Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk.

AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality.

Rate and risk predictors for development of self-reported type-2 diabetes mellitus over a 5-year period: the SHIELD study.

AIMS: This investigation determined the proportion of adults newly diagnosed as having type-2 diabetes mellitus (T2DM), and ascertained risk predictors for development of self-reported T2DM. METHODS: The US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) survey was a 5-year longitudinal study of adults with and without diabetes mellitus. Adults completed a baseline health questionnaire in 2004 and ≥1 annual follow-up survey through 2009. Respondents with no self-reported diagnosis of diabetes at baseline were followed to measure rate of and assess risk factors for development of T2DM over 5 years. RESULTS: Among 8582 respondents without diabetes at baseline, 622 (7.2%) reported a diagnosis of T2DM over the subsequent 5 years. Increasing age, family history of T2DM, body mass index ≥30 kg/m(2), abdominal obesity, excessive thirst, asthma, gestational diabetes and 'high blood sugar without diabetes' significantly increased the risk of developing T2DM (p < 0.05 for each). Good to excellent health status and self-reported circulatory problems decreased the risk (p < 0.05 for each). CONCLUSIONS: Among this representative US adult population, the rate of developing T2DM was 7.2% over 5 years. Predictors of T2DM diagnosis identified in this analysis were readily obtainable via self-report.

Extended-release niacin/laropiprant lipid-altering consistency across patient subgroups.

BACKGROUND: In patients with primary hypercholesterolemia or mixed dyslipidemia, extended-release niacin/laropiprant (ERN/LRPT) improves key lipid parameters associated with increased atherosclerotic coronary heart disease (CHD) risk. AIM: This analysis examined data from four Phase III, randomised, double-blind trials to determine the consistency of ERN/LRPT's lipid-altering efficacy among subgroups of patients. METHODS: Data from four Phase III, randomised, double-blind trials of ERN/LRPT were analysed to determine the consistency of ERN/LRPT's lipid-altering efficacy among subgroups of gender, race (white, non-white), region (US, ex-US), baseline age (<65, ≥65 years), use of statin therapy, CHD risk status (low, multiple, high) and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. End-points included the per cent change from baseline in LDL-C, HDL-C and TG levels. Consistency of the treatment effects on LDL-C, HDL-C and TG across subgroups was evaluated by examining treatment difference estimates with 95% confidence intervals. RESULTS: Treatment with ERN/LRPT significantly improved LDL-C, HDL-C and TG levels compared with placebo/active comparator in each study cohort. These effects were generally consistent across all examined subgroups. CONCLUSION: Extended-release niacin/laropiprant represents an effective therapeutic option for the treatment of dyslipidemia across a range of patient types.

Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus, metabolic syndrome or neither.

AIM: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid-altering drugs in these patient populations. METHODS: A double-blind, parallel group trial of adult patients with hypercholesterolaemia at high-CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL-C, total cholesterol, HDL-C , non-HDL-C , Apo A-I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). RESULTS: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL-C, triglycerides, Apo B, non-HDL-C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL-C , Apo A-I and high sensitivity C-reactive protein (hs-CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. CONCLUSIONS: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high-CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).

The Bile Acid Sequestrant Acceptability scale validation study.

AIMS: The primary objective of this study was to validate a novel Bile Acid Sequestrant Acceptability (BASA) Scale intended to assess the acceptability and/or tolerability of bile acid sequestrant (BAS) beverage preparations. A secondary objective was to assess the utility of weightings based on subjective clinical importance for the BASA scale individual components and its composite score. METHODS: This was a randomised, single-blind, single site, controlled study of oral administration of 4 g of orange-flavoured generic cholestyramine powder, 12 g of orange-flavoured generic cholestyramine powder and an orange-flavoured sweetened control drink powder, each mixed with water. RESULTS: The study sample included 42 subjects; 26 men and 16 women. Participants were non-Hispanic white (76.2%) or black/African American (23.8%), with a mean age of 51.4 years and body mass index of 30.1 kg/m(2). The components of the BASA scale were taste, texture, appearance and mixability; the possible total BASA scores ranged being 4-20; the higher the BASA scale score, the better the acceptability/tolerability. Composite BASA scale scores were significantly lower for the 4 g (mean BASA score = 10.3) and 12 g (mean BASA score = 9.4) cholestyramine compared with the control drink powder (mean BASA score = 16.7) (p < 0.001). BASA scale scores did not significantly differ between the 4 and 12 g of cholestyramine. (p = 0.215). Weighting of the components did not materially alter the results. Findings for the individual components of the BASA scale were similar to the composite values. CONCLUSION: The BASA scale effectively distinguished between an orange-flavoured BAS powder and a commercial orange-flavour control powder.

Attainment of Canadian and European guidelines' lipid targets with atorvastatin plus ezetimibe vs. doubling the dose of atorvastatin.

