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DL Van Gaal
Dept of Diabetology
University Hospital Antwerp
Type 2 diabetes mellitus is a common disorder associated with a markedly increased morbidity and mortality rate. It is a heterogeneous condition caused by both genetic and environmental factors.
Type 2 diabetes ranks highly on the list of clinical conditions for which obesity is a known risk factor for comorbidity. The proportion of people with type 2 diabetes attributable to obesity has been estimated to be between 57% and 61%, whereas with hypertension and coronary heart disease only 17% can be attributed directly to obesity. In addition, over 80% of people with type 2 diabetes are overweight or obese at the time of diagnosis, a situation that worsens after hypoglycaemic therapy is started.
The development of impaired glucose homeostasis results from a dynamic interaction between defects in insulin secretion and insulin action.
It has long been recognised that drugs represent only part of the management of type 2 diabetes, and that other interventions, such as patient education, modification of diet and promotion of physical activity play a crucial role.
Treatment includes drugs that control fasting and postprandial glycaemic excursions, such as sulphonylureas, biguanides (metformin), alpha-glucosidase inhibitors (acarbose) and insulin. These agents may be used as monotherapy or in various combinations. An alternative approach in the management of the obese diabetic is the use of drugs that aim to reduce weight by 5–10%.
The antidiabetic approach
Biguanide (metformin) therapy improves insulin sensitivity, as shown by a reduction in fasting plasma glucose (FPG) and insulin levels. In patients with type 2 diabetes, the glucose-lowering effect is attributed mainly to decreased hepatic glucose output and enhanced peripheral glucose uptake. Several other actions may contribute, such as increased intestinal use of glucose and decreased fatty acid oxidation. Various cellular actions of metformin have been described, especially an increase in the number of glucose transporters GLUT4, which transfer glucose into muscular and adipose cells. In the absence of contraindications (kidney, liver and/or heart failure), metformin can be considered as the first choice of therapy among overweight patients with type 2 diabetes.
Insulin resistance is a key feature of type 2 diabetes, especially when obesity is present. As metformin may improve insulin sensitivity, reduce hyperinsulinaemia and promote bodyweight reduction, or at least stabilise bodyweight, the drug would be more appropriate as the firstline antidiabetic agent in obese patients with diabetes. However, recent observations have shown that metformin is also active in type 2 diabetes patients in the absence of obesity.
Another interesting effect of metformin is its favourable action on various disorders associated with insulin resistance, such as high triglyceride levels, decreased high-density lipoprotein levels, and high plasminogen activator inhibitor (PAI-1) levels, frequently seen in obese type 2 diabetic individuals with abdominal adiposity. From a practical point of view, in order to enhance gastrointestinal tolerability, progressive dosage titration from 500mg to a maximum of 2g daily is an important recommendation, often neglected by physicians.
In contrast to the majority of sulphonylureas, metformin does not cause bodyweight gain. In addition, as shown in the recent UKPDS, it is the only hypoglycaemic drug that was associated with a reduction of cardiovascular outcome events after roughly nine years.
Sulphonylureas stimulate insulin secretion by interacting with specific receptors on the beta-cell surface that act by closing K(+) channels; this results in Ca2(+) entering the beta cell, which leads to a release of insulin-containing secretory granules. Extrapancreatic effects have also been described.
Sulphonylureas are a rational choice to begin pharmacological intervention because almost all patients with type 2 diabetes are relatively insulin-deficient. In responsive patients, therapy with a sulphonylurea can lower glycosylated haemoglobin (HbA1c) levels by 1–2%. However, at best, 60–70% of such patients might achieve “good” glycaemic targets, and those with high fasting blood glucose levels and severe obesity rarely succeed. In addition to the rather high initial failure rate, about 10% of patients per year will fail to respond to therapy.
Hypoglycaemia is the main problem associated with sulphonylurea therapy, especially in elderly people. The risk is increased when alcohol is taken or in association with drugs that may potentiate the action of the sulphonylureas, like aspirin-containing preparations or nonsteroidal anti-inflammatory drugs. Patient information and education is of great importance in this regard. Weight gain is also of considerable importance, mainly in subjects who are overweight at baseline.
The more recently developed nonsulphonylurea beta-cell secretagogues, such as the glinides, may have a more limited weight-increasing effect: both repaglinide and nateglinide have lesser impact on bodyweight, while improving overall metabolic control, mainly through a reduction of postprandial glucose. The newer beta-cell secretagogues are also known to have beta-cell-sparing capacities. If their efficacy is shown to be as good as the classical sulphonylureas, these newer agents will probably replace them in the future.
Another interesting recent development in the treatment of the obese type 2 diabetic patient is the insulin sensitisers or thiazolidinediones. Since these glitazones, rosiglitazone and pioglitazone in particular, have a specific action in reducing insulin resistance, they might be considered as the ideal first choice or combination strategy for the treatment of patients with type 2 diabetes who are overweight or obese. However, glitazones seem to be adipogenic, leading to weight gain, although this fat accumulation mostly occurs in the less dangerous subcutaneous (instead of the atherogenic abdominal visceral) fat cell compartment. In addition, European agencies allow glitazones to be prescribed only in combination therapy, and not as starting monotherapy. Taking the physiopathologically interesting approach into consideration for this newer group, we will have to wait to see what their exact place in management may be.
