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Is the Combination of Sulfonylureas andMetformin Associated With an IncreasedRisk of Cardiovascular Disease or All-

Cause Mortality?A meta-analysis of observational studiesAJAY D. RAO, MD1

NITESH KUHADIYA, MBBS2KRISTI REYNOLDS, PHD, MPH2,3

VIVIAN A. FONSECA, MD1

OBJECTIVE Observational studies assessing the association of combination therapy ofmetformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes haveshown conflicting results. We therefore evaluated the effects of combination therapy of sulfo-nylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD)among people with type 2 diabetes.

RESEARCH DESIGN AND METHODS A MEDLINE search (January 1966July2007) was conducted to identify observational studies that examined the association betweencombination therapy of sulfonylureas andmetformin on risk of CVDor all-causemortality. From299relevantreports, 9 were included in themeta-analysis. In these studies, combination therapyof metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, andadjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding vari-ance or equivalent was reported.

RESULTS The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetesprescribed combination therapy of sulfonylureas and metformin were 1.19 (0.881.62) forall-cause mortality, 1.29 (0.732.27) for CVD mortality, and 1.43 (1.101.85) for a compositeend point of CVD hospitalizations or mortality (fatal or nonfatal events).

CONCLUSIONS The combination therapy of metformin and sulfonylurea significantly

increased the RR of the composite end point of cardiovascular hospitalization or mortality (fataland nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy,or sulfonylurea monotherapy); however, there were no significant effects of this combinationtherapy on either CVD mortality or all-cause mortality alone.

Diabetes Care 31:16721678, 2008

Type 2 diabetes is associated with in-creased risk of all-cause mortalityand cardiovascular disease (CVD).

However, clinical trials to date have notdemonstrated that achieving normal glu-cose levels can reduce the risk for cardio-vascular events.

In the UK Prospective Diabetes Study(UKPDS), intensive blood glucose reduc-

tion was achieved using metformin ther-apy in diet-treated overweight patients,resulting in a decreased risk of myocardialinfarction and all-cause mortality. How-ever, when a combination of metforminand sulfonylurea was prescribed in thesame trial for glycemic control, there was

a significant increased risk of diabetes-related death and all-cause mortality

rather than a beneficial effect, a findingattributed by theinvestigators to be duetochance (1). In the UKPDS, sulfonylureasthemselves were not associated with therisk of diabetes-related death or myocar-dial infarction (2), but in previous studiessuch as the University Group DiabetesProgram (UGDP) some increased risk wasseen (3), and a warning about increased

risk of CVD is included in the FederalDrug Administrationapproved label forthis class of drugs.

A recent systematic review of clinicaltrials of diabetes therapies noted that dataon long-term outcomes were not availablein most clinical trials (4). Observationalstudies investigating the association be-tween combination therapy of metforminand sulfonylureas and risk of CVD andmortality have reported conflicting re-sults. Some studies have reported that theuse of this combination therapy increasesthe risk of all-cause and CVD mortality(5), while others have reported no associ-ation (6,7) or a decreased risk of mortalityfrom all causes and CVD (8). Since theseare likely the most commonly prescribedmedications for type 2 diabetes, the pos-sible increase in risk of all-cause mortalityand cardiovascular events is troubling (1).

Given these inconsistencies in the liter-ature and the lack of clinical trials assess-ing the long-term effects of combinationtherapy of sulfonylureas and metformin,we conducted a meta-analysis of observa-tional studies to examine the association

between combination therapy of sulfonyl-ureas and metformin and risk of CVD andall-cause mortality.

RESEARCH DESIGN AND

METHODS

A literature search of the MEDLINE data-base (from January 1966 through July2007) was conducted using the medicalsubject headings diabetes mellitus, type2; drug therapy, combination; drugcombinations; sulfonylurea com-pounds; acetohexamide; chlorprop-

From the 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana; the2Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine,New Orleans, Louisiana; and the 3Southern California Kaiser Permanente Medical Group, Pasadena,California.

