Simvastatin in non-insulin-dependent diabetic patients with hypercholesterolaemia.

The objective of this study was to evaluate the lipid-lowering effect of simvastatin in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypercholesterolaemia while possible clinical and biochemical adverse effects were monitored for. Forty-three NIDDM patients with hypercholesterolaemia (total cholesterol > 6.5 mmol/l) used simvastatin after a detailed clinical laboratory evaluation as well as a 4-week wash-out period and a 4-week placebo baseline period. Simvastatin treatment was initiated with a 10 mg dose for 6 weeks; this was increased to 20 mg and 40 mg at 12 and 18 weeks of follow-up respectively if the total cholesterol level had not decreased to below 5.17 mmol/l. Patients were placed on a lipid-lowering diet and continued to take any regular non-lipid-lowering medication throughout the trial; side-effects were monitored at 6-week intervals until patients had taken simvastatin for 24 weeks. The mean total cholesterol level was reduced by 22.2% at the first follow-up visit, and by 24.2%, 23.3%, and 28.5% at the second, third and fourth follow-up visits respectively compared with base-line levels. A dose of 10 mg simvastatin brought about a reduction in total cholesterol similar to those found with higher doses. The mean triglyceride level was reduced by 20.9% with 20 mg simvastatin. The high-density lipoprotein cholesterol level was not altered significantly and neither was the control of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Using changes in attributable risk to predict long-term efficacy of simvastatin treatment.

It is a common perception that coronary heart disease (CHD) deaths will decline by 2% for every 1% decrease in serum total cholesterol (TC). We investigated the changes in serum TC concentrations obtained with simvastatin, an inhibitor of hydroxymethylglutaryl-CoA reductase, in 70 hypercholesterolemic subjects. Although simvastatin reduced serum TC concentrations by 30% after 6 months, calculations from age- and risk-related TC quintiles show that the absolute difference in attributable CHD deaths would be just > 1%. These results are reminiscent of the experience from several large prospective primary drug trials that demonstrated impressive relative benefit ratios but much smaller absolute differences (< 2%) in CHD endpoints between the treated and untreated groups. This epidemiologically based approach of assessing efficacy and potential long-term benefit of a lipid-lowering drug may be more appropriate and potentially less misleading than just the percentage change of TC (or other lipoproteins) so frequently reported in short-term drug trials.

Experience with a provocative test of calcitonin release as a prospective screening for preclinical medullary thyroid carcinoma in MEN type 2A family members.

We report our experience with a provocative test of calcitonin (CT) release using a combined stimulus of intravenous 10% CaCl2 solution and pentagastrin on 34 normal adults (15 females: age 41 +/- 12.3 years and range 22-65 years; and 19 males: age 43 +/- 9.1 years and range 23-60 years) and in 44 family members of three proven multiple endocrine neoplasia type 2A syndrome (MEN 2A) patients. A commercial radioimmunoassay was used to determine the serum CT levels. Peak CT levels were reached within 2 to 5 minutes after administration of the stimulus in all subjects tested. In the group of normal subjects there was no significant difference in the mean basal CT levels between males (54.8 +/- 21.7 pg/ml) and females (56.5 +/- 34.8 pg/ml), whilst the mean peak response values for males was 146.3 +/- 120.6 pg/ml, which was significantly different from the mean value of females, namely 71.6 +/- 39.0 pg/ml. We did not find significant correlations between the basal CT level, peak CT response, and age. Of the 44 family members tested, 9 showed an exaggerated CT response to the combined stimulus and subsequently had a total thyroidectomy. Histological examination confirmed C-cell hyperplasia (CCH) in one and medullary thyroid carcinoma (MTC) in the other 8. Three of the 9 had high basal plasma CT levels. The 9 patients were retested postoperatively and all showed a flat response to the combined stimulus. Those family members with histological proof of MTC or CCH were screened for genetic linkage to the disease gene for MEN 2A using probe MCK2, and showed correlation in each instance.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple endocrine neoplasia type 2A (MEN 2A) syndrome in a South African family. Biochemistry and molecular genetics.

Multiple endocrine neoplasia type 2A (MEN 2A), an uncommon heritable disease, was investigated in an Afrikaner kindred. Serum calcitonin levels after combined pentagastrin and calcium chloride stimulation were measured to determine thyroid involvement, as were urinary metadrenalin levels to determine adrenal gland involvement. MEN 2A genotype status was determined using the DNA probe MCK2 (D10S15). The index patient, who showed both thyroid and adrenal gland involvement, died of phaeochromocytoma complications. Thirty-four of his 114 family members, in 4 generations, were investigated. Nine had positive histological and calcitonin tests and were predicted to be MEN 2A genotypes by DNA analysis. One asymptomatic individual had a positive calcitonin test after being predicted to be a MEN 2A genotype with the probe MCK2. In 3 DNA-positive cases calcitonin stimulation tests were negative. Preclinical detection of the heritable form of MEN 2A will be facilitated by utilising the DNA probe MCK2 to determine carrier status in this large South African family. It is also the first South African family in which biochemical and molecular genetic techniques were used to facilitate diagnosis.

Evaluation of a family at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome.

A multidisciplinary group was formed to advise on strategy and to co-ordinate the management of a family at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome. A proposed strategy is outlined in which DNA analysis and provocative calcitonin testing is central.

Early thyroidectomy for medullary thyroid carcinoma in children and young adults with the multiple endocrine neoplasia type 2A (MEN 2A) syndrome.

A South African family, at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome, was identified. The Bloemfontein MEN Study Group was founded, inter alia, to study the effects of early detection of medullary carcinoma of the thyroid (MTC) and treatment by total thyroidectomy in children and young adults with MEN 2A. Genotypes were identified by DNA probe and MTC diagnosed by basal and stimulated calcitonin levels. Between 1986 and 1989, 10 members of the family underwent total thyroidectomy and central lymph node dissection for MTC. There were 6 female and 4 male patients (mean age 22,0 years; range 10 - 35 years). Histological examination of the resected thyroid revealed MTC in all patients; 8 had bilateral disease and 2 unilateral. Lymph nodes were negative for MTC in all patients. None of the patients suffered injury to the recurrent nerve, while 1 experienced transient hypoparathyroidism postoperatively. Replacement therapy is maintaining thyroid hormone levels in all patients. Screening should probably begin at the age of 1 year, and total thyroidectomy should be performed when an elevated calcitonin level is observed.