Vanessa R. Panz

Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid-Lowering Therapy

Background— Homozygous familial hypercholesterolemia is an inherited disorder caused by mutations in both low-density lipoprotein receptor alleles, which results in extremely elevated plasma low-density lipoprotein cholesterol concentrations and very early morbidity and mortality due to cardiovascular disease. Methods and Results— To evaluate the impact of advances in lipid-lowering (predominantly statin) therapy on cardiovascular disease morbidity and mortality in a large cohort of patients with homozygous familial hypercholesterolemia, the records of 149 patients (81 females, 68 males) from 2 specialized lipid clinics in South Africa were evaluated retrospectively. Homozygous familial hypercholesterolemia was diagnosed by confirmation of mutations in genes affecting low-density lipoprotein cholesterol or by clinical criteria. A Cox proportional hazard model with time-varying exposure was used to estimate the risk of death and major adverse cardiovascular events among statin-treated patients compared with statin-naive patients. The hazard ratio for benefit from lipid therapy, calculated with the Cox proportional hazards model for the end point of death, was 0.34 (95% confidence interval 0.14–0.86; P=0.02), and for the end point of major adverse cardiovascular events, it was 0.49 (95% confidence interval 0.22–1.07; P=0.07). This occurred despite a mean reduction in low-density lipoprotein cholesterol of only 26.4% (from 15.9±3.9 to 11.7±3.4 mmol/L; P<0.0001) with lipid-lowering therapy. Conclusions— Lipid-lowering therapy is associated with delayed cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolemia.

Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High-Dose Statin Therapy

Background Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low‐density lipoprotein cholesterol (LDL‐C) clearance from the plasma by promoting LDL receptor degradation. Patients with familial hypercholesterolemia (FH) have reduced or absent LDL receptors and should therefore have elevated PCSK9 levels. Methods and Results Fasting lipograms and PCSK9 levels were measured 51 homozygous FH (HoFH), 20 heterozygous FH (HeFH), and 20 normocholesterolemic control subjects. Levels were repeated following high‐dose statin therapy. LDL‐C levels were significantly higher in untreated HoFH (13.4±0.7 mmol/L) and HeFH patients (7.0±0.2 mmol/L) compared with controls (2.6±0.1 mmol/L) (P<0.01). Statin therapy decreased LDL‐C levels from 13.4±0.7 to 11.1±0.7 mmol/L in HoFH and from 7.0±0.2 to 3.6±0.2 mmol/L in HeFH patients (P<0.01). PCSK9 levels were higher in untreated HoFH (279±27 ng/mL) and HeFH (202±14 ng/mL) than in controls (132±10 ng/mL) (both P<0.01). High‐dose statin therapy increased PCSK9 levels from 279±27 to 338±50 ng/mL in HoFH, and significantly so in the HeFH patients from 202±14 to 278±20 ng/mL (P<0.01). Linear regression analysis showed a correlation between PCSK9 and LDL‐C (r=0.6769; P<0.0001); however, this was eliminated following statin therapy (r=0.2972; P=0.0625). Conclusions PCSK9 levels are elevated in untreated FH patients, particularly in those with HoFH. High‐dose statin therapy further increases PCSK9 levels. PCSK9 inhibitors might be a beneficial therapy for FH patients, even in those with HoFH.

Pathogenesis of non-insulin-dependent diabetes mellitus in the black population of southern Africa

Non-insulin-dependent diabetes mellitus (NIDDM) is an important health problem in the black population of southern Africa. Whether the primary cause of NIDDM is insulin secretory dysfunction or peripheral insulin resistance is unknown. In westernised populations it is believed that insulin resistance and hyperinsulinaemia occur in the early stages of disease, followed later by progressive impairment of insulin secretion. However, we suggest that in the southern African black population a decrease in the mass of functioning beta cells is an important event, making these people vulnerable to the deleterious effects of insulin resistance induced by obesity and other factors. These abnormalities are, in turn, associated with insulin receptor down-regulation. An accelerated decline in beta-cell function then follows in susceptible individuals, ultimately producing striking insulinopenia. Insulinopenic NIDDM in black southern Africans may partly explain why this population has a comparatively low incidence of macrovascular complications and also predicts a short-lived therapeutic response to oral sulphonylureas in most patients.

Longitudinal Changes in Pituitary-Adrenal Hormones in South African Women With Burnout

The author’ goal was to document baseline pituitaryadrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare the changes with an equal number of untreated control subjects. At monthly intervals for 4 mo, 24-h urine samples were obtained for determination of free cortisol excretion. In addition, fasting blood samples were analyzed for levels of cortisol, dehydroepiandrosterone sulfate (DHEAS), ACTH, aldosterone, and catecholamines. Other biochemical measurements included growth hormone, prolactin, insulin, glucose, and lipid components. The Maslach Burnout Inventory, General Health Questionnaire-28, and Zung depression rating scale were completed on each consecutive visit. The most striking finding was the reduction of urine free-cortisol excretion in the patients compared with controls. Initial urinary free cortisol was significantly lower in the patients (mean ± SEM=47.2 ± 11.0 vs 79.0 ± 6.8 nmol/L, P=0.02) and remained significantly reduced at 4 mo (mean ± SEM=44.0 ± 6.1 vs 91.1 ± 8.8 nmol/L, p=0.0001). There were no significant changes in the other hormonal and biochemical data. We conclude that there is functional hypocortisolism in burnout, which is not immediately restored on stress management intervention despite clinical and psychological improvement.