Corresponding author: Vivian Fonseca, [email protected] 7 February 2008 and accepted 29 April 2008.Published ahead of print at http://care.diabetesjournals.org on 5 May 2008. DOI: 10.2337/dc08-0167. 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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amide; tolbutamide; tolazamide;glyburide; glipizide; biguanides;a n d m et f or m in a n d k e yw o rdglimepiride. The search was restrictedto include studies conducted only in hu-man subjects. Studies were also identifiedthrough a search of references cited in theoriginal published studies and relevant

review articles.The contents of 299 abstracts or full-

text manuscripts identified during the lit-erature search were reviewed inde-pendently by two investigators in dupli-cate to determine whether they met thecriteria for inclusion. When there werediscrepancies between investigators forinclusion or exclusion, a third investiga-tor conducted additional evaluation of thestudy and the discrepancies were resolvedin conference. The following inclusioncriteria were used for study selection: 1)

observational study that investigated therelationship between combination ther-apy with metformin (biguanides) plussulfonylureas and risk of CVD and/ormortality,2) adjusted relative risk (RR) orequivalent (i.e., hazard ratio, odds ratio)and corresponding variance or equivalentreported, and 3) diagnosis of type 2 dia-betes established using the standard crite-ria for the time of the study.

All data were independently ab-stracted in duplicate. Differences in dataextraction were resolved in conferenceand by referencing the original publica-

tion. No authors were contacted to re-quest additional information. A standar-dized abstraction form was used to recordthe following information: study title, firstauthors name, year of publication, studycountry, study years, name of cohort,study design (prospective or retrospectivecohort study or case-control study), du-ration of follow-up, characteristics of thestudy population (sample size, distribu-tion of age, race, and sex, mean diabetesduration, mean A1C), type of referencegroup, and confounding factors con-

trolled for. The RR of cardiovascular mor-tality/morbidity and/or all-cause or cause-spe c ific mort a l i t y a ssoc ia t e d wit hcombination therapy and their corre-sponding CIs or SEs were abstracted. Thenumber of events for all-cause mortalityand cardiovascular mortality/morbiditywere abstracted.

Statistical analysisRRs were used as the measure of associa-tion between combination therapy ofmetformin and sulfonylurea and CVDand all-cause mortality. The RRs of each

study were weighted by the inverse oftheir variance. To stabilize the variancesand to normalize the distributions, theRRs and corresponding SEs from each ofthe individual studies were transformedto their natural logarithms. When neces-sary, SEs were derived from the CIs pro-vided in each original study.

The primary data fortime to event anal-yses were not available for the combinedcohort. Therefore, for the overall analysis,RR estimates and 95% CIs for all-causemortality and CVD associated with combi-nation therapy were pooled irrespective ofthe reference group used. Subgroup analy-ses were conducted by reference group(diet, sulfonylurea monotherapy, or met-formin monotherapy).

Both fixed-effects and DerSimonianand Laird random-effects models wereused to calculate the pooled RR of CVD

and all-cause mortality associated withcombination therapy (9). Although bothmodels yielded similar findings, resultsfrom the random-effects model are pre-sented herein owing to significant heter-ogeneity among the studies.

CVD was defined by each of the indi-vidual studies. We used cardiovascularmortality and all-cause mortality, as wellas a composite end point of CVD hospi-talizations (the first cardiovascular eventeither fatal or nonfatal event), or mortalityas our study outcomes. One study re-ported RRs separately for coronary heart

disease and stroke (10). For this study, wefirst weighted both of the RRs by the in-verse of their variance and then pooledthe RRs by using a fixed-effects model toobtain an overall estimate for the study.

Beggs rank correlation test was usedto examine the association between effectestimates and their variances, and Eggerslinear regression test, which regresses Zstatistics on the reciprocal of the SE foreach study, was used to detectpublicationbias (11,12). Additionally, eachstudy wasomitted one at a time to evaluate the in-

fluence of that study on the pooled esti-mate. All analyses were performed usingSTATA version 8.2 (STATA, College Sta-tion, TX).

