C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c h
Metformin, Sulfonylureas, or Other
Antidiabetes Drugs and the Risk of Lactic
Acidosis or Hypoglycemia
A nested case-control analysis
mortality was not correlated withplasma lactate concentrations. Interest-ingly, plasma metformin concentrations OBJECTIVE — Lactic acidosis has been associated with use of metformin. Hypoglycemia is a
major concern using sulfonylureas. The aim of this study was to compare the risk of lactic acidosis and hypoglycemia among patients with type 2 diabetes using oral antidiabetes drugs.
with lactic acidosis had, in addition tometformin use, acute or chronic comor- RESEARCH DESIGN AND METHODS — This study is a nested case-control analysis
bidities predisposing to lactic acidosis.
using the U.K.-based General Practice Research Database to identify patients with type 2 diabeteswho used oral antidiabetes drugs. Within the study population, all incident cases of lactic acidosis and hypoglycemia were identified, and hypoglycemia case subjects were matched to up to four control patients based on age, sex, practice, and calendar time.
RESULTS — Among the study population of 50,048 type 2 diabetic subjects, six cases of lactic
acidosis during current use of oral antidiabetes drugs were identified, yielding a crude incidence rate of 3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas. Relevant comorbidities known as risk factors for Ͻ3.3 mmol/l and clinical response to glu- lactic acidosis could be identified in all case subjects. A total of 2,025 case subjects with hypo- glycemia and 7,278 matched control subjects were identified. Use of sulfonylureas was associ-ated with a materially elevated risk of hypoglycemia. The adjusted odds ratio for current use of sulfonylureas was 2.79 (95% CI 2.23–3.50) compared with current metformin use.
hypoglycemia for metformin users variedbetween 0 and 21%. Since metformin CONCLUSIONS — Lactic acidosis during current use of oral antidiabetes drugs was very
does not directly stimulate insulin secre- rare and was associated with concurrent comorbidity. Hypoglycemic episodes were substantially more common among sulfonylurea users than among users of metformin.
than for that of other oral antidiabetesdrugs. However, hypoglycemia in pa- Diabetes Care 31:2086–2091, 2008
tients using metformin may occur in as-sociation with strenuous physical activity Metforminplaysapivotalroleinthe eventhoughtheabsoluteriskappearsto orfasting.
be low, with incidence rates of lactic ac- users of sulfonylureas. Magnitude and se- and increasing glucose disposal in muscle (1,9,10). In an observational study (11), plasma lactate levels Ͼ4 mmol/l) contin- lactic acidosis in 36,893 person-years of ues to be discussed in the literature (2) years); long-acting formulations, renalimpairment, older age, and incidental use ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland; the 2Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Basel, Basel, Swit- reports on the risk of hypoglycemia in pa- zerland; the 3Boston Collaborative Drug Surveillance Program, Boston University School of Medicine,Lexington, Massachusetts; the 4Department of Epidemiology, School of Public Health, Boston University, tients using oral antidiabetes drugs, direct Massachusetts; and the 5Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland.
Corresponding author: Christoph R. Meier, [email protected]
Received 27 June 2008 and accepted 10 August 2008.
Published ahead of print at http://care.diabetesjournals.org on 9 September 2008. DOI: 10.2337/dc08-1171.
varies considerably across previous stud- 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly ies, and a comparison of their results is cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
therefore difficult (7). Additionally, no org/licenses/by-nc-nd/3.0/ for details.
previous study quantified both the risk of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. developing lactic acidosis and hypoglyce- DIABETES CARE, VOLUME 31, NUMBER 11, NOVEMBER 2008 Bodmer and Associates
Table 1—Oral antidiabetes drug use in seven case subjects with lactic acidosis
heart disease, nonexacerbatedchronic obstructive pulmonarydisease (survived) nonexacerbated chronicobstructive pulmonary disease(survived) *Patient no. 4 was classified as a “past metformin user” because the tablet supply of the last metformin prescription prior to the index date was likely to not last upto or beyond the index date (for details, see text).
validated and proven to be of high quality formin in the same study population.
Within this diabetic study population, we identified all patients between age 30 and tional study to compare the risk of lactic 89 years with a first-time diagnosis of lac- tic acidosis or hypoglycemia after the first of metformin, sulfonylureas, or other oral prescription for an oral antidiabetes drug.
The date of this first diagnosis of interest will be referred to as the index date. We RESEARCH DESIGN AND
manually reviewed all case subjects with a METHODS — Data were derived from
jects who received at least one prescrip- classified them into “mild to moderate” if gliclazide, glipizide, glimepiride, glib- GP or “severe” if they had to be hospital- general practitioners (GPs), covering ϳ50 thiazolidinedione (pioglitazone, rosiglita- U.K. for all potential lactic acidosis cases.
zone, or troglitazone), an ␣-glucosidase sentative of the U.K. with regard to age, inhibitor (acarbose), or a prandial glucose fied at random up to four control patients to case subjects with regard to age (same year of birth), sex, general practice, and index date (i.e., the date of the hypogly- not include type 1 diabetic subjects with excluded all patients with Ͻ3 years of re- corded history in the database before the first prescription for an antidiabetes drug, insulin before the index date in case and contains the name of the preparation, in- as well as all patients with alcoholism, a tion, dose, and number of tablets for each class (insulin, sulfonylureas, metformin, of gestational diabetes at any time in their thiazolidinediones, prandial glucose reg- ulators, or ␣-glucosidase inhibitors), the DIABETES CARE, VOLUME 31, NUMBER 11, NOVEMBER 2008 Antidiabetes drugs and hypoglycemia
Table 2—Characteristics and comorbidities of hypoglycemia case (n ؍ 2,025) and control (n ؍ 7,278) subjects
Data are n (%), unless otherwise indicated. *Adjusted for all the variables displayed in the table plus for use of oral antidiabetes drugs, insulin, antihypertensive drugs,lipid-lowering agents, diuretics, inhaled and systemic corticosteroids, anticonvulsants, antidepressants, neuroleptics, benzodiazepines, stomach acid–reducingdrugs, and analgesics.
