Deborah Anzalone

Lisinopril Versus Hydrochlorothiazide in Obese Hypertensive Patients A Multicenter Placebo-Controlled Trial

Because obesity-associated hypertension has unique hemodynamic and hormonal profiles, certain classes of antihypertensive agents may be more effective than others as monotherapy. Thus, we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week, multicenter, double-blind trial in 232 obese patients with hypertension. Patients with an office diastolic pressure between 90 and 109 mm Hg were randomized to treatment with daily doses of lisinopril (10, 20, or 40 mg), hydrochlorothiazide (12.5, 25, or 50 mg), or placebo. Mean body mass indexes were similar for all patients. At week 12, lisinopril and hydrochlorothiazide effectively lowered office diastolic (-8.3 and -7.7 versus -3.3 mm Hg, respectively; P<.005) and systolic (-9.2 and -10.0 versus -4.6 mm Hg, respectively; P<.05) pressures compared with placebo. Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo (P<.001). Significant dose-response differences were observed between treatments. Sixty percent of patients treated with lisinopril had an office diastolic pressure <90 mm Hg compared with 43% of patients treated with hydrochlorothiazide (P<.05). Responses to therapies differed with both race and age. Neither treatment significantly affected insulin or lipid profiles; however, plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril (+0.31 versus -0.21 mmol/L; P<.001). Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline. In conclusion, lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics, may have a more rapid rate of response, and may offer advantages in patients at high risk of metabolic disorders.

Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial

BACKGROUND The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING AstraZeneca.

Effect of tesaglitazar, a dual PPARα/γ agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12‐week dose-ranging trial

ABSTRACT Objective: The Glucose and Lipid Assessment in Diabetes (GLAD) trial examined the dose-response relationship of the dual peroxisome proliferatoractivated receptor (PPAR) α/γ agonist tesaglitazar in type 2 diabetic patients. Study design: GLAD was a 12‐week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged 30–80 years with type 2 diabetes (fasting plasma glucose [FPG] ≥ 126 mg/dL [≥ 7.0 mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or open-label pioglitazone (45 mg), included as a therapeutic benchmark. Main outcome measures: Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures. Results: At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6 kg/m2, 30.9 kg/m2, and 29.7 kg/m2, and mean HbA1c was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5 mg, 1.0 mg, 2.0 mg, and 3.0 mg produced statistically significant reductions in FPG (–30.3 mg/dL, –41.1 mg/dL, –55.0 mg/dL, –60.9 mg/dL; p < 0.0001), triglycerides (–17.2%, –32.9%, –41.0%, –40.9%; p < 0.01), and apolipoprotein B (–15.0%, –15.7%, –21.0%, –22.3%, respectively; p < 0.0001). Tesaglitazar at doses ≥ 1.0 mg significantly increased high-density lipoprotein-cholesterol (HDL‐C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL‐C (–13.2%, –22.2%, –25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL‐C) (–36.9%, –49.8%, –52.5%; p < 0.0001), and total cholesterol (–6.8%, –14.1%, –15.5%, respectively; p < 0.01). Tesaglitazar ≥ 0.5 mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0 mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar ≤ 1.0 mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses ≥ 1.0 mg. Conclusions: In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses ≥ 0.5 mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses ≥ 0.5 mg or ≥ 1.0 mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0 mg and 3.0 mg doses limits conclusions about the efficacy of these doses. The 0.5 mg and 1.0 mg tesaglitazar doses were identified for further investigation.

