Allan Gaw

Pravastatin and the Development of Diabetes Mellitus Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study

BackgroundWe examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. Methods and ResultsOur definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of ≥7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of ≥7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. ConclusionsWe concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P =0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.

Metabolic heterogeneity in low density lipoprotein (LDL) may be detected by examination of the daily urinary excretion rate of radioactivity after injection of trace-labeled lipoprotein. Two distinct pools are observed within LDL. The first (pool A) is cleared rapidly from the plasma, whereas the second (pool B) is catabolized more slowly. In the present study we examined LDL metabolism in seven hypercholesterolemic subjects (six women and one man) before and during fenofibrate therapy. Comparison with normocholesterolemic individuals showed that the pretreatment high LDL levels in the hypercholesterolemic subjects resulted from an accumulation of apoprotein-LDL (apo-LDL) mass in pool B (2,077 +/- 174 mg versus 787 +/- 70 mg in normal subjects, p < 0.002). Pool A apo-LDL was present at normal levels (approximately 1,000 mg), although its fractional catabolic rate was reduced (0.39 +/- 0.06 versus 0.61 +/- 0.03 pool/day in normal subjects, p < 0.01). Fenofibrate therapy (100 mg t.i.d. for 8 weeks) produced substantial reductions in plasma cholesterol (29%; p < 0.001), triglycerides (36%; p < 0.001), and LDL cholesterol (30%; p < 0.001). The latter was associated with a 30% decrease in circulating apo-LDL mass (2,312 +/- 200 mg versus 3,279 +/- 264 mg before treatment, p < 0.005). This resulted from a combination of two effects. First, although overall LDL apoprotein B production did not change, there was a shift from pool B to pool A. Pool A input was 400 +/- 74 mg/day pretreatment versus 706 +/- 62 mg/day on fenofibrate; pool B input was 422 +/- 35 mg/day pretreatment versus 258 +/- 41 mg/day on the drug. At the same time, catabolism of pool A rose from 0.39 +/- 0.06 to 0.66 +/- 0.08 pool/day (p < 0.05). We hypothesize that the shift from pool B to pool A resulted from a drug-induced decrease in the particle size of very low density lipoprotein made by the liver, which in turn favored the formation of more rapidly catabolized LDL. Overall, the rate of apo-LDL degradation by the receptor route (as detected using a combination of native and 1,2-cyclohexanedione-modified LDL tracers) rose 43% on the drug, whereas the amount cleared by the receptor-independent pathway did not change. Fenofibrate, therefore, appears not only to promote LDL catabolism via the receptor-mediated pathway but also, by lowering plasma triglyceride levels, inhibits the formation of slowly metabolized, potentially atherogenic LDL particles.

Effects of simvastatin on apoB metabolism and LDL subfraction distribution.

Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p < 0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), intermediate density lipoprotein (IDL) (Sf 12-20), and LDL (Sf 0-12), and metabolic changes were sought in dual-tracer VLDL1 and VLDL2 turnover studies. VLDL1 apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p < 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p < 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2 and IDL was increased (p < 0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2 but not VLDL1.

Association between apolipoprotein E4 and cognitive decline in elderly adults

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women.

