Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease

Lessons Learned from Taiwanese Data

Connie M. Rhee, Csaba Kovesdy, Kamyar Kalantar-Zadeh

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.

Original languageEnglish (US)
Pages (from-to)147-153
Number of pages7
JournalNephron
Volume135
Issue number2
DOIs
StatePublished - Jan 1 2017

Fingerprint

Metformin
Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Lactic Acidosis
Biguanides
Kidney
United States Food and Drug Administration
Buformin
Phenformin
Mortality
Endocrinology
Diabetic Nephropathies
Glomerular Filtration Rate
Taiwan
Hypoglycemia
Action Potentials
Observational Studies
Cardiovascular Diseases
History
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Physiology
  • Nephrology
  • Urology
  • Physiology (medical)

Cite this

Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease : Lessons Learned from Taiwanese Data. / Rhee, Connie M.; Kovesdy, Csaba; Kalantar-Zadeh, Kamyar.

In: Nephron, Vol. 135, No. 2, 01.01.2017, p. 147-153.

Research output: Contribution to journalArticle

Rhee, Connie M. ; Kovesdy, Csaba ; Kalantar-Zadeh, Kamyar. / Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease : Lessons Learned from Taiwanese Data. In: Nephron. 2017 ; Vol. 135, No. 2. pp. 147-153.
@article{20461d04e6494a0bba98ab83126cc148,
title = "Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease: Lessons Learned from Taiwanese Data",
abstract = "Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35{\%} higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.",
author = "Rhee, {Connie M.} and Csaba Kovesdy and Kamyar Kalantar-Zadeh",
year = "2017",
month = "1",
day = "1",
doi = "10.1159/000450862",
language = "English (US)",
volume = "135",
pages = "147--153",
journal = "Nephron - Experimental Nephrology",
issn = "0028-2766",
publisher = "S. Karger AG",
number = "2",

}

TY - JOUR

T1 - Risks of Metformin in Type 2 Diabetes and Chronic Kidney Disease

T2 - Lessons Learned from Taiwanese Data

AU - Rhee, Connie M.

AU - Kovesdy, Csaba

AU - Kalantar-Zadeh, Kamyar

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.

AB - Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.

UR - http://www.scopus.com/inward/record.url?scp=84991824414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991824414&partnerID=8YFLogxK

U2 - 10.1159/000450862

DO - 10.1159/000450862

M3 - Article

VL - 135

SP - 147

EP - 153

JO - Nephron - Experimental Nephrology

JF - Nephron - Experimental Nephrology

SN - 0028-2766

IS - 2

ER -