timing of exposure (current use, if the last ther model, we directly compared the risk prescription for a drug of interest was re- the number of prescriptions before the in- kg/m2); a variety of diagnosed comorbidi- dex date (none, 1– 4, 5–14, or Ն15 pre- ties potentially associated with an altered RESULTS — The study population en-
rates, in person-years, of the outcomes of at least one prescription for at least one interest for current metformin and sulfo- nylurea use, based on the number of users jects of the study population was 60.7 Ϯ perlipidemia, depression, and/or suicidal We identified 14 patients with a recorded code for lactic acidosis. After manual re- dosis, respiratory acidosis, or nonacidotic mic case subjects and control subjects.
tios with 95% CIs. P values are two-sided fonylureas with nonusers of sulfonylureas tient (no. 4) was classified as a past met- and considered statistically significant if Ͻ0.05. In one model, we compared met- other variables displayed above. In a fur- gliclazide user (Table 1). Among six case DIABETES CARE, VOLUME 31, NUMBER 11, NOVEMBER 2008 Bodmer and Associates
Table 3—Hypoglycemia risk by antidiabetes drug class and by duration of use among case (n ؍ 2,025) and control (n ؍ 7,278) subjects
Data are n (%), unless otherwise indicated. *Adjusted for each other, insulin, antihypertensive drugs, lipid-lowering agents, diuretics, inhaled and systemiccorticosteroids, anticonvulsants, antidepressants, neuroleptics, benzodiazepines, stomach acid–reducing drugs, and analgesics. Rx, prescription.
subjects with current use of oral antidia- worsening of known risk factors for lactic 1.22–1.64) and with current use of a sul- jects, but the numbers were too small for acidosis, namely acute heart failure, uro- fonylurea drug 3.73 (3.16 – 4.42), com- sepsis, hypovolaemia, seizure, or acute re- classes and adjusted for each other, cur- (nos. 1 and 5). Based on the number of rent use of insulin, other oral antidiabetes metformin users, prescriptions, and aver- rate of lactic acidosis in metfomin users of ϳ3.3 per 100,000 person-years. The analysis in which we directly compared fonlyureas only, 16 used gliclazide, 5crude incidence rate of lactic acidosis dur- ing current use of sulfonylureas was ϳ4.8 current sulfonylurea users to the risk in current metformin users in the absence of CONCLUSIONS — In our study, 5 of
odds ratio for current use of a sulfonyl- 10,000 subjects) developed lactic acidosis fied 2,025 case subjects with recorded hy- tantly. In only one patient on metformin, no acute deterioration of a medical condi- tion known to be a risk factor for lactic acidosis could be identified. However, in 3.05 (2.21–4.21), respectively, and for this patient suffered from liver cirrhosis, dence rates for current users of metformin 2.71 (2.04 –3.61) and 3.30 (2.18 –5.00), poses to lactic acidosis. One case subject tively (Table 2). The odds ratio of devel- DIABETES CARE, VOLUME 31, NUMBER 11, NOVEMBER 2008 Antidiabetes drugs and hypoglycemia
Table 4—Hypoglycemia risk by current exposure to sulfonylurea drugs, metformin, and/or insulin among case (n ؍ 2,025) and control (n ؍
7,278) subjects
Data are n (%) unless otherwise indicated. *Adjusted for use of other oral antidiabetes drugs, insulin, antihypertensive drugs, lipid-lowering agents, diuretics, inhaledand systemic corticosteroids, anticonvulsants, antidepressants, neuroleptics, benzodiazepines, stomach acid–reducing drugs, and analgesics.
case group was too small for formal anal- for hypoglycemia, as was use of sulfonyl- ureas (adjusted odds ratio 3.73). In con- current users of metformin or of sulfonyl- associated with only a small relative risk elevation, as reported previously (1,9).
ciated with a higher risk of hypoglycemic greater risk of lactic acidosis among met- (7,11). In our study, the odds ratios for all other oral antidiabetes drugs (3,17).
ies (9,11), although reported frequencies for most sulfonylureas (data not shown).
tic acidosis” describes a temporal rela- rence of lactic acidosis. Sometimes, this enough to lead to a GP or hospital visit, could only be proven by a positive rechal- high severity; randomized trials with pre- literature describe patients who had pre- cases of lactic acidosis, among whom five subjects were current users of metformin.
In these five case subjects, chronic dis- nary disease, or liver cirrhosis (2,18). Nu- was inversely related with the risk of de- clinical situation preceded lactic acidosis.
metformin with lactic acidosis in patientswith acute renal failure or severely im- diabetes control in obese patients. As pre- rare and is observed in association with an viously observed (22), sex did not predis- acutely worsening clinical condition. The paired renal function is considered to be a ers in our study. These results differ from formin-associated lactic acidosis. Inter- estingly, similar incidence rates for lactic risk of hypoglycemia in smokers (23).
risk of lactic acidosis associated with met- formin use, clinicians must carefully en- (3,5). These findings suggest that diabe- tes, rather than metformin, may be a lead- substantially higher in the early phase of ing risk factor for lactic acidosis.
before, with elevated risk for incidental 50,048 (4.1%) patients experienced a first Acknowledgments — This study was funded
with oral antidiabetes drugs. As expected, use of insulin was an important risk factor time, better patient education to avoid hy- DIABETES CARE, VOLUME 31, NUMBER 11, NOVEMBER 2008 Bodmer and Associates
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