Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial.

Disturbances in nitric oxide (NO) metabolism resulting in endothelial dysfunction play a central role in the pathogenesis of atherosclerosis in hypercholesterolemia and in individuals with type 2 diabetes. It is unclear whether lipid lowering therapy with HMG-CoA-reductase inhibitors might improve endothelial function in subjects with type 2 diabetes as it is demonstrated in non-diabetic subjects with hypercholesterolemia. We examined the influence of 0.2 mg and 0.8 mg cerivastatin on endothelial function in a multicenter, randomised, double-blind, and three-arm placebo-controlled clinical trial. Endothelial function was assessed by nitric oxide-dependent flow mediated vasodilatation (FMD) of the brachial artery. A total of 103 patients with type 2 diabetes were enrolled in the study. Bayer Company undertook a voluntary action to withdraw cerivastatin from market, therefore the study was terminated earlier. At this point 77 patients were randomised, of which 58 completed the study (mean age 60 +/- 8 years, HbA1c 7.4 +/- 0.9 %). At baseline mean FMD was disturbed in all three therapy arms (5.18 +/- 2.31 % in the placebo group, 3.88 +/- 1.68 in the 0.2-mg cerivastation group, and 4.86 +/- 2.25 in the 0.8-mg cerivastatin group). Despite a significant reduction in cholesterol and LDL-cholesterol-levels after 12 weeks of treatment (decrease in LDL-cholesterol - 26.8 +/- 13.9 % in the 0.2-mg group and - 40.3 +/- 16.0 % in the 0.8-mg group, p = 0.0001, ANCOVA) there was no difference in flow mediated vasodilatation (p = 0.52 and p = 0.56 vs. placebo, respectively, ANCOVA). HbA1c, CRP, and HDL-cholesterol did not change during the study. Furthermore no difference in safety profile between cerivastatin and placebo was found. Despite a significant improvement in lipid profile under statin therapy, no improvement of endothelial dysfunction in terms of nitric oxide bioavailability could be detected.

The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone.

OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.

Preclinical review of cerivastatin sodium--a step forward in HMG-CoA reductase inhibition.

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatin's high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.

Steroid receptor pattern of human colorectal neoplasms.

Twenty-four colorectal carcinomas were assayed for estrogen and progestin receptors by sucrose gradient centrifugation. Most biopsies were either completely estrogen receptor negative or displayed low titers of specific estrogen binding. Only three tumors demonstrated moderate estrogen binding activity (10-18 fmol/mg cytosol protein). In four tumors specific progestin binding exceeded 20 fmol/mg protein. Only a minor subset of the binders sedimented at 8S. Twenty-one colorectal tumors examined for the presence of glucocorticoid receptors were found to be receptor positive, without exception. Biopsies from normal colorectal mucosa displayed minute quantities of specific 8S estrogen and progestin binding, but significant titers of specific glucocorticoid binding. Our findings support the hypothesis that estrogens and progestins are unlikely to play a major role in endocrine control of colorectal neoplasms. The role of glucocorticoids in growth control of colorectal neoplasms remains to be defined.

Steroid receptor status of focal-nodular hyperplasia of the human liver.

As with normal human liver, both focal nodular hyperplasia (FNH) of the liver and a hepatocellular carcinoma were found to contain low levels of high affinity estrogen-binding components. In low-salt sucrose gradients the estrogen binders sedimented at 4S and 8S. Specificity studies indicated a requirement for estrogenic hormones. Progestin-binding studies using labeled and unlabeled ORG 2058 revealed high levels of specific binding in FNH and normal liver cytosol, whereas only insignificant amounts of ORG 2058 binding was found in the hepatocellular carcinoma. As judged by the high apparent dissociation constant (4-14 X 10(-8) mol/l) of the ORG 2058 - binder complex, the apparent lack of 8S binding in low-salt sucrose gradients and the atypical ligand specificity, the progestin receptor nature of these binding entities is unlikely. In contrast, normal liver, FNH, and the hepatocellular carcinoma were found to contain significant quantities of glucocorticoid receptors.

Effect of acarbose on weight maintenance after dietary weight loss in obese subjects.

AIMS: Acarbose is a well established antidiabetic drug and is known to exert a modest weight-lowering effect. The aim of this study was to assess the potential of acarbose to improve weight maintenance after a substantial weight loss by dietary measures in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled trial of the effect of acarbose on weight change over a 6-month follow-up period. PATIENTS AND METHODS: One hundred and ten obese subjects with a BMI > or = 32 and < or = 38 kg/m2 were included in the study and underwent a 10-16-week very-low-calorie diet programme to initiate weight loss. Then, subjects were randomised to receive either acarbose or placebo for 26 +/- 2 weeks. The primary variable was body weight. The primary efficacy analysis was performed in the per-protocol population (n = 75). RESULTS: After an initial mean weight loss of 10.0 +/- 3.4 kg, 54 subjects received acarbose at increasing dosage and 56 subjects received placebo treatment. After 14 weeks of follow-up, there was no change in body weight in the two groups. After 26 weeks, completed by 37 subjects in the acarbose group and by 38 subjects in the placebo group, a small weight regain of 0.6 kg was documented in the latter, whereas no weight increase was observed under acarbose treatment (p = 0.38, analysis of covariance with initial body weight as covariable). CONCLUSION: In obese individuals who undergo a hypocaloric diet and achieve a substantial loss of body weight, acarbose treatment provides only a very modest, not significant benefit to stabilise weight reduction. Thus, acarbose is not a useful adjunct to improve weight maintenance in obese subjects after weight loss.

Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies.

AIMS: To assess if treatment with the alpha-glucosidase inhibitor acarbose can reduce cardiovascular events in type 2 diabetic patients. METHODS AND RESULTS: This meta-analysis included seven randomized, double-blind, placebo-controlled acarbose studies with a minimum treatment duration of 52 weeks. Type 2 diabetic patients valid for safety were randomized to either acarbose (n=1248) or placebo (n=932). The primary outcome measure was the time to develop a cardiovascular event. Primary analysis was conducted using Cox regression analysis. The effect of acarbose on metabolic parameters was also investigated. Acarbose therapy showed favourable trends towards risk reduction for all selected cardiovascular event categories. The treatment significantly reduced the risk for "myocardial infarction" (hazards ratio=0.36 [95% Cl 0.16-0.80], P=0.0120) and "any cardiovascular event" (0.65 [95% Cl 0.48-0.88], P=0.0061). Glycaemic control, triglyceride levels, body weight and systolic blood pressure also improved significantly during acarbose treatment. CONCLUSION: Intervention with acarbose can prevent myocardial infarction and cardiovascular disease in type 2 diabetic patients while most of them are already on intensive concomitant cardiovascular medication.

Steroid receptor status of human testicular tumors.

Biopsies of 9 testicular tumors were examined for the presence of cytoplasmic receptor proteins for estrogens, progestins, androgens, and glucocorticoids. Using an arbitrary threshold value of 10 fmol/mg cytosol protein for a postive assay, only 1 of 9 tumors was estrogen-receptor positive. However, no receptor-specific 8S binding could be detected by low salt sucrose gradient centrifugation. 1 tumor was progesterone-receptor positive. No androgen receptors could be demonstrated. In contrast, 8 of 9 neoplasms contained significant quantities of glucocorticoid receptors exclusively sedimenting at 8S. Our findings suggest that androgens, estrogens, and progestins are unlikely to play a major role in the natural history of testicular tumors. The presence of glucocorticoid receptors might offer a chance for endocrine manipulation of the development and growth of these neoplasms by glucocorticoids.