Tandem CAG repeats of the androgen receptor gene and prostate cancer risk in black and white men

The most common malignancy in men worldwide is cancer of the prostate. Androgens play a direct role in normal and malignant growth of prostate cells via the androgen receptor (AR). This study analyzed the polymorphic CAG repeat sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of prostate cancer risk or aggressive disease. DNA was extracted from blood samples of 20 black and 20 white men with well-documented prostate cancer and 40 healthy, controls (20 blacks and 20 whites). PCR amplifications was followed by gel electrophoresis and DNA sequencing. This region normally contains between 9 and 29 repeats. Patients and controls both had minor variations in the number of repeats, which ranged from 13 to 27 with 21 being the most frequent allele. Black controls and patients both had a mean of 20±3, repeats; in whites the mean was significantly lower in patients than controls (21±2 versus 23±2; p=0.004). Combined black and white patients also had a lower number than the combined group of controls (20±3 versus 22±3; p=0.02). Similarly, black and white patients with aggressive disease has a lower number than patients whose disease was more slowly progressive (19±2 versus 22±3; p=0.02). We conclude that the small differences in the number of CAG repeats in both black and white patients do not appear to be a strong indicator of risk or aggressive disease but that this size polymorphism may be one of many genetic and environmental risk factors involved in prostate cancer.

Distribution of autoantibodies to glutamic acid decarboxylase across the spectrum of diabetes mellitus seen in South Africa.

SUMMARY

African women with depression: the effect of imipramine and fluoxetine on body mass index and leptin secretion.

Treatment of depression is often accompanied by weight changes. Previous studies indicate that leptin plays no role in this change despite showing a strong correlation with body mass index (BMI) in healthy people. The aim of this study was to evaluate the effect of imipramine and fluoxetine on BMI and its correlation with leptin. Eighteen depressed female patients randomly received either drug for 3 months. BMI was calculated and fasting blood samples were assayed for glucose, leptin, insulin, free fatty acids (FFA), and lipids. The difference between the changes in BMI (imipramine + 1.0 kg/m2, fluoxetine −0.5 kg/m2) was statistically significant (P < 0.05, t = 2.106). There was a significant positive correlation between overall BMI and leptin (r = 0.784, P < 0.001) but not between BMI and insulin or FFA. However, fasting insulin levels and calculated insulin resistance levels dropped substantially in the imipramine group. We conclude that the use of tricyclic antidepressants (TCAs) in depressed patients at risk for developing type 2 diabetes remains unresolved at this stage.

Atherosclerosis seems not to be associated with hyperinsulinaemia in patients with familial hypercholesterolaemia.

Objective. To study the relationship between hyperinsulinaemia, insulin resistance, leptin and atherosclerosis in subjects with familial hypercholesterolaemia (FH).

Diabetogenic effect of tacrolimus in South African patients undergoing kidney transplantation1.

BACKGROUND Diabetes mellitus (DM) is a complication of tacrolimus therapy. This prospective study evaluated the prevalence of DM in South African black and white patients receiving tacrolimus after kidney transplantation and factors that could identify patients before transplantation who may be at risk of developing DM. METHODS Fasting blood samples from 17 patients (11 black, 6 white) were analyzed immediately pretransplantation and at 1 and 3 months posttransplantation for glucose, HbAIC, insulin, C-peptide, free fatty acids, lipids, urea, and creatinine. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) formulas. RESULTS Eight patients (47%) became diabetic (six black, two white), and nine patients (five black, four white) remained nondiabetic. Mean glucose concentrations in the diabetic group were significantly higher at 1 month (P=0.03) and 3 months (P=0.01). Mean insulin level was also significantly raised at 3 months (P=0.01) as was HbAIC (P=0.001). C-peptide concentrations did not change significantly in either group. Significant correlations emerged between fasting glucose concentrations at 3 months posttransplantation and initial HOMA (r=0.486; P=0.048) and initial QUICKI (r=-0.582; P=0.014). CONCLUSIONS Occurrence of DM was high and somewhat greater in black patients. IR was the main mechanism involved, together with inadequate beta-cell compensation. IR pretransplantation predicts the subsequent development of DM.

Changes in Glucose Disposal and Cellular Insulin Binding in Obese Black Southern African Patients with Type 2 Diabetes Mellitus Before and After Sulphonylurea Therapy

Peripheral insulin action and cellular insulin binding were studied in 10 newly detected, obese, black, Southern African women with Type 2 diabetes mellitus before and after midterm oral sulphonylurea therapy and in five obese, non‐diabetic controls. Glucose disposal (assessed by the euglycaemic insulin clamp technique) was significantly reduced in diabetic patients compared to control subjects (4.4 ± 0.5 vs 6.4 ± 0.5 mg kg‐1 min‐1, p < 0.05), and increased after 1 and 3 months of sulphonylurea therapy to 6.8 ± 0.6 mg kg‐1 min‐1 (p = 0.01) and 6.3 ± 0.7 mg kg‐1 min‐1 (p = 0.04), respectively. The major change in the binding kinetics of insulin to peripheral monocytes was an increase in the mean receptor concentration in the diabetic patients which was significant after 3 months of therapy (0.2 ± 0.08 to 0.6 ± 0.01 nM, p = 0.05). The basal plasma C‐peptide concentration was significantly lower in the diabetic patients than in the controls and remained so following sulphonylurea therapy, despite significant reductions in fasting glucose and HbA‐1 concentrations. We conclude that newly diagnosed, obese, black Southern Africans with Type 2 diabetes showed diminished peripheral glucose disposal which increased following sulphonylurea therapy. This was accompanied by an increase in insulin receptor concentration but not with changes in basal insulin secretion.