Effects of ciprofibrate on LDL metabolism in man

This study examined the effects of ciprofibrate therapy (100 mg/day) on plasma lipids, lipoproteins and low density lipoprotein (LDL) kinetic heterogeneity in moderately hypercholesterolaemic subjects. The drug lowered plasma triglyceride and cholesterol by 41% and 17%, respectively. Very low density lipoprotein (VLDL) cholesterol fell by 38%, LDL cholesterol fell by 22%, while the content of the lipid in high density lipoprotein (HDL) increased by 11%. LDL structural and metabolic heterogeneity were assessed before and during therapy in eight subjects. Density gradient centrifugation was used to fractionate LDL into three species. LDL-I, the least dense, was not affected by therapy whereas LDL-II and LDL-III were decreased by 28% (P < 0.01) and 31% (N.S.). Baseline turnover studies revealed that LDL catabolism was subnormal and this was the cause of the raised cholesterol in these subjects. Ciprofibrate therapy increased the apoLDL fractional catabolic rate (FCR) by 19%, principally by inducing a 38% enhancement (P < 0.03) in apoLDL removal by the receptor pathway. ApoLDL kinetics exhibited metabolic heterogeneity both before and during drug therapy. Analysis of plasma decay curves for the LDL tracer and urinary excretion data indicated that the lipoprotein comprised two metabolically distinct species, one with an FCR of about 0.50 pools/day (Pool A), the other with an FCR of about 0.18 pools/day (Pool B). Drug therapy decreased synthesis of and hence reduced the plasma mass of apoLDL in the slow metabolised pool B. This perturbation in synthesis was linked to the change in plasma triglyceride concentration. The resultant reduced proportion of pool B vs. pool A material accounted for the observed promotion of LDL receptor-mediated clearance. Ciprofibrate, therefore, produced beneficial changes in the plasma levels of VLDL, LDL and HDL and in the metabolism of LDL.

Biogerontology: Mechanisms and Interventions

Abstract:  Proinflammatory cytokines, like interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α), are implicated in the development of atherosclerosis. The role of anti‐inflammatory cytokines, like IL‐10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL‐10 gene (4259AG, −1082GA, −592CA, and −2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the −592A variant allele) and risk of coronary events (P= 0.019). Moreover, analysis of separate SNPs found a significant association between −2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04–2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti‐inflammatory cytokines may play an important role.

Effects of Colestipol Alone and in Combination With Simvastatin on Apolipoprotein B Metabolism

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for ‘ideal’ lipid-lowering treatment in several respects; ‘super’ statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician non-acceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets.There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated — possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70–82 years) who either have preexisting vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke).Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.

Unblinding of trial participants to their treatment allocation: lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

Background The gold standard clinical trial design is the double-blind, randomized, controlled trial. No standard practice exists for the “unblinding” of trial participants and no legal obligation is placed on investigators to inform participants of their treatment allocation or study results at the end of a trial. Here we document our experiences of unblinding the 2520 Scottish participants in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Methods The objectives of the PROSPER unblinding process were to provide all study participants with their study medication status and on-trial cholesterol levels and to respect the rights of participants not to be unblinded. It was considered imperative by the study executive that the blind was maintained until the presentation and publication of the results. Staff therefore remained “blinded” throughout the unblinding process. Inappropriate contact with the PROSPER participants was avoided by confirming their current vital status and health status. Results To coincide with the presentation of the PROSPER results, all participants, for whom it was deemed appropriate, were sent a summary of the results and were offered the opportunity to be advised of their treatment allocation and on-trial lipid profiles. The majority of participants opted for telephone unblinding. All primary care physicians who had patients randomised to the study were also sent a summary of the study results and sealed documents detailing the treatment allocation and lipid profiles for each patient. Relocated patients were traced and the information forwarded to their new primary care physicians. Conclusion The dissemination of study results and treatment allocation to study participants is an integral part of the research process and should be included in the design of any clinical trial.

HDL-C and Triglyceride Levels: Relationship to Coronary Heart Disease and Treatment with Statins

The association between low-density lipoprotein cholesterol (LDL-C) levels and risk of coronary heart disease (CHD) is well established and LDL-C-lowering is currently the primary target for the treatment of dyslipidemia. However, low levels of high-density lipoprotein cholesterol (HDL-C), and high levels of triglycerides (TG) are also risk factors for CHD and modifying levels of these lipid subfractions, in addition to LDL-C lowering, may have clinical benefits in many patients.Statins are the first-line drug therapy for the treatment of dyslipidemia because of their efficacy in lowering LDL-C and good tolerability. Statins also have beneficial effects on TG and HDL-C levels although they differ in the degree to which they modify the levels of these lipoproteins. Improvements across the atherogenic components of the lipid profile may be optimized by the co-administration of a statin with a fibrate, niacin or omega-3 fatty acids; however, particular combination therapies have been associated with side effects and may be poorly tolerated. Newer combinations with better tolerability, or new statins with improved efficacy on non-LDL-C lipid subfractions, would be welcome additions to the currently available therapies for the treatment of dyslipidemia.