Treatment

There is huge variation in optimal dosing of each member of the SUs and the glinides (Table 1). If starting with monotherapy, it is best to start with the lowest recommended dose and to titrate upward every 7-14 days to achieve the desired glycaemic control without hypoglycaemia [23]. In some cases, the titration interval can be increased to 3-4 weeks, but there is no therapeutic advantage in waiting more than 4 weeks to increase the SU-dose [4]. About two thirds of the glucose lowering action of insulin sec-retagogues is already achieved at about half the maximal daily dose [24,30]. During SU monotherapy, most studies report a reduction in HbAlc of about 1-2% [10,11,24,25] compared with placebo.

After initiation of therapy, only ~25% of patients will achieve sufficient glycaemic control with HbA1c levels <7%. Those patients can be classified as complete responders [4]. Recently diagnosed diabetes mellitus, only moderate fasting hypergly-caemia at diagnosis (<~12 mmol/L or 220 mg/dL), absence of glutamic acid decarboxylase antibodies, no history of insulin therapy and good beta-cell function are predictors of good SU response [31]. Most of the diabetic patients (~50-60%) show good initial response, but do not achieve the desired treatment goals (fasting plasma glucose <7.8 mmol/L or <140 mg/dL) [4]. In such cases of partial response, a combination-therapy with other oral agents or even with basal insulin ("bed time insulin") will be necessary. In the rest of the patients (~15-25%) SUs or glinides will not be able to decrease fasting plasma glucose concentrations significantly (primary failure) [26]. Very high fasting plasma glucose concentrations (up to 17 mmol/L or >300 mg/dL) and low fasting C-peptide concentrations are predictors of primary failure. Some of those cases finally can be diagnosed as late onset autoimmune diabetes (LADA) [32] and need insulin treatment.

Although SUs are very effective in lowering blood glucose and HbA1c, this effect vanishes after some years. In the UKPDS, net HbA1c reduction after 10 years was only 0.9% [11]. After good initial response to SU therapy, the yearly secondary failure rate is about 5-7% [6,11,12]. After 10-12 years, most patients require additional oral medications or insulin therapy. The reasons for treatment failure are manifold: progression of disease-related factors (insulin resistance, weight gain), lack of exercise and concomitant medication (beta blockers and thiazide diuretics) [33,34]. In addition, beta cells lose their ability to maintain augmented insulin secretion continuously over the years [6]. That decline in beta-cell function parallels the progressive deterioration of glycaemic control, leading to the hypothesis that long-term SU exposure might cause desensitization and/or exhaustion of beta cells [9]. That concern was supported by studies that showed apoptosis in beta-cell lines and rodent islets [35]. In a recent study [36], repaglin-ide and nateglinide were compared with gliben-clamide in isolated human islets with regard to cell apoptosis. In that study, only small advantages for the non-SU secretagogues could be shown at low concentrations. However, at 4-day exposure of the islets to secretagogues, beta-cell apoptosis was similar for all secretagogues [36]. In addition, hyperglycaemia per se as well as increased concentrations of plasma free fatty acids [37,38] could have toxic effects on beta cells [39].

Differences between first- and second-generation SUs have been studied recently and indicate preserved insulin responsiveness in islets incubated with glimepiride in contrast to glibenclamide or chlorpropamide [40]. Another second-generation SU, gliclazide, could even have protective effects on beta cells by reducing free radicals and thereby protecting the cells from oxidative stress [41].

On the other hand, in large clinical trials like the UKPDS or the recently published ADOPT-study [42], the loss of beta-cell function was not unique for therapy with insulin secretagogues, but occurred at the same rate of decline during therapy with metformin or diet, suggesting that progressive reduction of insulin secretion is peculiar for diabetes mellitus type 2. In the ADOPT-study, the yearly loss of beta-cell function 3-5 years after diagnosis of diabetes mellitus was similar when comparing glibenclamide, metformin or rosiglitazone treatment. In that study, progression of disease, that is, increase in HbA1c and fasting plasma glucose,

Plasma Glucose Change During Fasting
Fig. 2. Changes of fasting plasma glucose (FPG), HbAlc and body weight after 4 years treatment with either rosiglitazone, metformin or glibenclamide in the ADOPT-study population (for details see text and ref. 42).

was lower during treatment with rosiglitazone or metformin than during treatment with glibenclamide (Fig. 2). However, the increase in HbAlc levels was less pronounced than the increase in fasting plasma glucose, indicating that postprandial glucose concentrations were still effectively lowered by glibenclamide.

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Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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