Valerie A. Cain

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).

The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden

Background— Previous studies using quantitative coronary angiography have demonstrated that statin therapy slows the progression of coronary stenoses in proportion to average low-density lipoprotein cholesterol levels during therapy. However, no major statin monotherapy study has demonstrated either halted progression or regression of angiographic disease. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) assessed whether rosuvastatin could regress coronary atherosclerosis by intravascular ultrasound and quantitative coronary angiography. Intravascular ultrasound showed atheroma volume regression in a single coronary artery with <50% angiographic luminal narrowing. Methods and Results— ASTEROID treated 507 coronary disease patients with rosuvastatin 40 mg/d for 24 months. Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimum lumen diameter were performed for up to 10 segments of coronary arteries and major branches with >25% diameter stenosis at baseline. For each patient, the mean of all matched lesions at baseline and study end was calculated. There were 292 patients with 613 matched stenoses. Rosuvastatin reduced low-density lipoprotein cholesterol by 53.3% to 61.1±20.3 mg/dL and increased high-density lipoprotein cholesterol by 13.8% to 48.3±12.4 mg/dL. Mean±SD percent diameter stenosis decreased from 37.3±8.4% (median, 35.7%; range, 26% to 73%) to 36.0±10.1% (median, 34.5%; range, 8% to 74%; P<0.001). Minimum lumen diameter increased from 1.65±0.36 mm (median, 1.62 mm; range, 0.56 to 2.65 mm) to 1.68±0.38 mm (median, 1.67 mm; range, 0.76 to 2.77 mm; P<0.001). Conclusions— Rosuvastatin treatment for 24 months to average low-density lipoprotein cholesterol levels well below 70 mg/dL, accompanied by significant increases in high-density lipoprotein cholesterol, produced regression by decreasing percent diameter stenosis and improving minimum lumen diameter as measured by quantitative coronary angiography in coronary disease patients.

Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial

SUMMARY In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor*) was compared with that of atorvastatin (Lipitor †), simvastatin (Zocor‡), and pravastatin (Pravachol§) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20,40, or 80 mg, atorvastatin 10, 20,40, or 80 mg, simvastatin 10,20,40, or 80 mg, or pravastatin 10, 20, or 40 mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels <100 mg dl−1 (<2.6 mmol l−1), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of <100 mg dl−1 (<2.6 mmol l−1) (55% to 77% compared with 0 to 64%), <3.0 mmol l−1 (<116 mg dl−1) (76% to 94% compared with 6% to 81%), and <2.5 mmol l−1 (<97mg dl−1) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides >200 mg dl−1 (>2.3 mmol l−1), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of <2.5 (<97 mg dl−1) to <5.0 mmol l−1 (< 193mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (<3.0 mmol l−1 [< 266 mg dl−1] to < 2.0 mmol l−1 [<177 g dl−1]), and the total cholesterol/high-density lipoprotein-cholesterol ratio (<4 to <7) (70% to 83% versus 35% to 79%). * Crestor is a registered trademark of the AstraZeneca group of companies and is licensed to AstraZeneca from Shionogi & Co, Ltd, Osaka, Japan. † Lipitor is a registered trademark of Pfizer Inc. ‡ Zocor is a registered trademark of Merck & Co., Inc. § Pravachol is a registered trademark of Bristol-Myers Squibb Company.

Statin Therapy Alters the Relationship Between Apolipoprotein B and Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol Targets in High-Risk Patients: The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) Trial

OBJECTIVES The purpose of this analysis was to compare concentrations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apoB) before and during statin therapy. BACKGROUND Reducing LDL-C to a pre-determined goal may still leave an excess of atherogenic lipoproteins, as reflected in apoB levels. METHODS The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial examined the effects of statin treatment in patients with high coronary heart disease (CHD) risk, LDL-C > or =130 and <250 mg/dl, and triglycerides <400 mg/dl. Therapy consisted of rosuvastatin (10 or 20 mg), atorvastatin (10 or 20 mg), or simvastatin (20 or 40 mg). The apoB and LDL-C or non-HDL-C at baseline and after 16 weeks of therapy were compared using linear regression. RESULTS In untreated patients, the apoB target of <90 mg/dl was roughly equivalent to an LDL-C level <100 mg/dl and a non-HDL-C level <130 mg/dl, which is consistent with existing apoB and lipoprotein guidelines. However, during statin therapy, to reach an apoB target of <90 mg/dl it was necessary to reduce non-HDL-C to <100 mg/dl or to reduce LDL-C to <70 mg/dl (in high-triglyceride patients) or <80 mg/dl (in lower-triglyceride patients). The tight correlation seen for non-HDL-C with apoB while on statin therapy (R(2) = 0.92) implies that non-HDL-C may be an acceptable surrogate for direct apoB measurement. CONCLUSIONS These data are consistent with the more aggressive cholesterol goals suggested for CHD patients, because achieving such targets also reduced apoB to the recommended level. (Mercury II-Compare the Efficacy and Safety of Lipid Lowering Agents Atorvastatin and Simvastatin With Rosuvastatin in High Risk Subjects With Type IIa and IIb Hypercholesterolemia; NCT00654407).

Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study

BACKGROUND Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension. METHODS In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries across five continents. Patients had uncontrolled type 2 diabetes (HbA1c 7·0%-10·5%; 53-91 mmol/mol) and hypertension (systolic 140-165 mm Hg and diastolic 85-105 mm Hg at both enrolment and randomisation, and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving oral antihyperglycaemic drugs, insulin, or both, plus a renin-angiotensin system blocker and an additional antihypertensive drug. Using an interactive voice-response system, we randomly assigned (1:1) patients to dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set, which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered with ClinicalTrials.gov, number NCT01195662. FINDINGS Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change from baseline -11·90 mm Hg [95% CI -13·97 to -9·82]) compared with those assigned to placebo (-7·62 mm Hg [-9·72 to -5·51]; placebo-adjusted difference for dapagliflozin -4·28 mm Hg [-6·54 to -2·02]; p=0·0002). Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change from baseline -0·63% [95% CI -0·76 to -0·50]) than in those assigned to placebo (-0·02% [-0·15 to 0·12]; placebo-adjusted difference -0·61% [-0·76 to -0·46,]; p<0·0001). In a post-hoc analysis, we found difference in blood pressure versus placebo was greater in patients receiving a β blocker (-5·76 mm Hg [95% CI -10·28 to -1·23]) or a calcium-channel blocker (-5·13 mm Hg, [-9·47 to -0·79]) as their additional antihypertensive drug than in those receiving a thiazide diuretic (-2·38 mm Hg [-6·16 to 1·40]). Adverse events were similar in the dapagliflozin and placebo groups (98 [44%] patients vs 93 [42%], respectively, had at least one adverse event), with few adverse events related to renal function (1% vs <1%) or volume depletion (<1% vs 0%). INTERPRETATION Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens. FUNDING Bristol-Myers Squibb, AstraZeneca.

Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers

To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR.

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.

Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein Cholesterol Levels With Rosuvastatin 40 mg Daily (from the ASTEROID Study)

Clinical trial evidence supports the use of intensive statin therapy for patients with coronary artery disease. High doses of potent statins have shown the greatest clinical benefit, but concerns persist regarding the efficacy and safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. We grouped patients treated with 40 mg of rosuvastatin daily by the LDL cholesterol achieved according to previous work (<40, 40 to <60, 60 to <80, 80 to <100, and > or =100 mg/dl) and by National Cholesterol Education Program targets (<70, 70 to <100, and > or =100 mg/dl) in A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID). The rates of key safety end points, including death, hemorrhagic stroke, and liver and muscle enzyme elevations, and key efficacy end points (atheroma burden) were compared using chi-square testing or Fishers exact testing. The analysis included 471 patients who had had their LDL cholesterol measured at 3 months, of whom 340 (72.2%) had LDL cholesterol of <70 mg/dl, exhibiting excellent achievement of even the most stringent guideline-based goals. Of these 471 subjects, 192 (40.8%) had LDL cholesterol > or =40 mg/dl but <60 mg/dl, and 57 (12.1%) had LDL cholesterol <40 mg/dl. Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol. Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol. In conclusion, although the power to detect such changes was limited, these data showed no clear relation between the LDL cholesterol achieved by intensive statin therapy with rosuvastatin and adverse effects. Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved.

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.

An evaluation of the effects of an angiotensin receptor blocker on health-related quality of life in patients with high-normal blood pressure (prehypertension) in the Trial of Preventing Hypertension (TROPHY).

The Trial of Preventing Hypertension (TROPHY) demonstrated the feasibility of possibly reducing the incidence of hypertension with the angiotensin receptor blocker candesartan compared with placebo. The long‐term benefits of pharmacologic therapy in high‐normal blood pressure, or prehypertension are not known, and the long‐term effect on health‐related quality of life (HRQL) has not been determined. An analysis of covariance model was used to assess treatment differences from baseline in the HRQL scores using Short Form (SF)‐36, and component measures at subsequent visits. Of the 809 randomized patients, 734 had both baseline and ≥1 HRQL follow‐up assessment: 95% (379 of 397) of patients receiving candesartan and 91% (355 of 388) of patients receiving placebo. There were no statistically significant between‐group differences in least‐squares mean physical component survey and mental component survey scores or the individual scales at each scheduled visit relative to baseline values (P >.05). In TROPHY, patients with prehypertension had relatively high baseline HRQL, and HRQL was maintained with the angiotensin receptor blocker candesartan over both the 2‐year treatment period and a total 4‐year trial period.