{"id":763,"date":"2015-07-23T20:00:34","date_gmt":"2015-07-23T20:00:34","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=763"},"modified":"2017-08-21T11:36:58","modified_gmt":"2017-08-21T11:36:58","slug":"primary-care-corner-with-geoffrey-modest-md-metformin-ckd-and-death","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/07\/23\/primary-care-corner-with-geoffrey-modest-md-metformin-ckd-and-death\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Metformin, CKD, and death"},"content":{"rendered":"

By: Dr. Geoffrey Modest\u00a0<\/strong><\/p>\n

A rather unusual quick-and-dirty\u00a0study 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\u00a0a window of time until 2009, when\u00a0metformin was used in Taiwan\u00a0without restriction in those with renal disease\u00a0(See\u00a0doi.org\/10.1016\/S2213-8587(15)00123-0<\/strong>). The researchers\u00a0looked at a large database of diabetics\u00a0with severe CKD — (those with diabetes plus a primary diagnosis of chronic kidney disease and those receiving erythropoiesis-stimulating agents, which\u00a0was prescribed for\u00a085% of\u00a0non-dialysis patients with stage 5 chronic kidney disease –ie,\u00a0 GFR<15 ml\/min), and compared outcomes of\u00a0those\u00a0who were prescribed metformin to \u00a0a propensity-match scored group of\u00a0patients not on metformin (a mathematical tool to attempt to adjust for patients with similar levels of comorbidities), and looked at outcomes.<\/p>\n

Details:<\/p>\n

–813 metformin users were compared to 2439 non-users, with no difference in 30 baseline clinical and socioeconomic variables. Patients had a serum\u00a0creatinine of at least 6 mg\/dL (the researchers did\u00a0not have more specific\/individual\u00a0information)<\/p>\n

–median follow-up of 2.1 years (range 0.3-9.8).\u00a0Mean 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\u00a0metformin users and 1012 (41%) of non-users.<\/p>\n

Results:<\/p>\n

–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<\/p>\n

–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)<\/p>\n

–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.<\/p>\n

–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)]<\/p>\n

So, pretty striking study in that those with very advanced renal disease DID\u00a0NOT have any increase in lactic acidosis —\u00a0the feared complication,\u00a0since this is a highly\u00a0lethal condition, metformin is excreted unchanged in the urine and accumulates with renal dysfunction, and the kissing-cousin of metformin (phenformin,\u00a0which was used in the US) was associated with lots of lactic acidosis-related deaths.<\/p>\n

A few comments:<\/p>\n

–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\u00a0creatinine>1.4 in 1994, because metformin\u00a0has the best data\u00a0in 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\u00a01957)<\/p>\n

–there were data from other studies\u00a0suggesting cardiovascular benefit in those with moderate CKD\u00a0(eGFR of 30-60 ml\/min)<\/p>\n

–the cause of the 35%\u00a0increased all-cause mortality in the high-dose metformin users is unclear.<\/p>\n

–on the one hand, metformin users seemed less sick (shorter duration of diabetes than non-users, had\u00a0less retinopathy, and were\u00a0less likely to go on to dialysis). \u00a0The increased mortality was\u00a0even in the subgroup of those on metformin monotherapy (suggesting that hypoglycemia was not the cause of death), and metformin\u00a0use was associated with an 86% increased risk of admission for cardiovascular disease before death [HR 1.86 (1.31-2.23), p<0.0001].\u00a0And, there was no increased death risk in those on non-metformin oral anti-diabetic agents.\u00a0So, all of this suggests that metformin was the bad actor.<\/p>\n

–on the other hand,\u00a0\u00a0this was a quick-and-dirty study with much missing information: were there unknown and\u00a0uncontrolled reasons why\u00a0the Taiwanese doctors chose metformin for some patients over others?\u00a0did those on metformin actually have worse renal function than those not? (and there may well be\u00a0increasing atherosclerotic risk with decreasing renal function). Were there unaccounted for variables in their propensity-matching–\u00a0eg they did not have data on the intensity of the diabetes control or even the smoking history.\u00a0Perhaps physicians treating\u00a0those at the highest risk of heart disease (smokers, with diabetes and ESRD) might have been disproportionately prescribed\u00a0metformin to lower their cardiac risk? Or\u00a0perhaps more patients with\u00a0poorly-controlled diabetes and perhaps higher risk of heart disease\u00a0got metformin???<\/p>\n

–the lack of association with lactic acidosis is pretty striking in this cohort with severe CKD. Part\u00a0of the lactic acidosis\u00a0fear is that some studies have found increased lactic acid levels in those on metformin who have\u00a0CKD, but the relationship between high lactate levels and clinical lactic acidosis is not clear, leading to recommendations NOT to follow lactic acid levels.<\/p>\n

So, I would still not use metformin in those with eGFR<30 (see prior blog<\/a> for more information on this)\u00a0but the dreaded fear of the highly lethal lactic acidosis is unlikely to be an issue at any level of renal dysfunction…<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

By: Dr. Geoffrey Modest\u00a0 A rather unusual quick-and-dirty\u00a0study 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\u00a0a window of time until 2009, when\u00a0metformin was used in Taiwan\u00a0without restriction in those with renal disease\u00a0(See\u00a0doi.org\/10.1016\/S2213-8587(15)00123-0). The […]<\/p>\n

Read More…<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-763","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/763","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=763"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/763\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=763"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=763"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=763"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}