Christine McCrary Sisk

Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes.

BACKGROUND Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS. STUDY DESIGN The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg. Follow-up visits are at 1 and 4 months, and every 4 months thereafter. If consecutive measures of LDL-C are >79 mg/dL at follow-up visits, the simvastatin dose will be increased to 80 mg in a double-blind manner. The primary end point is the first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke. Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point. SUMMARY IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.

BACKGROUND High-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia. METHODS A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia (53.8% of the study population had low HDL-C) were randomized equally to one of 10 groups: 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not, and each of these was randomized to placebo, anacetrapib 10, 40, 150, and 300 mg once daily for 8 weeks. An equal proportion of patients had triglycerides >150 mg/dL in each group. RESULTS For placebo and anacetrapib monotherapy (10, 40, 150, and 300 mg), least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol (LDL-C) were 2%, -16%, -27%, -40%, and -39%, respectively, and for HDL-C were 4%, 44%, 86%, 139%, and 133%, respectively (P < .001 vs placebo for all doses). Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy. For both anacetrapib monotherapy and coadministration with atorvastatin, the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median. Anacetrapib was well tolerated, and the incidence of adverse events was similar for placebo and all active treatment groups. There were no increases in systolic or diastolic blood pressure in any treatment arm. CONCLUSIONS Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL-C and increases in HDL-C; the net result of treatment with anacetrapib + atorvastatin was approximately 70% lowering of LDL-C and more than doubling of HDL-C. Anacetrapib was generally well tolerated with no discernable effect on blood pressure.

Efficacy and Safety of Sitagliptin Versus Glipizide in Patients With Type 2 Diabetes and Moderate-to-Severe Chronic Renal Insufficiency

OBJECTIVE Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control. RESEARCH DESIGN AND METHODS Patients (n = 426) were randomized 1:1 to sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1) renal status (moderate or severe renal insufficiency); 2) history of cardiovascular disease; and 3) history of heart failure. RESULTS At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (−0.8 vs. −0.6%; between-group difference −0.11%; 95% CI −0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (−0.6 kg) versus an increase (1.2 kg) with glipizide (difference, −1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments. CONCLUSIONS In patients with T2DM and chronic renal insufficiency, sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.

Flushing Profile of Extended-Release Niacin/Laropiprant Versus Gradually Titrated Niacin Extended-Release in Patients With Dyslipidemia With and Without Ischemic Cardiovascular Disease

Niacin has beneficial effects on a patients lipid and lipoprotein profiles and cardiovascular risk, particularly at doses >2 g/day, but is underused due to flushing. Laropiprant (LRPT), a selective prostaglandin D(2) receptor-1 antagonist, decreases flushing associated with extended-release niacin (ERN). We compared flushing with ERN/LRPT dosed by a simplified 1-g --> 2-g regimen versus gradually titrated niacin extended-release (N-ER; given as NIASPAN, trademark of Kos Life Sciences LLC). Patients with dyslipidemia (n = 1,455) were randomized 1:1 to ERN/LRPT (1 g for 4 weeks advanced to 2 g for 12 weeks) or N-ER (0.5 g for 4 weeks titrated in 0.5-g increments every 4 weeks to 2 g for the final 4 weeks). Aspirin/nonsteroidal anti-inflammatory drugs were allowed to mitigate flushing. Flushing severity was assessed using the validated Global Flushing Severity Score (GFSS; none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme 10). Patients on ERN/LRPT, despite more rapid niacin titration, had less flushing than those on N-ER, as measured by number of days per week with moderate or greater GFSS across the treatment period (p <0.001). More than 2 times as many patients had no episodes of moderate, severe, or extreme flushing (GFSS > or =4) with ERN/LRPT than with N-ER (47.0% vs 22.0%, respectively) across the treatment period. Fewer patients on ERN/LRPT discontinued due to flushing than those on N-ER (7.4% vs 12.4%, p = 0.002). Other than the decrease in flushing, the safety and tolerability profile of ERN/LRPT was similar to that of N-ER. In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia

OBJECTIVE To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program. METHODS Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931). RESULTS The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin. CONCLUSION The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

Effect of Reversal of Neuromuscular Blockade with Sugammadex versus Usual Care on Bleeding Risk in a Randomized Study of Surgical Patients

Background:Previous studies show a prolongation of activated partial thromboplastin time and prothrombin time in healthy volunteers after treatment with sugammadex. The authors investigated the effect of sugammadex on postsurgical bleeding and coagulation variables. Methods:This randomized, double-blind trial enrolled patients receiving thromboprophylaxis and undergoing hip or knee joint replacement or hip fracture surgery. Patients received sugammadex 4 mg/kg or usual care (neostigmine or spontaneous recovery) for reversal of rocuronium- or vecuronium-induced neuromuscular blockade. The Cochran–Mantel–Haenszel method, stratified by thromboprophylaxis and renal status, was used to estimate relative risk and 95% confidence interval (CI) of bleeding events with sugammadex versus usual care. Safety was further evaluated by prespecified endpoints and adverse event reporting. Results:Of 1,198 patients randomized, 1,184 were treated (sugammadex n = 596, usual care n = 588). Bleeding events within 24 h (classified by an independent, blinded Adjudication Committee) were reported in 17 (2.9%) sugammadex and 24 (4.1%) usual care patients (relative risk [95% CI], 0.70 [0.38 to 1.29]). Compared with usual care, increases of 5.5% in activated partial thromboplastin time (P < 0.001) and 3.0% in prothrombin time (P < 0.001) from baseline with sugammadex occurred 10 min after administration and resolved within 60 min. There were no significant differences between sugammadex and usual care for other blood loss measures (transfusion, 24-h drain volume, drop in hemoglobin, and anemia), or risk of venous thromboembolism, and no cases of anaphylaxis. Conclusion:Sugammadex produced limited, transient (<1 h) increases in activated partial thromboplastin time and prothrombin time but was not associated with increased risk of bleeding versus usual care.

Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia

This report describes the lipid and safety data collected during an off-drug period that followed 8 weeks of treatment with the cholesteryl ester transfer protein inhibitor, anacetrapib (ANA). A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomized to placebo, atorvastatin (ATV) 20 mg, and varying doses of ANA, provided as monotherapy or coadministered with ATV 20 mg daily. Patients were treated for 8 weeks, followed by an 8-week follow-up period, during which ANA was switched to placebo. At week 16 (8 weeks after ANA was stopped), persistent reductions in low-density lipoprotein cholesterol (LDL-C) were evident for the monotherapy groups receiving ANA 150 and 300 mg (-9.3% and -15.3%, respectively), and residual increases in high-density lipoprotein cholesterol (HDL-C) were observed for the monotherapy groups receiving ANA 40 mg (18.6%), 150 mg (40.5%), and 300 mg (43.4%). The effects on apolipoprotein B and apolipoprotein A-I were consistent with the changes observed for LDL-C and HDL-C, respectively. Corresponding residual changes in LDL-C and HDL-C were also noted in the ATV coadministration groups at the similar doses of ANA compared with ATV 20 mg alone. Residual plasma drug levels accompanied by reductions in cholesteryl ester transfer protein activity were observed at week 16 and may account for the alterations in plasma lipids 8 weeks after cessation of ANA.

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes

Aim:  The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate‐to‐severe hyperglycaemia (A1C = 7.5–12.0%).

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia

OBJECTIVE This study evaluated the effects of anacetrapib (ANA) on lipids and safety when administered as monotherapy or in combination with atorvastatin (ATV) in Japanese patients with dyslipidemia. METHODS Patients (n = 407) were randomized equally to 1 of 10 groups: placebo, ATV 10 mg, ANA 10, 40, 100, or 300 mg once daily, and the same ANA doses in combination with ATV 10 mg. Patients were treated with study medication for 8 weeks and followed for an additional 8 weeks, during which ANA was switched to placebo. RESULTS For the placebo and ANA monotherapy groups (10, 40, 100, and 300 mg), least squares mean percent changes from baseline at Week 8 for low-density lipoprotein cholesterol (LDL-C) calculated by the Friedewald equation were 3%, -12%, -27%, -32%, and -32%, respectively, and for high-density lipoprotein-cholesterol (HDL-C) were 1%, 56%, 116%, 134%, and 159%, respectively (p < 0.001 vs. placebo for all doses). All ANA doses co-administered with ATV 10 mg produced significantly greater LDL-C reductions and HDL-C increases compared with ATV 10 mg monotherapy. ANA was well tolerated, and dose-dependent relationships for adverse events were not observed across treatment groups. Changes from baseline in blood pressure and electrolytes were not significantly different between the active and control treatment groups. CONCLUSION ANA, as monotherapy or co-administered with ATV, produced significant reductions in LDL-C and increases in HDL-C. ANA was generally well tolerated in Japanese patients with dyslipidemia.

Flushing Profile of Extended-Release Niacin/Laropiprant at Initiation of Therapy in Asian Lipid Clinic Patients

Objective: Niacin is underutilized due to flushing, which occurs in over 90% of niacin-treated patients. Laropiprant (LRPT) reduces flushing associated with niacin. This study compared flushing with a combination tablet of extended-release (ER) niacin (ERN)/LRPT to niacin ER (N-ER; without LRPT) during the first week of therapy among patients in Asia. Methods: Following a 1-week placebo run-in, 332 patients with dyslipidemia from China, Korea and Singapore were randomized to ERN/LRPT 1 g/20 mg, N-ER 1 g (given as Niaspan®) or placebo in a 2:2:1 ratio for 1 week. Patient-reported flushing severity was assessed using the Global Flushing Severity Score (GFSS; none/mild = 0–3; moderate = 4–6; severe = 7–9; extreme = 10). Results: Compared with N-ER, the ERN/LRPT group experienced significantly less flushing (p < 0.001), as measured by maximum GFSS categorized as none/mild, moderate, severe or extreme. Overall, 23.8% of patients in the ERN/LRPT group and 50.0% in the N-ER group (p < 0.001), versus 12.1% in the placebo group, had moderate or greater flushing (GFSS ≥4). Except for flushing, which occurred more frequently in the N-ER group, ERN/LRPT had a safety/tolerability profile similar to that of N-ER. Conclusion: ERN/LRPT produced significantly less flushing than N-ER during the initiation of therapy and was generally well tolerated in Asian patients with dyslipidemia.