Comparative effects of glimepiride and glibenclamide on blood glucose, C-peptide and insulin concentrations in the fasting and postprandial state in normal man.

A single-center, randomised, placebo- controlled, cross-over study was conducted to characterize the new sulfonylurea glimepiride and to compare its profile of action with the second generation sulfonylurea glibenclamide. The total duration of each experiment was 5 hours. At zero time an i.v. injection of 2 and 4 mg glimepiride, 1 mg glibenclamide or placebo was given i.v. to 24 healthy volunteers. Blood samples were collected for three hours after the injection (0-3 hours, preprandial experiment). At 3 hours, a standard mixed meal was given (20%, of a 30 Kcal/Kg Body Weight diet) and blood samples were collected for 2 more hours (postprandial experiment). Pre-prandially (0-3 hrs) blood glucose (expressed as the area under the curve divided by the time) was significantly lower (p < 0.0001) after the administration of 2 and 4 mg glimepiride (3.8 +/- 0.22 and 3.5 +/- 0.3 mM respectively) compared to placebo (4.63 +/- 0.31 mM), but not compared to glibenclamide. Insulin and C-peptide were not different after glimepiride or glibenclamide. Both glimepiride and glibenclamide had similar effects on insulin secretion. Post-prandially (3-5 hrs) blood glucose was significantly higher after glibenclamide (6.54 +/- 0.8 mM) (p < 0.0001) than after 2 mg glimepiride (5.75 +/- 0.5 mM). Despite this C-peptide was significantly higher (p < 0.002) glibenclamide (5.7 +/- 1.5 ng/ml) compared to glimepiride (5.1 +/- 1.3 ng/ml); the trend was the same for insulin but the results were not significantly different (p = 0.06) In conclusion, in the fasting state, glimepiride and glibenclamide had similar effects on the changes in blood glucose levels after i.v. administration. After the meal, less pronounced hyperglycemia and lower insulin and C-peptide levels following glimepiride (2 mg) suggests either that glimepiride induces insulin secretion through a pathway which is different from that of glibenclamide or that glimepiride facilitates insulin action through extrapancreatic effects.

Beta cell response to oral glimepiride administration during and following a hyperglycaemic clamp in NIDDM patients.

The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.

Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl): a double-blind comparison with glibenclamide.

An international, prospective, double-blind trial compared the long-term therapeutic value of glimepiride with glibenclamide in patients with Type 2 diabetes mellitus. Patients stabilised on glibenclamide were randomised to 1 mg glimepiride (524 patients) or 2.5 mg glibenclamide (520 patients). The treatment groups were comparable at baseline with respect to age (60.2 years), body mass index (26.5 kg/m2), duration of diabetes (5.0 years) and fasting blood glucose levels (163 mg/dl [9.0 mmol/l]). Doses were increased stepwise, up to 8 mg for glimepiride (once-daily) and 20 mg for glibenclamide (> 10 mg as divided dose), until metabolic control (fasting blood glucose < or = 150 mg/dl [8.3 mmol/l]), or maximum dose was achieved. After one year of treatment, patients entered a long-term follow-up study. Primary endpoints for evaluation of metabolic control, mean glycated haemoglobin and mean fasting blood glucose, were 8.4% and 174 mg/dl (9.7 mmol/l) for glimepiride and 8.3% and 168 mg/dl (9.3 mmol/l) for glibenclamide. Differences between treatment groups were not considered clinically relevant (95% confidence intervals (-0.05, 0.19%) for glycated haemoglobin and (2, 11 mg/dl) [0.1, 0.6 mmol/l] for fasting blood glucose). Statistically significant lower fasting insulin and C-peptide values were observed in glimepiride patients compared with glibenclamide (differences: insulin, -0.92 microU/ml [p = 0.04]; C-peptide, -0.14 ng/ml [p = 0.03]). Both treatment groups showed an equivalent safety profile. Adverse events were consistent with the nature of the diabetic patient population studied. Fewer hypoglycaemic reactions occurred with glimepiride than with glibenclamide (105 versus 150 episodes). The long-term follow-up (457 patients) confirmed that glimepiride (1-8 mg) once daily provides equivalent metabolic control to a higher dosage (2.5-20.0 mg) of glibenclamide. Both treatments were well tolerated.

Increase in circulating basement membrane antigens in diabetic rats and effects of insulin treatment.

The serum concentrations of two recently discovered antigens derived from basement membranes (7-S collagen and laminin P2) were assayed in streptozotocin-diabetic rats as possible indicators of basement membrane metabolism. The concentrations of both increased significantly after 8 weeks of diabetes, and that of 7-S collagen at least remained elevated up to 24 weeks. Treatment with insulin, which did not correct the metabolic disturbances, inhibited the increase in the concentration of 7-S collagen in serum, but did not completely normalize that of laminin P2.

A modified assay system for collagen glucosyltransferase.

A simplified assay procedure has been developed for the determination of collagen glucosyltransferase activity in tissue extracts. Using degraded gelatine as acceptor it was possible to isolate the reaction product by precipitation on to a glass fibre disc. Under our conditions degraded gelatine is glucosylated with a reaction rate which is 3--4 times lower compared with the glucosylation of basement membrane derived glycopeptides. Good reproducibility is demonstrated by the coefficient of variation of 4% in the same assay and an interassay variation coefficient below 8%. As the assay allows the testing of large numbers of samples in a few hours, it should prove a useful tool to determine the enzyme level in the tissue of diabetic animals. In humans the activity of the glucosyltransferase could provide a biochemical parameter related to diabetic microangiopathy.