Renal safety of intensive cholesterol-lowering treatment with rosuvastatin: A retrospective analysis of renal adverse events among 40,600 participants in the rosuvastatin clinical development program

OBJECTIVE Intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular risk but can cause liver-, muscle-, and possibly renal-related adverse events (AEs). We assessed the effects of rosuvastatin on the risk of developing renal impairment or renal failure among participants in the rosuvastatin clinical development program. METHODS The analysis was based on AE data reported by investigators from 36 studies that included 40,600 participants who did not have advanced, pre-existing renal disease. Rates of renal AEs were determined based on time to first occurrence of renal impairment or renal failure. RESULTS Renal impairment or renal failure was reported in 536 study participants during 72,488 patient-years of follow-up. Renal event rates were higher in patients with history of heart failure (n = 5011), hypertension (n = 21,864), diabetes (n = 5165), or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) (n = 9507) at baseline but did not differ with rosuvastatin compared with placebo or with rosuvastatin 40 mg compared with rosuvastatin 10mg. Relative risk (RR) estimates obtained from pooled analysis of placebo-controlled trials were RR: 1.03 (95% CI: 0.86-1.23, p = 0.777) for any reported renal impairment or renal failure event, RR: 1.02 (95% CI: 0.76-1.37, p = 0.894) for serious renal AEs, and RR: 0.70 (95% CI: 0.36-1.35, p = 0.282) for renal AEs leading to death. CONCLUSION These findings suggest that intensive LDL-C-lowering treatment with rosuvastatin does not affect the risk of developing renal insufficiency or renal failure in patients who do not have advanced, pre-existing renal disease.

Statin treatment patterns and clinical profile of patients with risk factors for coronary heart disease defined by National Cholesterol Education Program Adult Treatment Panel III

Abstract Objective: To compare clinical characteristics, statin treatment patterns and adherence among patients at different risk for coronary heart disease (CHD) as defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines. Methods: Patients ≥18 years old with ≥1 claim for dyslipidemia, ≥1 statin claim, or ≥1 LDL-C value ≥100 mg/dL were identified from 1 January 2007 to 31 July 2012. Patients were classified as low risk (LR) (0–1 risk factor: hypertension, age ≥45 years [men] or ≥55 years [women], or low HDL-C), moderate/moderately high risk (MR) (≥2 risk factors), high risk (HR) (CHD or CHD risk equivalent), or very high risk (VHR) (acute coronary syndrome, or established cardiovascular disease plus diabetes or metabolic syndrome). Medication use and lipid levels during the 12 months before and statin use during the 6 months after index were compared across risk groups. Results: There were 1,524,351 LR, 242,357 MR, 188,222 HR, and 57,469 VHR patients identified. Statin use was observed in 15% of all patients, but was higher in the VHR group (45%) versus LR (12%), MR (18%), and HR (29%) groups. Simvastatin accounted for 50%–52% of all statin use, and average statin dose was higher among VHR patients compared with all other groups. Adherence was low overall (mean proportion of days covered [PDC]: 0.57), but higher among VHR (0.69) versus others (mean PDC: 0.55, 0.59, and 0.59 in LR, MR, and HR groups, respectively). Conclusions: Statin treatment was low across all risk groups, and VHR patients had higher doses and better adherence compared with other risk groups. However, adherence was not optimal, indicating a potential limited benefit from statin treatment.

Familial factors in the antihypertensive response to lisinopril.

BACKGROUND Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

Initiation Patterns of Statins in the 2 Years After Release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guideline in a Large US Health Plan

Background The purpose of this study was to characterize changes in statin utilization patterns in patients newly initiated on therapy in the 2 years following the release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol management guideline in a large US health plan population. Methods and Results This retrospective, observational study used administrative medical and pharmacy claims data to identify patients newly initiated on statin therapy over 4 quarters prior to and 8 quarters following the release of the guideline (average N/quarter=3596). Patients were divided into the 4 statin benefit groups (SBGs) based on risk factors and laboratory lipid levels as defined in the guideline: SBG1 (with atherosclerotic cardiovascular disease [ASCVD]; N=1046/quarter), SBG2 (without ASCVD, with low‐density lipoprotein cholesterol ≥190 mg/dL; N=454/quarter), SBG3 (without ASCVD, aged 40–75 years, with diabetes mellitus, low‐density lipoprotein cholesterol 70–189 mg/dL; N=1391/quarter), SBG4 (no ASCVD or diabetes mellitus, age 40–75 years, low‐density lipoprotein cholesterol 70–189 mg/dL, estimated 10‐year ASCVD risk of ≥7.5%; N=705/quarter). Demographic variables, statin utilization patterns, lipid levels, and comorbidities were analyzed for pre‐ and postguideline periods. Postguideline, gradually increased high‐intensity statin initiation occurred in SBG1, SBG2, and in SBG3 patients with 10‐year ASCVD risk ≥7.5%. Moderate‐ to high‐intensity statin initiation gradually increased among SBG4 patients. Recommended‐intensity statin choice changed to a greater degree among patients treated by specialty care physicians. Regarding sex, target‐intensity statin initiation was lower in women in all groups before and after guideline release. Conclusions Prescriber implementation of the guideline recommendations has gradually increased, with the most marked change in the increased initiation of high‐intensity statins in patients with ASCVD and in those treated by a specialist.