BACKGROUND: Canadian and European treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as a primary treatment target for hypercholesterolaemia. OBJECTIVES: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high-sensitivity C-reactive protein (hs-CRP) levels. METHODS: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL-C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL-C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks. RESULTS: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL-C, most lipids and lipoproteins and/or hs-CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL-C and: Apolipoprotein (Apo) B, total cholesterol (total-C), total-C/high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, Apo B/Apo A-I or hs-CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose. CONCLUSIONS: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively.

Does nicotinic acid (niacin) lower blood pressure?

Nicotinic acid (niacin) is a well-established treatment for dyslipidaemia - an important cardiovascular disease (CVD) risk factor. However, niacin may also reduce blood pressure (BP), which is another important CVD risk factor. This review examines the limited publicly available data on niacin's BP effects. Acute administration of immediate-release niacin may lower BP because of niacin's acute vasodilatory effects. Although not always supported by clinical trial data, the package insert of a prescription, extended-release niacin describes niacin-induced acute hypotension. From a chronic standpoint, larger studies, such as the Coronary Drug Project, suggest that niacin may lower BP when administered over a longer period of time. Post hoc analyses of some of the more recent niacin clinical trials also support a more chronic, dose-dependent, BP-lowering effect of niacin. Because laropiprant [a prostaglandin D(2) (PGD(2)) type 1 (DP1) receptor antagonist] does not attenuate niacin's BP-lowering effects, it is unlikely that any chronic lowering of BP by niacin is due to dilation of dermal vessels through activation of the DP1 receptor by PGD(2.) Further research is warranted to evaluate the extent and mechanisms of niacin's effects on BP.

Adiposopathy and bariatric surgery: is 'sick fat' a surgical disease?

OBJECTIVE: To review how bariatric surgery in obese patients may effectively treat adiposopathy (pathogenic adipose tissue or 'sick fat'), and to provide clinicians a rationale as to why bariatric surgery is a potential treatment option for overweight patients with type 2 diabetes, hypertension, and dyslipidaemia. METHODS: A group of clinicians, researchers, and surgeons, all with a background in treating obesity and the adverse metabolic consequences of excessive body fat, reviewed the medical literature regarding the improvement in metabolic disease with bariatric surgery. RESULTS: Bariatric surgery improves metabolic disease through multiple, likely interrelated mechanisms including: (i) initial acute fasting and diminished caloric intake inherent with many gastrointestinal surgical procedures; (ii) favourable alterations in gastrointestinal endocrine and immune responses, especially with bariatric surgeries that reroute nutrient gastrointestinal delivery such as gastric bypass procedures; and (iii) a decrease in adipose tissue mass. Regarding adipose tissue mass, during positive caloric balance, impaired adipogenesis (resulting in limitations in adipocyte number or size) and visceral adiposity are anatomic manifestations of pathogenic adipose tissue (adiposopathy). This may cause adverse adipose tissue endocrine and immune responses that lead to metabolic disease. A decrease in adipocyte size and decrease in visceral adiposity, as often occurs with bariatric surgery, may effectively improve adiposopathy, and thus effectively treat metabolic disease. It is the relationship between bariatric surgery and its effects upon pathogenic adipose tissue that is the focus of this discussion. CONCLUSIONS: In selective obese patients with metabolic disease who are refractory to medical management, adiposopathy is a surgical disease.

Measuring flushing symptoms with extended-release niacin using the flushing symptom questionnaire: results from a randomised placebo-controlled clinical trial.

INTRODUCTION: Niacin is underutilised because of flushing. Lack of a quantitative tool to assess niacin-induced flushing has precluded the objective evaluation of flushing associated with extended-release (ER) niacin formulations. We developed the Flushing Symptom Questionnaire((c)) (FSQ), a quantitative tool to assess patient-reported flushing, and assessed its ability to characterise ER niacin-induced flushing. METHODS: This study focused on the responses to one question in the FSQ, the Global Flushing Severity Score (GFSS), reported on a 0-10 scale (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9 and extreme = 10) to assess flushing during ER niacin initiation (week 1) and maintenance (weeks 2-8). RESULTS: Flushing severity with ER niacin was greatest during week 1 and remained greater than placebo for the study duration. During weeks 2-8, 40% of patients on ER niacin vs. 8% of those on placebo had > 1 day/week with 'moderate or greater' GFSS. CONCLUSIONS: In conclusion, the GFSS component of the FSQ was a sensitive and responsive quantitative measure of ER niacin-induced flushing that will aid in the objective comparison of novel strategies intended to improve tolerability and adherence to niacin, an agent proven to reduce cardiovascular risk.

Is adiposopathy (sick fat) an endocrine disease?

