Dieter Petzinna

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.

Effect of acarbose treatment on the risk of silent myocardial infarctions in patients with impaired glucose tolerance: results of the randomised STOP-NIDDM trial electrocardiography substudy

Background The moderate increase in postprandial plasma glucose in subjects with impaired glucose tolerance has been shown to be a predictor of cardiovascular disease. In the randomised STOP-NIDDM trial, we could demonstrate that lowering postprandial plasma glucose with acarbose in subjects with impaired oral glucose tolerance could reduce the risk of diabetes. Methods The current report focuses on the effect of acarbose on silent ischaemic events evaluated in the electrocardiographic substudy, using the Minnesota code classification. Results A total of 1181 patients were included in the ECG substudy. From these 72 patients had significant changes between the baseline and end of treatment ECG, 33 in the acarbose and 39 in the placebo group. Higher rates of myocardial infarctions occurred in the placebo group (P=0.07 with Fishers Exact test and P = 0.023 with Chi-square test), while there were no differences between the two groups with ECG changes classified under the other Minnesota codes. Conclusions In this prospective intervention study we could show that acarbose, by decreasing postprandial hyperglycaemia, can reduce the incidence of silent myocardial infarctions in subjects with impaired glucose tolerance. This approach should therefore be evaluated in other higher risk populations.

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 cerivastatins 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.

Long-Term Efficacy and Tolerability of Acarbose Treatment in Patients with Type 2 Diabetes Mellitus

AbstractObjective:The aim of the study was to investigate the efficacy and tolerability of long-term acarbose therapy in type 2 diabetic patients. Study design: In this double-blind, single-centre group comparison, patients were randomised to receive either acarbose or matching placebo, in addition to their regular antidiabetic therapy, over a period of 78 weeks. Eligibility for inclusion in the efficacy evaluation included a study duration of ≥510 days. Methods: The primary efficacy parameter was the change in glycosylated haemoglobin (HbA1) from baseline to end of study. Secondary variables included changes in blood glucose and lipid parameters, as well as signs of retinopathy and nephropathy. Patients: A total of 139 patients were assessed for safety and 88 patients (44 in each treatment group) were included in the efficacy analysis. Patients were generally overweight and the majority had previously been treated with sulphonylureas. Results: Acarbose significantly improved fasting and 1-hour postprandial blood glucose levels compared with placebo (p = 0.039 and 0.009), and improvements in HbA1 with acarbose versus placebo fell just short of significance (p = 0.057). There were no differences between treatments in changes in microvascular complications, but blood pressure improved with acarbose treatment. Two patients in the acarbose group experienced elevated liver enzyme levels. Generally, acarbose had a good safety profile and was well tolerated. Conclusion: Long-term treatment with acarbose was safe and efficacious in patients with type 2 diabetes mellitus that was insufficiently controlled by other oral antidiabetics.

Long-Term Improvement of Metabolic Control by Acarbose in Type 2 Diabetes Patients Poorly Controlled with Maximum Sulfonylurea Therapy

Background and objectiveMultiple oral therapies are required long term for the majority of patients with type 2 diabetes mellitus to achieve acceptable glycaemic levels; alternatively, insulin therapy has to be initiated. This study investigated the addition of acarbose to maximum doses of sulfonylurea in very poorly controlled type 2 diabetes patients and assessed its effect in delaying further glycaemic deterioration.Study designIn this 78-week, double-blind, placebo-controlled European study, patients were randomised to receive acarbose, titrated to a maximum dose of 100mg three times daily, or matching placebo. Concomitant sulfonylurea treatment (glibenclamide/gliclazide) was to remain unchanged throughout the study. A sample size of 171 patients per treatment arm was calculated. The primary efficacy analysis was intention to treat.MethodsThe change in glycosylated haemoglobin (HbA1c) levels from baseline to the end of the study was regarded as the primary efficacy variable. Patients whose HbA1c levels increased above 10.5% on two consecutive visits terminated the study prematurely because of insulin administration. Secondary efficacy variables included the changes in blood glucose and C-peptide, both at fasting and at the 1h-postprandial level.PatientsA total of 330 patients (acarbose 164, placebo 166) were valid for the efficacy analysis. Patients were generally overweight (body mass index 29.0 kg/m2) and showed very poor metabolic control (HbA1c >9%, fasting blood glucose >200 mg/dL, and lh-postprandial blood glucose >300 mg/dL).ResultsAcarbose significantly improved HbA1c levels compared with placebo (least square mean [LS-mean] difference −0.54%, 95% CI −0.86 to −0.22; p = 0.001). A number of patients had to discontinue the study prematurely because of insulin administration (24.5% in the placebo and 14.2% in the acarbose group). There was a significant LS-mean difference of −14.8 mg/dL (p = 0.0195) in fasting blood glucose levels and highly significant differences in 1h-postprandial blood glucose (LS-mean difference −33.4 mg/dL, p < 0.0001) and in the rise in blood glucose from fasting to lh-postprandial (LS-mean difference −19.6 mg/dL, p = 0.0001), all in favour of acarbose. Acarbose was shown to have a good safety profile and was generally well tolerated.ConclusionAcarbose was shown to have the potential to delay further deterioration of glucose control in type 2 diabetes patients who are very poorly controlled with maximum sulfonylurea doses.