metformin, ckd, and death

a rather unusual quick-and-dirty study was just published looking at the relationship between metformin use and mortality, as well as lactic acidosis, in those with severe chronic kidney disease, CKD. This study was based on a window of time until 2009, when metformin was used in Taiwan without restriction in those with renal disease (Seedm metformin ckd death lancet 2015 in dropbox, or doi.org/10.1016/S2213-8587(15)00123-0). The researchers looked at a large database of diabetics with severe CKD -- (those with diabetes plus a primary diagnosis of chronic kidney disease and those receiving erythropoiesis-stimulating agents, which was prescribed for 85% of non-dialysis patients with stage 5 chronic kidney disease --ie,  GFR<15 ml/min), and compared outcomes of those who were prescribed metformin to  a propensity-match scored group of patients not on metformin (a mathematical tool to attempt to adjust for patients with similar levels of comorbidities), and looked at outcomes. details:

--813 metformin users were compared to 2439 non-users, with no difference in 30 baseline clinical and socioeconomic variables. Patients had a serum creatinine of at least 6 mg/dL (the researchers did not have more specific/individual information)

--median follow-up of 2.1 years (range 0.3-9.8). Mean age 67.2, mean eGFR in men was 10 ml/min and 7 ml/min in women. All-cause mortality was reported in 434 (53%) of metformin users and 1012 (41%) of non-users.

--results:

        --after multivariate adjustment, metformin use was associated with increased all-cause mortality [HR 1.35 (1.20-1.51, p<0.001)] and was consistent among all subgroups

        --the increased mortality was dose-dependent: no increase in the groups on <= 500mg metformin/d (nonsignificant 14% increase), or 501-1000 mg/d (nonsignificant 30% increase), but was significant for those on >1000 mg/d (57% increased risk)

        --for those with "metabolic acidosis", which includes those with lactic acidosis, there was no significant increase in those on metformin, independent of metformin dose and without any trend of increase in those on the highest dose.

        --the incidence of metabolic acidosis was pretty small: 1.6 vs 1.3 events per 100 patient-years ([HR 1.30 (0.88-1.93, p=0.19)]

so, pretty striking study in that those with very advanced renal disease DID NOT have any increase in lactic acidosis -- the feared complication, since this is a highly lethal condition, metformin is excreted unchanged in the urine and accumulates with renal dysfunction, and the kissing-cousin of metformin (phenformin, which was used in the US) was associated with lots of lactic acidosis-related deaths. a few comments:

--metformin was likely used at such a high rate in Taiwan, even after the US FDA proscribed its use in men with creatinine>1.5 and women with creatinine>1.4 in 1994, because metformin has the best data in preventing both cardiovascular and all-cause mortality in diabetics (metformin was the preferred biguanide used in Europe and has been used on many millions of people since 1957)

--there were data from other studies suggesting cardiovascular benefit in those with moderate CKD (eGFR of 30-60 ml/min)

--the cause of the 35% increased all-cause mortality in the high-dose metformin users is unclear. 

        --on the one hand, metformin users seemed less sick (shorter duration of diabetes than non-users, had less retinopathy, and were less likely to go on to dialysis).  The increased mortality was even in the subgroup of those on metformin monotherapy (suggesting that hypoglycemia was not the cause of death), and metformin use was associated with an 86% increased risk of admission for cardiovascular disease before death [HR 1.86 (1.31-2.23), p<0.0001]. And, there was no increased death risk in those on non-metformin oral anti-diabetic agents. So, all of this suggests that metformin was the bad actor.

        --on the other hand,  this was a quick-and-dirty study with much missing information: were there unknown and uncontrolled reasons why the Taiwanese doctors chose metformin for some patients over others? did those on metformin actually have worse renal function than those not? (and there may well be increasing atherosclerotic risk with decreasing renal function). were there unaccounted for variables in their propensity-matching-- eg they did not have data on the intensity of the diabetes control or even the smoking history. Perhaps physicians treating those at the highest risk of heart disease (smokers, with diabetes and ESRD) might have been disproportionately prescribed metformin to lower their cardiac risk? or perhaps more patients with poorly-controlled diabetes and perhaps higher risk of heart disease got metformin???

--the lack of association with lactic acidosis is pretty striking in this cohort with severe CKD. Part of the lactic acidosis fear is that some studies have found increased lactic acid levels in those on metformin who have CKD, but the relationship between high lactate levels and clinical lactic acidosis is not clear, leading to recommendations NOT to follow lactic acid levels.

--so, i would still not use metformin in those with eGFR<30 (see prior blog for more information on this: (http://gmodestmedblogs.blogspot.com/2015/01/metformin-in-renal-failure.html ​ ), but the dreaded fear of the highly lethal lactic acidosis is unlikely to be an issue at any level of renal dysfunction.