OBJECTIVE: To review current consensus and controversy regarding whether obesity is a 'disease', examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of 'adiposopathy' and 'sick fat' as scientifically and clinically useful terms in defining when excessive body fat may represent a 'disease'. METHODS: A group of clinicians and researchers, all with a background in endocrinology, assembled to evaluate the medical literature, as it pertains to the pathologic and pathogenic potential of adipose tissue, with an emphasis on metabolic diseases that are often promoted by excessive body weight. RESULTS: The data support pathogenic adipose tissue as a disease. Challenges exist to convince many clinicians, patients, healthcare entities and the public that excessive body fat is often no less a 'disease' than the pathophysiological consequences related to anatomical abnormalities of other body tissues. 'Adiposopathy' has the potential to scientifically define adipose tissue anatomic and physiologic abnormalities, and their adverse consequences to patient health. Adiposopathy acknowledges that when positive caloric balance leads to adipocyte hypertrophy and visceral adiposity, then this may lead to pathogenic adipose tissue metabolic and immune responses that promote metabolic disease. From a patient perspective, explaining how excessive caloric intake might cause fat to become 'sick' also helps provide a rationale for patients to avoid weight gain. Adiposopathy also better justifies recommendations of weight loss as an effective therapeutic modality to improve metabolic disease in overweight and obese patients. CONCLUSION: Adiposopathy (sick fat) is an endocrine disease.

Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet. METHODS AND RESULTS: Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN. CONCLUSION: Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.

Lorcaserin and metabolic disease: weight-loss dependent and independent effects.

OBJECTIVE: Weight management pharmacotherapies can improve metabolic diseases through weight-dependent and weight-independent effects. Lorcaserin is a selective 5-hydroxytryptamine 2C receptor agonist. The objective of this analysis is to quantify the relative contribution of weight loss to the treatment effects of lorcaserin 10 mg twice a day on key metabolic parameters. METHODS: This retrospective analysis evaluated 6,897 patients with overweight or obesity (with or without diabetes mellitus) across three randomized, placebo-controlled, double-blind, 52-week clinical trials that evaluated lorcaserin 10 mg twice daily (BID; NCT00395135, NCT00603902, and NCT00603291); 509 patients from only one of the studies had type 2 diabetes mellitus. A mediation analysis was applied to help rank the relative contribution of weight loss to metabolic study outcomes. RESULTS: According to this mediation analysis, lorcaserin 10 mg BID improved a spectrum of adiposopathic metabolic abnormalities with varying contributions attributable to weight loss. Improvements in waist circumference and blood pressure were almost exclusively attributable to weight loss. Less than 50% of the improvement in glucose parameters (fasting blood glucose and haemoglobin A1c) were attributable to weight loss. CONCLUSIONS: Across Phase III clinical trials, lorcaserin 10 mg BID improved multiple cardiometabolic parameters through both weight-loss dependent and independent mechanisms.

Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia.

Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.

Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group.

This randomized, multicenter, double-blind parallel-group study was performed to evaluate the lipid-altering efficacy and safety of simvastatin 80 mg/day, a dose twice the current maximum recommended dose. At 20 centers in the United States, 521 male and female hypercholesterolemic patients were randomly assigned in a ratio of 2:3 to receive simvastatin 40 or 80 mg once daily, respectively, for 24 weeks in conjunction with a lipid-lowering diet. Patients met National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol averaged at weeks 18 and 24 were 38% (-40 to -36) and 46% (-47 to -45) for the 40- and 80-mg groups, respectively (p <0.001 between groups). One third of patients on the 40- and 80-mg doses achieved an LDL cholesterol reduction of 46% and > or = 53%, respectively. Decreases in apolipoprotein B, total cholesterol, and triglycerides were also significantly greater among patients receiving 80 mg/day. Simvastatin was well tolerated in both groups. Two patients (0.6%) in the 80-mg group developed myopathy. Consecutive, clinically significant hepatic transaminase elevations occurred in 3 (1.0%) and 6 (1.9%) patients in the 40- and 80-mg groups, respectively (p= 0.486). In conclusion, simvastatin 80 mg/day provided substantial reductions in LDL cholesterol, allowing most patients to reach their NCEP target levels; it also had an excellent safety and tolerability profile.

Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia.