RESULTS Online appendix Figure A1 (available at http://dx.doi.org/10.2337/dc08-0167) depicts the flow ofstudies in the meta-analysis. Among 25studies that met the inclusion criteria, 16were excluded from the meta-analysis.Eleven studies did not report CVD ormortality as an outcome, three studieswere duplicated, and two involved multi-

ple drug combinations. Two studies ex-a m i n e d t h e a s s o c i a t i o n b e t w e e ncombination therapy of metformin andsulfonylurea in different groups of indi-viduals according to which drug wasgiven first, and these groups were treatedas separate studies in the meta-analysis.

The characteristics of the study par-

ticipants and the design of the nine obser-vational studies included in the meta-analysis are presented in Table 1 (58,10,1316). Six of the studies wereretrospective cohort studies, two wereprospective cohort studies, and one was anested case-control study. Of the ninestudies, one was conducted in the U.S.,two in Canada, one in Israel, and five inEuropean countries. The number of par-ticipants in these studies ranged from 910in the study by Olsson et al. (10) to39,721 in the study by Kahler et al. (7).

Mean age ranged from 58.9 to 71.3 years.The mean follow-up time ranged from 2.1to 7.7 years. Among the nine studies,seven reported all-cause mortality, fourreported cardiovascular mortality, andthree reported cardiovascular hospitaliza-tions. Of the 101,733 participants in-c l u d e d i n t h e s e s t u d i e s , 2 5 , 0 9 1participants received a combination ther-apy of metformin and sulfonylurea.Bruno et al. (13) and Koro et al. (16) didnot specify the number of participants re-ceiving combination therapy.

Figure 1 depicts the results from the

random-effects models pooling the ad-justed RRs for all-cause mortality, CVDmortality, and CVD hospitalizations ormortality, respectively, associated withcombination therapy of metformin andsulfonylurea. In addition, it shows thenumber of events associated with combi-nation therapy in comparison with thecontrol group for all-cause mortality,CVD mortality, and CVD hospitalizationsor mortality. Pooled RR estimates werenot statistically significant for all-causemortality or CVD mortality, while the use

of combination therapy was significantlyassociated with an increased risk of car-diovascular hospitalizations or mortality.

In sensitivity analyses, significant het-erogeneity was present for studies report-ing all-cause mortality (P 0.001).However, exclusion of any study did notchange the pooled estimate. For studiesreporting CVD mortality, significant het-erogeneity was present (P 0.001), andexclusion of the study by Johnson et al.(15) led to a significant increased risk ofCVD mortality associated with combina-tion therapy of metformin and sulfonyl-

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ureas (RR 1.63 [95% CI 1.112.39]).Significant heterogeneity was also presentfor studies that reported cardiovascular

hospitalizations or mortality (P 0.001),and the exclusion of any study did notalter the pooled estimate. There was no

evidence of publication bias by rank cor-relation or regression testing (P0.10 forall). In the study by Evans et al. (5), par-

Figure 1RR estimates and 95% CIs for all-cause mortality (A), CVD mortality (B), and composite end point of CVD hospitalizations or CVDmortality (C) associated with combination therapy of metformin and sulfonylurea by study and pooled along with proportion of events for eachoutcome.

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ticipants of the reference group were usedmore than once in computing the pooledestimate. Analyses were repeated omit-

ting various combinations of this study,and no substantive changes in resultswere noted. Furthermore, we conducteda sensitivity analysis in which those stud-ies that did not adjust for duration of di-abetes or previous CVD were excluded(6,8,13,14,17). This information is in-cluded in Table 2.

Subgroup analysisRR estimates of all-cause mortality, CVDmortality, and CVD hospitalizations ormortality associated with combinationtherapy of metformin and sulfonylurea

for subgroups defined according to thecomparator treatment are presented inonline appendix Table A1. The estimatedRRs were1.0 in all subgroups exceptforthe association between all-cause mortal-ity and combination therapy comparedwith sulfonylurea.

