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Published in: Journal of General Internal Medicine 2/2018

01-02-2018

Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease

Authors: Zachary A. Marcum, PharmD, PhD, Christopher W. Forsberg, MS, Kathryn P. Moore, PhD, Ian H. de Boer, MD, MS, Nicholas L. Smith, PhD, Edward J. Boyko, MD, MPH, James S. Floyd, MD, MS

Published in: Journal of General Internal Medicine | Issue 2/2018

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Abstract

Background

For patients with type 2 diabetes and chronic kidney disease (CKD), high-quality evidence about the relative benefits and harms of oral glucose-lowering drugs is limited.

Objective

To evaluate whether mortality risk differs after the initiation of monotherapy with either metformin or a sulfonylurea in Veterans with type 2 diabetes and CKD.

Design

Observational, national cohort study in the Veterans Health Administration (VHA).

Participants

Veterans who received care from the VHA for at least 1 year prior to initiating monotherapy treatment for type 2 diabetes with either metformin or a sulfonylurea between 2004 and 2009.

Main Measures

Metformin and sulfonylurea use was assessed from VHA electronic pharmacy records. The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR). The outcome of death from January 1, 2004, through December 31, 2009, was assessed from VHA Vital Status files.

Key Results

Among 175,296 new users of metformin or a sulfonylurea monotherapy, 5121 deaths were observed. In primary analyses adjusted for all measured potential confounding factors, metformin monotherapy was associated with a lower mortality hazard ratio (HR) compared with sulfonylurea monotherapy across all ranges of eGFR evaluated (HR ranging from 0.59 to 0.80). A secondary analysis of mortality risk differences favored metformin across all eGFR ranges; the greatest risk difference was observed in the eGFR category 30–44 mL/min/1.73m2 (12.1 fewer deaths/1000 person-years, 95% CI 5.2–19.0).

