Metformin Linked to Decreased Mortality in CKD, CHF, and Liver Disease

Metformin is associated with lower all-cause mortality in patients with moderate chronic kidney disease (CKD), congestive heart failure (CHF) and chronic liver disease (CLD), according to a study published in the February issue of the Annals of Internal Medicine.¹

“Although data were limited, we found no evidence to suggest that metformin's benefits do not extend to patients with moderate CKD, CHF, or CLD with impaired hepatic function. Together with reports regarding the safety of metformin with respect to lactic acidosis, our findings support the FDA's recent actions,” wrote first author Matthew Crowley, MD, of Durham Veterans Affairs Medical Center (Durham, NC) and Duke University, and colleagues.²

When metformin was first approved in 1994, it was contraindicated in patients with CKD and CLD, due to concerns over lactic acidosis. Several years later, the US Food and Drug Administration (FDA) also advised against its use in CHF. These warnings were motivated, in part, by concerns for lactic acidosis with use of phenformin, a related drug that was pulled from the market in 1977.^1,2

Over the years, the FDA has relaxed some of the restrictions over metformin’s use. In 2006, the agency removed CHF as a contraindication for the drug, though still cautioned about its use in acute or unstable CHD.² In April 2016, the FDA changed metformin’s boxed warning, expanding its use to patients with mild kidney impairment and some patients with moderate renal impairment.³ Collectively, these changes will likely increase metformin use in patients who would have had contraindications in the past.

Effective in more patients?

To evaluate whether metformin use improves outcomes in an expanded population of patients, researchers searched Medline from January 1994 to September 2016, as well as Cochrane Library, EMBASE and International Pharmaceutical Abstracts from January 1994 to November 2015. Included studies were published in English only and evaluated metformin in adults with type 2 diabetes (T2D) and CKD (estimated GFR 60 mL/min/1.73 m²), CHF, or CLD with hepatic impairment. The analysis included 17 observational studies.

Key Results:

• CKD: 22% lower relative chance of dying for metformin vs no metformin (HR 0.78 [95% CI, 0.63 to 0.96]; Q = 29.7, P < .001; I² =79.8%)

          -- One study suggested lower hypoglycemia with metformin vs glyburide (adjusted OR, 6.0 [3.8 to 9.5]) and insulin (adjusted OR, 7.9 [CI, 5.0 to 12.4]), with metformin as reference

• CHF: 22% lower relative chance of dying for metformin vs no metformin (HR 0.78 [0.71 to 0.87]; Q = 26.6, P = 0.003; I² = 62.3%)

         -- 13% lower chance of readmission for CHF with metformin vs no metformin (HR 0.87 [ 0.78 to 0.97]; Q = 11.7 [P = 0.009]; I2 = 74.3%)

• CLD: Studies suggested lower all-cause mortality with metformin, but reported outcomes were too different for a meta-analysis on all-cause mortality

       -- No studies evaluated glycemic control, lipid control, weight gain or B12 deficiency in patients with CKD, CHF, or CLD

The authors noted that evidence strength was low, probably because most trials exclude patients with CKD, CHF or CLD and there is a dearth of randomized clinical trials in these patients.

Peer reservations

In a linked editorial, Kasia Lipska, MD, MHS, of the Yale School of Medicine (New Haven, CT) pointed out several other limitations of the study. Included studies were unblinded, only evaluated metformin use at baseline, and did not completely evaluate drop-out rates.²

She called for higher quality comparative effectiveness research for metformin in these patient groups. The most widely cited evidence supporting metformin’s cardiovascular benefits comes from a small subgroup analysis of the UKPDS (United Kingdom Prospective Diabetes Study). That study was conducted more than 20 years ago, she wrote, before the widespread use of statins and ACE inhibitors. Moreover, a number of large cardiovascular outcomes trials have reported on cardiovascular benefits for several classes of newer antihyperglycemics.

“The resulting imbalance in the available evidence may potentially lead to greater use of newer medications, in lieu of metformin, and cost an already taxed health care system billions of dollars,” she concluded. “In light of the recently relaxed contraindications for its use, bolstering the evidence base for metformin might be a wise investment.”

  Take Home Points

• Meta-analysis of observational studies found that metformin was associated with decreased all-cause mortality in patients with CKD, CHF, and CLD with hepatic impairment

• The results support the FDA’s recent relaxation of contraindications for the use of metformin

• Strength of the evidence was low overall

• Patients with CKD, CHF and CLD are often excluded from RCTs, and comparative effectiveness studies are needed that evaluate the use of metformin in these patient groups

The study was funded by the Veterans Affairs Administration.

Drs. Crowley, Kosinski, and Williams report grants from the Veterans Administration Quality Enhancement Research Initiative.

Dr. Lipska reports grants from the National Institute on Aging, and financial support from the Centers for Medicaid and Medicare Services.

References

1. Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med. 2017 Feb 7;166:191-200. doi: 10.7326/M16-1901.

2. Lipska K. Metformin use in patients with historical contraindications. Ann of Intern Med. 2017;166:225-226. doi: 10.7326/M16-2712.

3. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. April 8 2016.  Accessed April 14 2017 at: https://www.fda.gov/Drugs/DrugSafety/ucm493244.htm

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