Compared with diet therapy, combi-nation therapy significantly increased theRR of all-cause mortality, and combina-tion therapy compared with metforminmonotherapy significantly increased theRR of CVD hospitalizations or mortality.

CONCLUSIONS In the currentmeta-analysis, combination therapy ofmetformin and sulfonylurea significantlyincreased the RR of cardiovascular hospi-talization or mortality (fatal and nonfatalevents) irrespective of the reference group(diet therapy, metformin monotherapy,or sulfonylurea monotherapy) used.However, there were no statistically sig-nificant effects of combination therapy ofsulfonylurea and metformin on CVDmortality or all-cause mortality. These re-sults may help clarify the conflicting find-

ings of several large observational studiesthat examined the effect of combinationtherapy with metformin and sulfonyl-

ureas on the risk of CVD events amongpatients with type 2 diabetes, while theassociation of this combination with all-cause and cardiovascular mortality re-mains obscure.

Due to the progressive nature of type2 diabetes, many patients are put on com-binations of oral antihyperglycemicagents in order to meet glycemic goals.For instance, in the recommended algo-rithm, the combination of sulfonylureaand metformin is the second step in themanagement of patients with type 2 dia-betes (18). It is likely that patients on

combination therapy are likely to have ei-ther a more rapidly progressive form ofthe disease or a longer duration of diabe-tes, perhaps both. The reduction of bloodglucose in high-risk obese patients withtype 2 diabetes on metformin therapyalone in the UKPDS was associated with adecrease in adverse cardiovascular events(2). However, when a combination ofmetformin and sulfonylurea was pre-scribed, there was an increased risk,which is in contrast with some of the ob-servational studies. This discrepancy may

be due to differences in the populationbetween these studies.It may not only be important to re-

duce blood glucose, but also to considerthe choice of agent used to make such areduction. A recent meta-analysis has cre-ated much controversy about some of thenewer medications used to reduce bloodglucose by suggesting that rosiglitazonemay be associated with an increased riskof myocardial infarction and possiblydeath (19). It is noteworthy that much ofthis increased risk with rosiglitazone wasseen in combination therapies (20). How-

ever, the interim analysis of the Rosiglita-zone Evaluated for Cardiac Outcomesand Regulation of Glycaemia in Diabetes

(RECORD) trial has shown inconclusiveresults (21). Our meta-analysis is impor-tant in the context of that study, as thecombination of metformin and sulfonyl-urea is the comparator group to the ros-iglitazone combinations.

Several observational studies have ex-amined the association between combina-tion therapy and risk of CVD and all-cause mortality. Evans et al. (5) carriedout an analysis of a database of 400,000people in Scotland and identified 5,730patients who were prescribed oral hypo-glycemia agents between 1994 and 2001.

Patients treated with sulfonylureas aloneor in combination with metformin ap-peared to have an increased RR of adversecardiovascular outcomes compared withthose treated with metformin alone. Itwas particularly disturbing to note thatthe combination of sulfonylurea withmetformin seemed to abrogate the poten-tial benefit of metformin on CVD out-come, as seen in the UKPDS (2). A studyby Fisman et al. (14) was carried outamong 2,275 patients with type 2 diabe-tes and coronary artery disease, as part of

the Bezafibrate Infarction PreventionStudy. The patients were followed forover 7 years, and the authors demon-strated that cardiovascular events andmortality were the same whether gly-buride, a sulfonylurea, or metformin wasused for treatment. However, there was asignificant time-related increased mortal-ity when the combination therapy wasused. Olsson et al.(10) analyzed mortalityin a small cohort of patients taking sulfo-nylureas alone or in combination withmetformin and demonstrated a highercardiovascular mortality in patients tak-

Table 2Pooled RR (95% CI) of all-cause mortality, CVD mortality, and composite end point of CVD hospitalizations or CVD mortality

according to different exclusion criteria

All-cause mortality CVD mortality

CVD hospitalizations or CVD

mortality

No. of studies RR (95% CI) No. of studies RR (95% CI) No. of studies RR (95% CI)

