Crestor What to Expect: Week-by-Week First Month on Rosuvastatin

How fast does rosuvastatin start working?

Rosuvastatin blocks HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a cholesterol precursor. Unlike simvastatin it is not a prodrug: more than 90% of active plasma HMG-CoA reductase inhibitory activity comes from the parent compound [2].

Peak plasma concentration arrives 3 to 5 hours after a dose, absolute bioavailability is about 20%, food does not change the AUC, and the half-life is about 19 hours [2]. The AUC is the same whether Crestor is taken in the morning or the evening [2].

The lipid effect arrives faster than most people expect. In two dose-ranging studies combined for analysis (rosuvastatin 1, 2.5, 5, 10, 20, 40 and 80 mg versus placebo, 6 weeks), roughly 90% of the LDL cholesterol reduction occurred within the first 2 weeks of treatment [1].

Week 1: what actually changes

LDL-C changes are measured with a blood test, so the first week is unlikely to bring an obvious sign that the drug is working. The early lipid effect is already under way [1].

Side effects in the placebo-controlled trials were mostly close to placebo rates. In pooled trials lasting up to 12 weeks (382 people on placebo, 744 on rosuvastatin 5 to 40 mg) [2]:

Two practical points from the label: Crestor can be taken at any time of day, with or without food. The label says to take Crestor at least 2 hours before an aluminum or magnesium hydroxide antacid; taking them at the same time lowered rosuvastatin AUC by about 50% [2].

Week 2: most of the lipid drop is already in

By the end of week 2, about 90% of the 6-week LDL reduction is present [1].

The six-week comparison trial STELLAR randomized 2,431 adults with hypercholesterolemia. Across the dose ranges studied, rosuvastatin 10 to 80 mg lowered 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. HDL cholesterol rose 7.7% to 9.6% in the rosuvastatin groups [4].

Week 3: muscle symptoms and how often they occur

In PRIMO, an observational survey of 7,924 hyperlipidemic patients on high-dose statin therapy in French outpatient practice, 10.5% reported muscle symptoms, with a median onset of 1 month after starting [3]. That survey covered several high-dose statins, not rosuvastatin alone.

Rosuvastatin's own trial figures put the rates in context. In JUPITER, 17,802 participants were randomized in total, with 8,901 assigned to rosuvastatin 20 mg and 8,901 to placebo; mean follow-up was 2 years [2][5]. Myalgia was reported by 7.6% on rosuvastatin versus 6.6% on placebo, and arthralgia by 3.8% versus 3.2% [2]. In the pooled 12-week trials the myalgia rates were 2.8% versus 1.3% [2]. METEOR randomized 984 people 5:2 to rosuvastatin 40 mg or placebo. In the label's safety analysis (700 on 40 mg vs 281 on placebo, mean 1.7 years), myalgia was reported in 12.7% versus 12.1%, and increased CPK in 2.6% versus 0.7% [2][6].

The label lists risk factors for myopathy: age 65 or older, uncontrolled hypothyroidism, renal impairment, certain other drugs, and higher dosage. Myopathy risk is greater on 40 mg daily than on lower doses, and Asian patients may be at higher risk [2]. The label says patients should be instructed to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever, and says to discontinue Crestor if markedly elevated CK levels occur or myopathy is diagnosed or suspected [2].

Week 4: the first lipid panel

The label says to assess LDL-C as early as 4 weeks after starting Crestor and adjust the dose if necessary [2].

The size of the response depends on the dose. In an analysis of 5 trials, 194 of 580 patients completing 12 weeks of rosuvastatin 10 mg had metabolic syndrome; in that group LDL cholesterol fell 47%, non-HDL cholesterol 43% and triglycerides 23%, while HDL cholesterol rose 10% [7]. Across the dose-ranging studies, LDL reductions ran from 34% at 1 mg to 65% at 80 mg, with an extra 4.5% reduction for each doubling of the dose [1]. Crestor itself is sold as 5, 10, 20 and 40 mg tablets; 80 mg is not a marketed strength [2][8].

Liver enzymes are the other number that can shift. In pooled placebo-controlled trials, transaminases above 3 times the upper limit of normal occurred in 1.1% of people on Crestor versus 0.5% on placebo; in METEOR, on 40 mg, ALT above 3 times the upper limit occurred in 2.2% versus 0.7% [2]. The label says to consider liver enzyme testing before starting Crestor and as clinically indicated [2].

Blood sugar can drift too. In JUPITER the mean HbA1c rose 0.1% more on Crestor than on placebo, and diabetes mellitus was reported in 2.8% versus 2.3% [2]. The label notes that HbA1c and fasting glucose can rise, in some cases past the diabetes threshold [2].

What changes the plan in the first month

• Warfarin. The label says rosuvastatin significantly increased the INR in patients on warfarin, and that INR should be checked before starting and often enough after starting, titration or stopping [2].
• Asian patients. The label says to start at 5 mg once daily because exposure is roughly 2-fold higher, and to weigh risks and benefits if control is not reached at up to 20 mg daily [2]. In a single-dose study of 40 mg in Singapore, AUC was 2.31-fold higher in Chinese, 1.91-fold in Malay and 1.63-fold in Asian-Indian subjects than in white subjects [9].
• Severe renal impairment. With creatinine clearance under 30 mL/min/1.73 m2 (not on hemodialysis), the label says start at 5 mg and do not exceed 10 mg daily; exposure is about 3-fold higher [2].
• Cyclosporine. With cyclosporine, the Crestor label limits the dose to 5 mg once daily; cyclosporine raised rosuvastatin exposure about 7-fold by AUC and about 11-fold by peak concentration [2]. In a 10-patient heart transplant study the increases were 7.1-fold and 10.6-fold [10].
• Gemfibrozil. The label says avoid the combination; if unavoidable, start at 5 mg and do not exceed 10 mg daily. Gemfibrozil raised rosuvastatin AUC about 1.9-fold and Cmax about 2.2-fold, and the 20-volunteer crossover study measured 1.88-fold and 2.21-fold [2][11].
• Resmetirom (Rezdiffra). That label limits rosuvastatin to 20 mg daily when the two are used together (rosuvastatin AUC 1.4-fold higher). The limit is in the Rezdiffra label, not in the Crestor interaction table [12].

Serious safety warnings in the label

Myopathy and rhabdomyolysis are the label's main safety concern. Acute kidney injury from myoglobinuria and rare fatalities have occurred with statins, and immune-mediated necrotizing myopathy is a rare complication [2]. The label says to temporarily discontinue Crestor during acute conditions that raise the risk of renal failure from rhabdomyolysis, such as sepsis, shock or major surgery [2].

The label notes rare fatal and non-fatal hepatic failure with statins; acute liver failure or decompensated cirrhosis is a contraindication [2]. Hypersensitivity reactions reported with Crestor include rash, pruritus, urticaria and angioedema [2].