LDL cholesterol levels after switch from atorvastatin to rosuvastatin

Abstract Objective: Initial statin therapy may not always adequately reduce elevated low-density lipoprotein cholesterol (LDL-C) levels. Although alternative therapies are available, switching to another statin may be beneficial, especially for those at highest risk of cardiovascular disease and events. This study examined changes in LDL-C levels following a switch from 40/80 mg of atorvastatin (ATV) to 20/40 mg of rosuvastatin (RSV). Methods: This retrospective cohort study used data from the MarketScan administrative claims databases linked to laboratory values. Patients with or at risk for atherosclerotic cardiovascular disease (ASCVD) who switched from ATV 40/80 mg to RSV 20/40 mg and had LDL-C values measured within 90 days before and 30–180 days after the switch were included. The change in LDL-C was quantified for each patient and summarized across all patients and within each switch pattern (e.g. ATV40 to RSV20). Results: There was a significant mean (SD) decrease in LDL-C of 21% (30%) across the whole sample (N = 136) after switching from ATV to RSV. The greatest decrease occurred in patients who switched from ATV40 to RSV40 (N = 20; −29% [19%]; p < .001). Similar changes were observed overall and within each switch pattern when the analysis was limited to patients who were persistent on RSV in the post-switch period (N = 112; −24% [24%]; p < .001). Conclusions: Switching from ATV to RSV was associated with a significant decrease in LDL-C among high-risk patients. Switching between these two high-intensity statins may offer a viable alternative to other treatment modifications aimed at lowering LDL-C in this population.

A Comparison of Statin Therapies in Hypercholesterolemia in Women: A Subgroup Analysis of the STELLAR Study.

Abstract Objective: Cardiovascular disease is the leading cause of mortality in women in the United States. Aggressive treatment of modifiable risk factors (e.g., hypercholesterolemia) is essential in reducing disease burden. Despite guidelines recommending the use of statin treatment in hypercholesterolemic women, this patient group is often undertreated. This subgroup analysis of the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial examines the effects of statin therapy in hypercholesterolemic women. Methods: As part of the STELLAR trial, 1,146 women with elevated low-density lipoprotein cholesterol (LDL-C ≥160 and <250 mg/dL) and triglycerides <400 mg/dL were randomized to rosuvastatin 10–40 mg, atorvastatin 10–80 mg, simvastatin 10–80 mg, or pravastatin 10–40 mg for 6 weeks. Results: LDL-C reduction with rosuvastatin 10 mg, atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg was 49%, 39%, 37%, and 30%, respectively, after 6 weeks. High-intensity statins (rosuvastatin 20–40 mg and atorvastatin 40–80 mg) reduced LDL-C to the greatest extent: 53% with rosuvastatin 20 mg, 57% with rosuvastatin 40 mg, 47% with atorvastatin 40 mg, and 51% with atorvastatin 80 mg. Similar results were observed for non-high-density lipoprotein cholesterol (non-HDL-C). Increases in HDL-C were greater with rosuvastatin across doses than with other statins. All treatments were well tolerated, with similar safety profiles across dose ranges. Conclusions: Statin therapies in the STELLAR trial led to reductions in LDL-C, non-HDL-C, and triglycerides and increases in HDL-C among hypercholesterolemic women, with rosuvastatin providing the greatest reductions in LDL-C and non-HDL-C.