Conclusions

Initiation of metformin versus a sulfonylurea among individuals with type 2 diabetes and CKD was associated with a substantial reduction in mortality, in terms of both relative and absolute risk reduction. The largest absolute risk reduction was observed among individuals with moderately–severely reduced eGFR (30–44 mL/min/1.73m2).
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Literature
1.
go back to reference American Diabetes Association. Standards of medical care in diabetes—2017: Summary of revisions. Diabetes Care. 2017;40:S4–5.CrossRef American Diabetes Association. Standards of medical care in diabetes—2017: Summary of revisions. Diabetes Care. 2017;40:S4–5.CrossRef
2.
go back to reference Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312:2668–75.CrossRefPubMedPubMedCentral Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312:2668–75.CrossRefPubMedPubMedCentral
3.
go back to reference Flory JH, Hennessy S. Metformin use reduction in mild to moderate renal impairment: possible inappropriate curbing of use based on Food and Drug Administration contraindications. JAMA Intern Med. 2015;175:458–9.CrossRefPubMed Flory JH, Hennessy S. Metformin use reduction in mild to moderate renal impairment: possible inappropriate curbing of use based on Food and Drug Administration contraindications. JAMA Intern Med. 2015;175:458–9.CrossRefPubMed
5.
6.
go back to reference Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4:53–8.CrossRefPubMed Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4:53–8.CrossRefPubMed
7.
8.
go back to reference Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111:583–90.CrossRefPubMed Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111:583–90.CrossRefPubMed
9.
go back to reference Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Association between first-line monotherapy with sulfonylurea versus metformin and risk of all-cause mortality and cardiovascular events: a retrospective, observational study. Diabetes Obes Metab. 2014;16:957–62.CrossRefPubMed Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Association between first-line monotherapy with sulfonylurea versus metformin and risk of all-cause mortality and cardiovascular events: a retrospective, observational study. Diabetes Obes Metab. 2014;16:957–62.CrossRefPubMed
10.
go back to reference Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9.CrossRefPubMed Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9.CrossRefPubMed
11.
go back to reference Weir MA, Gomes T, Mamdani M, et al. Impaired renal function modifies the risk of severe hypoglycemia among users of insulin but not glyburide: a population-based nested case-control study. Nephrol Dial Transplant. 2011;26:1888–94.CrossRefPubMed Weir MA, Gomes T, Mamdani M, et al. Impaired renal function modifies the risk of severe hypoglycemia among users of insulin but not glyburide: a population-based nested case-control study. Nephrol Dial Transplant. 2011;26:1888–94.CrossRefPubMed
12.
go back to reference 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;166:191–200.CrossRefPubMed 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;166:191–200.CrossRefPubMed
13.
go back to reference Hampp C, Borders-Hemphill V, Money DG, Wysowski DK. Use of antidiabetic drugs in the U.S., 2003-2012. Diabetes Care. 2014;37:1367–74.CrossRefPubMed Hampp C, Borders-Hemphill V, Money DG, Wysowski DK. Use of antidiabetic drugs in the U.S., 2003-2012. Diabetes Care. 2014;37:1367–74.CrossRefPubMed
14.
go back to reference American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26:S33–50.CrossRef American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003;26:S33–50.CrossRef
15.
go back to reference Floyd JS, Blondon M, Moore KP, Boyko EJ, Smith NL. Validation of methods for assessing cardiovascular disease using electronic health data in a cohort of Veterans with diabetes. Pharmacoepidemiol Drug Saf. 2016;25:467–71.CrossRefPubMed Floyd JS, Blondon M, Moore KP, Boyko EJ, Smith NL. Validation of methods for assessing cardiovascular disease using electronic health data in a cohort of Veterans with diabetes. Pharmacoepidemiol Drug Saf. 2016;25:467–71.CrossRefPubMed
16.
go back to reference Wheeler S, Moore K, Forsberg CW, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia. 2013;56:1934–43.CrossRefPubMed Wheeler S, Moore K, Forsberg CW, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia. 2013;56:1934–43.CrossRefPubMed
19.
go back to reference Cowper DC, Kubal JD, Maynard C, Hynes DM. A primer and comparative review of major US mortality databases. Ann Epidemiol. 2002;12:462–8.CrossRefPubMed Cowper DC, Kubal JD, Maynard C, Hynes DM. A primer and comparative review of major US mortality databases. Ann Epidemiol. 2002;12:462–8.CrossRefPubMed
20.
go back to reference Schafer JL. Analysis of Incomplete Multivariate Data. Boca Raton, FL: Chapman & Hall/CRC; 1997.CrossRef Schafer JL. Analysis of Incomplete Multivariate Data. Boca Raton, FL: Chapman & Hall/CRC; 1997.CrossRef
21.
go back to reference Danaei G, Rodriguez LA, Cantero OF, Logan R, Hernán MA. Observational data for comparative effectiveness research: an emulation of randomised trials of statins and primary prevention of coronary heart disease. Stat Methods Med Res. 2013;22:70–96.CrossRefPubMed Danaei G, Rodriguez LA, Cantero OF, Logan R, Hernán MA. Observational data for comparative effectiveness research: an emulation of randomised trials of statins and primary prevention of coronary heart disease. Stat Methods Med Res. 2013;22:70–96.CrossRefPubMed
22.
go back to reference Bansal N, Katz R, Robinson-Cohen C, et al. Absolute rates of heart failure, coronary heart disease, and stroke in chronic kidney disease: an analysis of 3 community-based cohort studies. JAMA Cardiol. 2017;2:314–8.CrossRefPubMed Bansal N, Katz R, Robinson-Cohen C, et al. Absolute rates of heart failure, coronary heart disease, and stroke in chronic kidney disease: an analysis of 3 community-based cohort studies. JAMA Cardiol. 2017;2:314–8.CrossRefPubMed
23.
go back to reference Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and disease of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017;40:31–44.CrossRefPubMed Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and disease of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017;40:31–44.CrossRefPubMed
24.
go back to reference Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001;58:1161–7.CrossRefPubMed Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001;58:1161–7.CrossRefPubMed
25.
go back to reference Flory JH, Ukena JK, Floyd JS. Novel anti-glycemic drugs and reduction of cardiovascular risk in diabetes: expectations realized, promises unmet. Curr Atheroscler Rep. 2016;18:79.CrossRefPubMedPubMedCentral Flory JH, Ukena JK, Floyd JS. Novel anti-glycemic drugs and reduction of cardiovascular risk in diabetes: expectations realized, promises unmet. Curr Atheroscler Rep. 2016;18:79.CrossRefPubMedPubMedCentral
26.
go back to reference Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39:738–42.CrossRefPubMed Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39:738–42.CrossRefPubMed
27.
go back to reference Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther. 2009;31:2608–17.CrossRefPubMed Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther. 2009;31:2608–17.CrossRefPubMed
Metadata
Title
Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease
Authors
Zachary A. Marcum, PharmD, PhD
Christopher W. Forsberg, MS
Kathryn P. Moore, PhD
Ian H. de Boer, MD, MS
Nicholas L. Smith, PhD
Edward J. Boyko, MD, MPH
James S. Floyd, MD, MS
Publication date
01-02-2018
Publisher
Springer US
Published in
Journal of General Internal Medicine / Issue 2/2018
Print ISSN: 0884-8734
Electronic ISSN: 1525-1497
DOI
https://doi.org/10.1007/s11606-017-4219-3

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