any diabetes-related endpoint, which includes various cardiac diseases, renal failure, amputations, and eye problems; (2) diabetes-related death; and (3) all-cause mortality. The UKPDS also analyzed the cost-benefit relationship and treatment of hypertension.
The main points that can be drawn from these studies are:
1. Intensive blood glucose lowering therapy with glibenclamide, metformin, or insulin (NB not with chlorpropamide [130]) delays the onset and progression of microvascular complications in type 2 diabetes.
2. The HbAlc lowering potency of these drugs was comparable.
3. Intensive treatment of obese type 2 diabetic subjects with metformin can also reduce the risk of macrovascular complications.
In none of the studies was diabetes management ideal. The goals of blood glucose control were rarely met, the rates of chronic complications of diabetes remained high, and adverse events were frequent during sulfonylurea and insulin treatment. The need for combination therapy was realized [125], but the addition of metformin to sulfonylurea had adverse effects. Other combinations were not systematically studied. New drugs could not be investigated. These shortcomings make it difficult to select the best therapy for each individual patient solely on the basis of these important studies. For this reason, the therapeutic options will now also be considered from the practical and patho-physiological points of view.
Intensive treatment with sulfonylurea or insulin has adverse effects. It increases the risk of hypoglycemia. In the past this used to be a minor problem, but it becomes a question of safety and quality of life if the goal of therapy is near-normoglycemia. The other adverse effect is weight gain. Most type 2 diabetic subjects are overweight and are advised to lose weight. The patients experience both hypoglycemia and weight gain as causing distress and impairing their quality of life [130]. Weight gain is a precipitating factor for diabetes and a macrovascular risk factor. Therefore, it is legitimate to ask whether the benefit of lowering HbA1c by insulin or glibenclamide is not jeopardized by the risk of this side effect. Therapy with either drug alone may not be a first choice.
Another concern is the fact that neither human insulin nor sulfonylurea corresponds with the pathogenetic defects of type 2 diabetes. They do not restore early insulin secretion because they are too sluggish; that is, the meal-related early phase of insulin action comes too late and the postprandial insulin action lasts too long.
Both types of drugs may overcome insulin resistance but they do not restore insulin sensitivity. If insulin sensitivity improves, this is not a direct drug effect but a nonspecific effect of lowering blood glucose and decreasing glucose toxicity. In the future, rather than insulin and sulfonylurea, rapid-and short-acting insulin analogues and glinides should be considered to initiate a more physiological insulin substitution, and metformin and glitazones to improve insulin sensitivity. However, the new drugs urgently need to be evaluated in controlled prospective studies using hard endpoints.
Intensive treatment with oral drugs or insulin over three years will lower HbA1c below 7% in only half of the patients. In the majority, combination therapy is indicated. Combinations of oral antidiabetic drugs have already been discussed. The combination of insulin with oral antidiabetic drugs may be even more important. The combination of insulin with sulfonylurea has been extensively studied [381,420,421,427,428]. It is convenient and may save some insulin. If postprandial hyperglycemia after breakfast is the main problem, the morning sulfonylurea dose may be replaced by regular or mixed insulin or short-acting insulin analogues. If fasting hyperglycemia is the main problem, the evening oral antidiabetic drug dose may be replaced by NPH insulin at bedtime. Metabolic control can be improved by various combinations without increasing the risk of hypoglycemia [423,424,427,428]. The combination of insulin with metformin is also possible. This combination offers the advantage of avoiding weight gain [133,425].
Fig. 1.3 Proposed stepwise treatment algorithm based on the pathophysiology of type 2 diabetes. For the rationale of this proposal, see text. The warnings with respect to possible unknown long-term side effects must be taken into account.(Modified after Matthaei et al. [395])
A proposed rationale for the selection of drugs in the treatment of type 2 diabetes mellitus is given in Figure 1.3.
Metabolic Syndrome
The outstanding significance of treating the metabolic syndrome to prevent type 2 diabetes mellitus has already been discussed. The metabolic syndrome usually persists in clinical type 2 diabetes, and therefore its treatment remains important.
The impact of overweight/obesity and the importance of weight reduction have been repeatedly confirmed. Weight reduction is not easy. Even more difficult is maintaining reduced body weight over long periods of time. The ideal aim is normal body weight, which will very seldom be achieved. However, much lesser weight reduction is also beneficial [53,54,62,336]. In support of nonpharmacological treatment with nutrition and physical activity, two drugs have recently been introduced: the intestinal lipase inhibitor orlistat, which reduces nutritional fat absorption, and the serotonin/norepinephrine reuptake inhibitor sibutramine, which is an appetite suppressant. Both drugs have been shown to enhance weight loss during conventional weight reduction programs. Orlistat may inhibit absorption not only of fat but also of lipid-soluble drugs and essential nutrients. Sibutramine may evoke psycho-neurological symptoms and increase arterial blood pressure. The drug also has the drawback of a variety of contraindications and drug interactions.
The beneficial effect of lowering elevated blood pressure and specific drug effects on nephropathy and coronary artery disease have already been discussed. The UKPDS [158] has shown that lowering blood pressure from 154/87 to 144/82 mmHg significantly reduced diabetes-related endpoints by 24%, microvascular endpoints by 37%, and stroke by 44%. The epidemiological analysis of this study offers the conclusion that the lowest risk will be “in those with systolic blood pressure less than 120 mm Hg” [159].
Dyslipoproteinemia that does not respond to weight reduction should be corrected by pharmacological therapy. Statins are the first-choice drug if serum cholesterol is elevated. They have favorable effects on small, dense LDL and lower the risk of macroangiopathy complications [429,
