6 Feb, 17 | by EBM
By Dr. Geoffrey Modest
A systematic review from the VA synthesized data on use of metformin in patients with chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment (see doi:10.7326/M16-1901). The goal was to assess all-cause mortality, major adverse cardiac events (MACEs), and other outcomes in patients with these underlying diseases (patients with these diseases having been the ones in whom the FDA initially had warned against using metformin).
- 17 observational studies that included patients with CKD, CHF, or CLD with hepatic impairment were analyzed. These studies compared patients on diabetes regimens that included Metformin vs those that did not.
- 6 studies were included, with sample sizes ranging from 1246 to 11,481 patients, median age ranging from 65 to 76. Only one study reported median daily metformin dose (1100 to 1900 mg in the different subgroups)
- All-cause mortality
- 22% lower for patients on metformin, HR 0.78 (0.63-0.96)
- 2 studies reported CKD severity subcategories:
- eGFR of 30 to <45 had neither benefit nor harm
- eGFR of 30 to 60 had clear benefit of around 38%
- eGFR <30 (one study) had neither benefit nor harm
- 2 studies were evaluated, finding no difference in outcomes with metformin in the subgroups of patients with eGFR <45
- And much, much more hypoglycemia in those on non-metformin-based regimens (specifically, glyburide or insulin)
- 11 observational studies were included, with sample sizes from 346 to 13,930 patients, median age 55 to 77 years old. No studies included median metformin dose
- All-cause mortality:
- 22% lower for patients on metformin, HR 0.78 (0. 71-0.87)
- 2 studies reported CHF severity subcategories:
- One study looked at LVEF, finding that both an LVEF of 30-39% and LVEF<30% had a nonsignificant 13% decreased mortality; another study looked at patients with LVEF < 40%, finding a nonsignificant 21% decrease
- The relative chance of readmission for CHF during follow-up was 13% lower for patients on metformin: HR 0.87 (0.78-0.97)
- The relative risk for cardiovascular mortality was 23% lower in those on metformin (their figure shows that the three studies that looked at this found statistically significant improvement with metformin, but their overall summary said it was nonsignificant?????)
- 3 observational studies included, with sample sizes ranging from 82 to 250 patients, median age 60-61. No studies reported median metformin dose.
- All cause mortality:
- The one study with low risk of bias (n=250) found significantly longer survival: HR 0.43 (0.24-0.78), regardless of cirrhosis severity. Post hoc analysis found a positive association between metformin and survival only in those with nonalcoholic steatohepatitis, though the number of patients in the other subgroups was small.
- The other studies in those with moderate-to-high risk of bias showed a trend to lower all-cause mortality with metformin
- Metformin is accepted as the first line drug for diabetes in the US and other countries that I know of. It is such a good and appropriate drug, given both its positive effects on diabetes (including its being weight-neutral or leading to weight loss) as well as data suggesting decreased cardiovascular disease and all-cause mortality. As a result, many clinicians have been using it despite FDA precautions/contraindications, with estimates that 20-30% of patients have been prescribed metformin who have had these precautions/contraindications. The FDA itself has been progressively relaxing these restrictions. In 2006 they removed CHF as a contraindication (though acute or unstable CHF remains a precaution). In addition in 2016, the FDA changed the warning for CKD to be based on eGFR instead of creatinine, making approximately 1 million additional patients with moderate CKD eligible to receive metformin. See blogs noted below for other studies promoting the use of metformin.
- Most of the above conclusions were based on studies which had low strength-of-evidence, moderate risk-of-bias. However there was consistency in their finding that metformin therapy was associated with reduced all-cause mortality among patients with moderate CKD, CHF, or CLD; fewer CHF admissions among those with moderate CKD or CHF; and a much lower hypoglycemia rate among those with moderate CKD
- There are other concerns about a meta-analysis such as above, including the fact that they don’t have data on doses of metformin for most studies, what other medications were being used in addition to metformin (the studies did not have rigorous details about which patients were on which other hypoglycemic medications), whether there was “confounding by indication” (where people might have been selected to be on or off metformin based on unknown individual clinical considerations), or even more than baseline data on metformin use in most studies (i.e. patients may have started on metformin but somewhere during the study had stopped it; or alternatively patients may have started off metformin but then put on it during the course of the study)
But, bottom line, these studies reinforce not just the safety of metformin in what had previously been considered concerning underlying comorbidities, but strongly suggest a significant benefit of metformin-based regimens. I.e., there really is an imperative to use metformin as the first-line therapy. We know through our clinical practice that metformin’s major adverse reactions are GI. This is clearly less the case in those on lower doses or if metformin is taken with meals. The somewhat skimpy data suggest that much of the benefit of metformin is conferred by much less than full doses (one oft-repeated quote is that about 80% of the benefit of metformin is by giving 1000mg vs 2000mg). My personal experience is that many people get much better glucose control on just 500mg once a day (which is my starting dose, though I leave it there if there is good control, as happens pretty frequently), and I even have a person on 250mg (1/2 tablet) because of GI intolerance, who seems to get benefit…
Relevant past blogs:
http://blogs.bmj.com/ebm/2015/01/23/primary-care-corner-with-geoffrey-modest-md-metformin-in-renal-failure/ is a systematic review of studies in patients with chronic kidney disease, finding for example no cases (as in, zero) of lactic acidosis in 70,490 patient-years on metformin
http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-fda-changes-metformin-guidelines/ which gives the updated FDA changes for metformin prescribing in those with CKD, with reference to a study of 813 patients with creatinine >6 who did NOT have increased mortality on low dose metformin (<= 500 mg/d), as well as the study finding that metfomrin induces changes in the microbiome, which leads to decreased insulin resistance.