The glucosidase inhibitors acarbose and the more recently developed miglitol and voglibose may have a supportive effect in glucose lowering. As enzymes that break down nonadsorptive complex carbohydrates into adsorbable monosaccharides, with no weight gain, they may be considered as additional therapeutic possibilities in the treatment of the obese patients with diabetes. The major adverse effect of these glucosidase inhibitors is gastrointestinal intolerance, with a high incidence of flatulence and mild abdominal pain. Although these symptoms are dose-related and transient, they may limit their broad use among type 2 diabetic patients.
The antiobesity approach
Weight gain is a known risk factor for the development of type 2 diabetes, and even modest weight reduction can reduce the risk of diabetes development; so controlling bodyweight is an important health goal in the fight against diabetes and its comorbidities. Weight reduction is also a cornerstone in the management of diabetes, improving glycaemic control and reducing other risk factors associated with this disease.
New antiobesity drugs, such as orlistat and sibutramine, can contribute to the prevention of diabetes and to the management of type 2 diabetes in overweight and obese diabetic patients. Generally, a modest weight reduction should be considered as successful, although findings show that among those with diabetes, weight loss is difficult to obtain.
Orlistat – the lipase inhibitor
Orlistat is an inhibitor of gastric and pancreatic lipases, which are instrumental in the digestion and absorption of fat from the gastrointestinal tract. Inhibition of lipase activity has the effect of decreasing fat absorption by 30%, independent of the amount of fat intake, and increasing the excretion of triglycerides in the faeces.
There are seven studies that among them look at over 2,500 diabetic subjects who were treated for between six months and one year with orlistat, and who received different antidiabetic medications.
Orlistat has been proven to improve metabolic control, with a reduction in HbA1c of up to 0.53% and a decrease in the concomitant ongoing antidiabetic therapy. More patients treated with orlistat achieve clinically beneficial changes in HbA1c, particularly those with baseline levels of HbA1c >8%.
Pooled data from a retrospective analysis of seven multicentre, double-blind trials enrolling overweight or obese patients (BMI 28–43kg/m(2)) with type 2 diabetes and treated with metformin, sulphonylurea and/or insulin showed that orlistat-treated patients had significantly greater improvements in HbA1c and FPG than placebo. These improvements were similar across the diabetic medication subgroups.
One study randomised 550 insulin-treated patients to receive either placebo or orlistat 120mg three times a day for one year. Weight loss in the orlistat-treated group was greater than the placebo-treated group. HbA1c decreased by 0.6% in the orlistat-treated group, but only by 0.27% in the placebo group. The required dose of insulin decreased more in the orlistat group, as did plasma cholesterol.
Independent effects of orlistat on lipids have also been shown. Orlistat also has an acute effect on postprandial lipaemia in overweight patients with type 2 diabetes.
Sibutramine – a centrally active drug
Sibutramine is a serotonin and noradrenaline reuptake inhibitor, active at the hypothalamic area to reduce food intake and to enhance satiety. As a monoamine reuptake inhibitor, it does not show the disadvantages of monoamine-releasers (such as the former fenfluramines and amphetamine-like products).
Sibutramine is the first of a new generation of weight management drugs and offers improved long-term control of weight when used as an adjunct to diet and exercise. Its efficacy for weight loss in obese patients with diabetes has been investigated in a number of controlled clinical studies. A meta-analysis of data from three such studies shows that three times as many sibutramine-treated patients achieved 5% and 10% weight loss compared with controls. Over 50% of the diabetes patients receiving daily sibutramine achieved >5% weight loss, and of these over 20% achieved >10% weight loss.
Irrespective of the diabetes management programme prescribed to improve glycaemic control, sibutramine therapy improved weight loss compared with diabetic control programmes alone.
For many of the patients with type 2 diabetes studied, sibutramine was used at a daily dose of 15mg. This dose is higher than usually used as startup treatment for nondiabetic obese patients, and was chosen in an attempt to overcome the known difficulties of promoting and inducing weight loss in type 2 diabetes.
Side-effects of sibutramine include the classical serotonin-like side-effects such as fatigue, nausea, constipation and dry mouth. Because of the mechanism of action as a noradrenergic drug, a slight increase in pulse rate (3–5bpm) and a modest increase in blood pressure are often seen, mostly in patients with normal baseline blood pressure. Careful follow-up is advisable.
A well-chosen therapy for the obese type 2 diabetic patient includes both the antiobesity and the antidiabetes approach. In noninsulin-requiring subjects, the logical approach seems to be a combination therapy with a weight-reducing drug like sibutramine or orlistat with metformin. If contraindications for obesity-lowering drugs are present, a combination of metformin and the more recent beta-cell nonsulphonylurea secretagogues seems adequate. In insulin-requiring subjects, the addition of either metformin or the lipase inhibitor orlistat seems to have good long-term effects.
In overweight subjects with clinically diagnosed type 2 diabetes, increasing the rate and the extent of weight loss can help to improve glycaemic control and help to normalise the metabolic abnormalities associated with type 2 diabetes. In so doing, such a combined approach can improve the prognoses for many patients. If the combined diabetes approach and obesity approach can reach the 10% HbA1c reduction target, diabetic subjects may benefit from the important risk reduction in all diabetes-related complications (21%) and diabetic microangiopathy (35%), as was shown in the UKPDS study.
For details, please contact the author
International Obesity Task Force
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Dr Xavier Formiguera Sala
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North American Association for the Study of Obesity
24–29 August 2002
9th International Congress on Obesity
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