, Disilvio L, et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes 36: 632-640, 1987 Jarrett RJ. The epidemiology of diabetes mellitus. In Pickup J, Williams G (Eds) Textbook of diabetes, p. 47, Blackwell, london, 1991 Jenkins DJA, Jenkins AL, Wolever TMS, Vuksan V, Wong GS, et al. Aims of diet in diabetes management. In Creutzfeldt W, Lefebvre P (Eds) Diabetes mellitus : pathophysiology and therapy, pp. 299-308, Springer Verlag, Berlin, 1989 Kemmer FW, Berger M. Therapy and better quality of life: the dichotomous role of exercise in diabetes mellitus . DiabetesMetabolism Reviews 2: 62-68, 1986 Lebovitz HE, Pasmantier RM. Combination insulin-sulfonylurea therapy . Diabetes Care 13: 667-675, 1990 Lithell HOL. Effect of antihypertensive drugs on insulin , glucose and lipid metabolism. Diabetes Care 14: 203-209, 1991 Melander A, Bitzen P-O, Faber 0 , Groop L. Sulphonylurea antidiabetic drugs . An update of their clinical pharmacology and rational therapeutic use. Drugs 37: 58-72, 1989 Melander A, Lebovitz HE, Faber OK. Sulfonylureas. Why, which, and how? Diabetes Care 13 (Suppl. 3): 18-25, 1990 Mori TA, Vandongen R, Masarei JRL. Fish oil-induced changes in apolipoproteins in IDDM subjects . Diabetes Care 13: 725732, 1990 Nosadini R, Avogaro A, Trevisan R, Valerio A, Tessari P, et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care 10: 62-67, 1987 Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, et al. Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects . Acta Endocrinologica 121: 16-20, 1989a Paolisso G, Scheen A, D'Onofrio F, Lefebvre P. Magnesium and glucose homeostasis. Diabetologia 33: 511-514, 1990 Paolisso G, Sgambato S, Deriu S, Gambardella A, Verza M, et al. Simvastatin reduces plasma-lipid levels and improves insulin action in elderly, non-insulin-dependent diabetics . European Journal of Clinical Pharmacology 40: 27-31, 1991 Paolisso G, Sgarnbato S, Pizza G, Passariello N, Varricchio M, et al. Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects. Diabetes Care 12: 265-269, 1989b Pestell RG, Crock PA, Ward GM, Alford FP, Best JD. Fentluramine increases insulin action in patients with NIDDM . Diabetes Care 12: 252-258, 1989 Prager R, Schernthaner G, Graf H. Effect of metformin on peripheral insulin sensitivity in non insulin dependent diabetes mellitus. Diabete et Metabolisme 12: 346-350, 1986 Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 2: 131-141, 1979 Quatraro A, Consoli G, Ceriello A, Giugliano D. Is there a role for chloroquine treatment in diabetes? A three case report (letter). Diabete et Metabolisme 14: 666-667, 1988 Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, et al. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus . A new job for an old drug? Annals oflnternal Medicine 112: 678-681, 1990 Reaven GM . Role of insulin resistance in human disease. Diabetes 37: 1595-1606, 1988 Reaven GM . Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension: parallels between human disease and rodent models . Diabetes Care 14: 195-202, 1991 Reaven GM, Lardinois CK, Greenfield MS, Schwartz HC, Vre· man HJ . Effect of acarbose on carbohydrate and lipid metab-

38

olism in NIDDM patients poorly controlled by sulfonylureas . Diabetes Care 13 (Suppl. 3): 32-36, 1990 Ross S, Hunt J, Josse R, Mukherjee J, Palmason C, er al. Acarbose significantly improves glucose control in non-insulin-dependent diabetes mellitus subjects (NIDDM): results of the multicentre Canadian trial. Diabetes 41 (Suppl. I): 193A, 1992 Scheen AJ, Castillo MJ, Lefebvre PJ. Decreased or increased insulin metabolism after glipizide in type II diabetes? Diabetes Care II : 687-689, 1988 Scheen AJ, Ferreira Alves de Magalhaes AC, Salvatore T, Lefebvre PJ. Modifications de la pharrnacocinetique de la metformine apres inhibition des alpha-glucosidases intestinales par l'acarbose chez Ie sujet sain. Diabete et Metabolisme 15 (Suppl. XIV), resume no. 53, 1989 Scheen AJ, Lefebvre PJ. Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary failure to sulfon ylureas. Diabetes Research and Clinical Practice 6: S33-S43, 1989 Scheen AJ, Lefebvre PJ, Luyckx AS. Glipizide increases plasma insulin but not Cvpeptide level after a standardized breakfast in type 2 diabetic patients. European Journal of Clinical Pharmacology 26: 471-474, 1984 Scheen AJ, Paolisso G, Salvatore T, Lefebvre PJ. Improvement of insulin -induced glucose disposal in obese patients with NIDDM after I-wk treatment with d-fenfluramine, Diabetes Care 14: 325·332, 1991 Schneider SH, Ruderman NB. Technical review: exercise and NIDDM . Diabetes Care 13: 785-789, 1990 Shafer G. Biguanides. A review of history , pharmacodynamics and therapy . Diabete et Metabolisme 9: 148-163, 1983 Sjostrom L, William-Olsson T. Relapse-reducing effects of acarbose after weight reduction in severely obese subjects. In Creutzfeldt W (Ed.) Proceedings of the Second International Symposium on Acarbose, p. 137, Springer Verlag, Berlin, 1988 Slama G. L'alimentation des diabetiques. In Tchobroutsky et al. (Eds) Traite de Diabetologie, pp. 657-678, Editions Pradel, Paris, 1990

Drugs 44 (Suppl. 3) 1992

Smith GD, Amos TA, Mahler R. Peters TJ. Effect of chloroquine on insulin and glucose homeostasi s in normal subjects and in patients with non-insulin-dependent diabetes mellitus. British Medical Journal 294: 465-467, 1987 Toeller M. Modulation of intestinal glucose absorption: postponement of glucose absorption by a-glucosidase inhibitors. In Mogensen CE, Standi E (Eds) Pharmacology of diabetes, Vol. 3, pp. 93-112, de Gruyter, Berlin, 1991 Torlone E, Rambotti AM, Perriello G , Botta G, Santeusanio F, et al. ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension . Diabetologia 34: 119-125, 1991 Turner RC, Holman RR. Insulin use in NIDDM . Rationale based on pathophysiology of disease. Diabetes Care 13: 1011-1020, 1990 Uttenthal LO, Ukponmwan 00, Ghiglione M, Wood SM, Ghatei MA, et al. Long-term effects of acarbose treatment on postprandial glucose, pancreatic and gut hormone responses and fasting serum lipids in non-insulin-dependent diabetics on sulphonylureas. In Creutzfeldt W (Ed.) Proceedings of the Second International Symposium on Acarbose, p. 133, Springer-Verlag, Berlin, 1988 Verdy M, Charboneau L, Verdy I, Belanger R, Bolte E, et al. Fenfluramine in the treatment of non-insulin dependent diabetics: hypoglycemic versus anorectic effect. International Journal of Obesity 7: 289-297, 1983 Vessby B, Boberg M. Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulindependent diabete s mellitus. Journal ofInternal Medicine 228: 165-171, 1990 Correspondence and reprints : Dr P.J. Lefebvre. Diabetes, Nutrition and Metabolic Disorders Unit, c'H.U . Sart Tilman (B 35), B-4000 Liege I, Belgium.