Metformin and Rosuvastatin Interaction: Safety, Risks, and Clinical Guidance

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Is there a known interaction between metformin and rosuvastatin?

Neither label names the other drug. The metformin label's table of clinically significant interactions covers carbonic anhydrase inhibitors, drugs that reduce metformin clearance through the kidney's OCT2 and MATE transporters (ranolazine, vandetanib, dolutegravir, cimetidine), alcohol, insulin and insulin secretagogues, and drugs that tend to raise blood glucose [1]. The Crestor label's dose-limit tables cover cyclosporine, gemfibrozil, several hepatitis C and HIV antivirals, ticagrelor and others; metformin is not among them [2].

The two drugs are handled by separate systems. Metformin is a biguanide that is not metabolized, is negligibly bound to plasma proteins and is cleared unchanged by the kidney, with a plasma half-life of about 6.2 hours and renal clearance about 3.5 times creatinine clearance [1]. Rosuvastatin is an HMG-CoA reductase inhibitor that is not extensively metabolized: about 10% of a dose is recovered as a metabolite formed mainly by CYP2C9, with roughly 90% excreted in feces and a half-life of about 19 hours [2].

What each label flags

Rosuvastatin is a substrate of the OATP1B1 and BCRP transporters, and the interactions the Crestor label focuses on are drugs that inhibit them [2]. Cyclosporine raised rosuvastatin AUC about 7-fold and Cmax about 11-fold, and the label caps Crestor at 5 mg daily with it [2]; in a 10-patient study of heart transplant recipients, AUC rose 7.1-fold and Cmax 10.6-fold [4]. Gemfibrozil 600 mg twice daily for 7 days raised the AUC of a single 80 mg rosuvastatin dose 1.88-fold and the Cmax 2.21-fold in 20 healthy volunteers, and the label says to avoid that combination [2][5].

Metformin's labeled transporter issue sits in the kidney: OCT2 and MATE inhibitors can raise metformin exposure and with it the risk of lactic acidosis [1]. Rosuvastatin appears in neither of those lists, and metformin appears in neither of rosuvastatin's [1][2].

Kidney function: the checkpoint both labels share

Metformin is substantially excreted by the kidney, and the label's postmarketing cases of lactic acidosis occurred mainly in patients with significant renal impairment [1]. The label asks for an eGFR before starting and at least yearly thereafter, contraindicates metformin below 30 mL/min/1.73 m2, does not recommend starting it at 30 to 45, and asks for a fresh benefit-and-risk assessment if eGFR later falls below 45 [1]. It also says to stop metformin at the time of or before an iodinated contrast procedure in patients with an eGFR of 30 to 60, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used, then recheck eGFR 48 hours later and restart only if renal function is stable [1].

The Crestor label has its own renal instruction, written in terms of creatinine clearance rather than eGFR: in severe renal impairment (creatinine clearance under 30 mL/min/1.73 m2, not on hemodialysis), treatment starts at 5 mg and does not exceed 10 mg daily; exposure is about 3-fold higher in that group [2]. No adjustment is listed for mild or moderate impairment [2].

So both labels use kidney function in their dosing rules, but with different measures: metformin uses eGFR thresholds (30 and 45), while Crestor's cap applies when creatinine clearance is below 30 mL/min/1.73 m2 [1][2].

Muscle symptoms on the combination

The Crestor label lists myopathy and rhabdomyolysis among its warnings and names the risk factors: age 65 or older, uncontrolled hypothyroidism, renal impairment, certain other drugs, and higher doses, with Asian patients possibly at higher risk [2]. The label says patients should be told to report unexplained muscle pain, tenderness or weakness promptly, especially with malaise or fever [2]. Reported rates: in METEOR (40 mg daily, mean 1.7 years) myalgia occurred in 12.7% on rosuvastatin versus 12.1% on placebo; in JUPITER (20 mg daily) 7.6% versus 6.6% [2].

Metformin's boxed warning lists myalgias among the nonspecific symptoms that can accompany lactic acidosis, alongside malaise, respiratory distress, somnolence and abdominal pain; the label says patients and families should be educated to stop metformin and report these symptoms, and that suspected lactic acidosis is managed in hospital, with prompt hemodialysis recommended [1].

Blood sugar and HbA1c

The Crestor label states that HbA1c and fasting glucose can rise on rosuvastatin, in some cases past the diabetes threshold [2]. In JUPITER, diabetes mellitus was reported in 2.8% of rosuvastatin patients versus 2.3% of placebo patients over a mean 2 years, and mean HbA1c was 0.1% higher on rosuvastatin [2]. Metformin's labeled indication is as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes: adults and children 10 and older for the immediate-release tablets, adults for the extended-release tablets [1][3].

Taking both on the same day

Rosuvastatin is taken once daily at any time of day, with or without food; AUC does not differ between morning and evening dosing [2]. One timing rule does exist on the Crestor label: take it at least 2 hours before an aluminum- or magnesium-hydroxide antacid, which cuts rosuvastatin AUC by about 50% when taken at the same time [2].

Metformin immediate-release is started at 500 mg twice daily or 850 mg once daily with meals and raised gradually to a maximum of 2,550 mg a day in divided doses [1]. Extended-release metformin is swallowed whole, never crushed, cut or chewed, starting at 500 mg once daily with the evening meal up to 2,000 mg once daily [3].

Other label warnings worth knowing

• Vitamin B12. Subnormal B12 was seen in about 7% of patients in 29-week metformin trials, and the label asks for B12 measurement every 2 to 3 years [1].
• Liver enzymes. Transaminases above 3 times the upper limit of normal occurred in 1.1% of Crestor patients versus 0.5% of placebo patients in pooled placebo-controlled trials; the label says to consider liver enzyme testing before starting and as clinically indicated [2].
• Hepatic impairment. The metformin label says to avoid metformin in patients with clinical or laboratory evidence of hepatic disease [1].
• Pregnancy. The Crestor label does not list pregnancy as a contraindication and says to discontinue when pregnancy is recognized [2]; the metformin label reports limited data with no clear association with major birth defects or miscarriage [1].