In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol for normal steroidogenesis, we evaluated whether extending the therapeutic dose of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to 80 mg/d would affect adrenal and gonadal steroid synthesis in men with hypercholesterolemia. To evaluate this question, we enrolled men into a multicenter randomized, placebo-controlled study lasting 12 weeks. Men with serum low-density lipoprotein cholesterol (LDL-C) more than 145 mg/dL after 6 weeks of a lipid-lowering diet were randomized to 80 mg simvastatin or placebo. Half of the subjects were asked to undergo a 6-hour infusion of corticotropin (ACTH) to evaluate cortisol synthesis, and the entire cohort received a human chorionic gonadotropin (hCG) stimulation test to assess gonadal hormone secretion using pooled serum samples taken 15 minutes apart. A total of 81 men (age, 45 +/- 11 years; 93% Caucasian) with baseline serum LDL-C of 197 mg/dL (placebo, n = 39) and 184 mg/dL (simvastatin 80 mg, n = 42) completed the study. After 12 weeks, serum LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) in the simvastatin group changed by -43%, -25%, and 8%, respectively (all P < .001). The basal cortisol level and the peak serum cortisol and area under the curve response to the 6-hour ACTH infusion were comparable between the two treatment groups at baseline and after 12 weeks. The pooled total testosterone level at baseline was 541 and 513 ng/dL in the placebo and simvastatin-treated groups, respectively, which declined to 536 +/- 20.5 ng/dL (-1.5%) and 474 +/- 30.4 ng/dL (-13.6%, P = .09) after treatment (mean +/- SD). The pooled free testosterone declined by 6.3% in the simvastatin group, versus a 4.9% increase in the placebo group (P = .588), while pooled bioavailable testosterone declined 10.2% in the simvastatin group and increased 1.4% in the placebo group (P = .035). There were no changes in serum gonadotropin levels or sex hormone-binding globulin (SHBG). After administration of hCG, there were no differences in the peak total pooled testosterone level before or after 12 weeks of treatment. Simvastatin 80 mg was well tolerated compared with placebo. In conclusion, basal and stimulated cortisol production was unaffected by the use of simvastatin 80 mg versus placebo. As reported with other statins and cholestyramine, there were small declines in the simvastatin-treated group for pooled total, free, and bioavailable testosterone after 12 weeks, although there was no compensatory increase in serum follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels.

Drug interactions of lipid-altering drugs.

The use of lipid-altering drugs has been shown to reduce the progression of atherosclerotic lesions and reduce the risk of atherosclerotic events (such as myocardial infarction and stroke). In general, these lipid-altering drugs are well tolerated but there is the potential for drug interactions. For example, HMG-CoA reductase inhibitors may interact with macrolides, azalides, azole antifungals and cyclosporin. Resins (such as cholestyramine and colestipol) may impair the absorption of many concurrent medications. Fibrates have potential drug interactions with warfarin, furosemide (frusemide), oral hypoglycaemics and probenecid. Nicotinic acid (niacin) may have potential drug interactions with high dose aspirin (acetylsalicylic acid), uricosuric agents (such as sulfapyrazone) and alcohol (ethanol). Finally, probucol may have potential drug interactions with antidysrhythmics, tricyclic antidepressants and phenothiazines. In addition, lipid-altering drugs, used in combination, may have the potential for drug interactions, enhancing some of the risks of adverse effects, such as myositis and hepatotoxicity. Therefore, in order to use lipid-altering drugs in the most effective, and safest manner, it is important for the clinician to have an understanding of the mechanisms of potential drug interactions, which drug interactions may theoretically occur, and specifically, which spe cific drug interactions have already been described.

Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study.

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.

Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.

BACKGROUND: Ezetimibe (SCH 58235) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol. OBJECTIVE: Data from 2 multicenter, placebo-controlled, double-blind, randomized, parallel-group, 12-week studies of ezetimibe were pooled to evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolemia. METHODS: After dietary stabilization (National Cholesterol Education Program Step I diet or a stricter diet), washout of lipid-altering drugs, and a 6-week placebo lead-in period, patients with baseline plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride (TG) levels < or = 300 mg/dL were randomized to receive either ezetimibe 0.25, 1, 5, or 10 mg, or placebo administered once daily before the morning meal in study A (dose-response study) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B (dose-regimen study). RESULTS: A total of 432 patients were included in this pooled analysis, 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7% and 18.5%, respectively (P < 0.01 vs placebo) and significantly increased high-density lipoprotein cholesterol (hDL-C) levels by 2.9% and 3.5%, respectively (P < 0.05 vs placebo). A reduction in plasma TG levels was observed (P = NS). With the 10-mg dose of ezetimibe, 67.8% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 22.0% achieved > or = 25% reduction. With the 5-mg dose, 54.0% of patients achieved > or = 15% reduction in plasma LDL-C levels, and 15.3% achieved > or = 25% reduction. The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg (P < 0.05). Ezetimibe was well tolerated, with an adverse event profile similar to that of placebo. CONCLUSIONS: In these two 12-week studies, ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo.

Peripheral diabetic neuropathy.

Diabetic neuropathy is a common complication of diabetes mellitus with significant morbidity and mortality. Hyperglycemia with its secondary metabolic, vascular, and enzymatic consequences is most likely to be the predominant cause. The clinical manifestations includes a wide range of somatic and autonomic syndromes. Painful diabetic neuropathy may require symptomatic treatment. The precise role of therapies such as continuous subcutaneous insulin therapy and aldose reductase inhibitors remains to be clarified.