All studies 10 1.19 (0.881.62) 6 1.29 (0.732.27) 7 1.43 (1.101.85)

Studies that controlled for importantconfounding factors*

6 1.36 (0.932.04) 5 1.63 (1.112.39) 6 1.55 (1.281.87)

Studies that controlled for importantconfounding factors

4 1.34 (0.732.47) 3 1.72 (0.933.20) 4 1.50 (1.251.78)

*Studies that did not control for duration of diabetes excluded. For all-cause mortality, excluding the studies by Gulliford (12), Johnson (14), and Fisman (21). ForCVDmortalityand thecompositeend point of CVDhospitalizations or CVDmortality, excludingthe study by Johnson (23). Studies that didnot controlof durationof diabetes or previous CVD excluded.For all-causemortality, excluding thestudies by Gulliford (12), Johnson (14), Olsson (16), Bruno (20), and Fisman (21). ForCVD mortality and the composite end point of CVD hospitalizations or CVD mortality, excluding the studies by Olsson (16), Johnson (23), and Bruno (20).

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ing the combination than those takingsulfonylurea alone.

In our meta-analysis, exclusion of thestudy by Johnson et al. (15) led to a sig-nificant increased risk of CVD mortalityassociated with combination therapy ofmetformin and sulfonylurea. The studyby Johnson et al. (15) reported a reduced

risk of CVD mortality associated withcombination therapy of metformin andsulfonylurea when compared with sulfo-nylurea monotherapy, but the study hadmany limitations. A large number of pa-tients were excluded because of short-term insulin use. Patients prescribed thecombination therapy were 2.3 yearsyounger than those prescribed metforminmonotherapy and 5.8 years younger thanthose prescribed sulfonylurea mono-therapy, a discrepancy that is difficult toexplain. Patients with more severe disease

or intercurrent illnesses including hospi-talization for cardiovascular events mayhave required insulin use and were there-fore excluded from the study.

In our analysis, we found a relativelygreater association with fatal and nonfatalCVD events than in fatal events alone,suggesting that the incidence of CVDevents may be increased with combina-tion therapy, but there may have been alower case-fatality rate. This contrastswith the recent data from the Action toControl Cardiovascular Risk in Diabetes(ACCORD) study (22) in which intensive

treatment with multiple combinations ofdiabetes therapies was associated with de-creased nonfatal CVD events but in-creased fatal events. It is impossible todetermine the reason for this discrepancy,although it is possible that patients in theobservational studies included in ouranalysis did not have a level of glycemia aslow as that attempted in the ACCORDtrial.

Several hypothetical considerationsmay explain the increased risk associatedwith such a combination. First, it is pos-

sible that patients needing such a combi-nation have a more aggressive form of thedisease and therefore more rapid deterio-ration in glycemic control over time. Sec-ond, sulfonylureas are associated withweight gain, whereas metformin is associ-ated with weight loss, as well as some im-provement in a variety of cardiovascularrisk factors. Any weight gain induced bythe combination may negate some ofthese beneficial effects and increase risks.

Other possible explanations includethe known propensity of sulfonylureas tocause hypoglycemia. When used in com-

bination with a drug like metformin,which may decrease hepatic glucose pro-duction, recovery from hypoglycemiamay be impaired. Hypoglycemia may in-crease the risk of cardiovascular abnor-malities, including ischemia and apropensity to cause arrhythmias (23,24).There is also considerable controversy

about the impact of sulfonylureas on isch-emic preconditioning (25), but nothing isknown about the effects of combinationtherapy.

Although a meta-analysis is notthe bestway to test the efficacy and safety of such acombination of treatments, it is highly un-likely that a large-scale clinical trial to testthis hypothesis will be carriedout.Thus,wemust rely on data from observational stud-ies to arrive at conclusionsand make appro-priate recommendations. It is also unclearto what extent certain biases and method-

ological limitations, such as residual con-founding, might exist in the studiesincluded in this meta-analysis, since themajority of these studies were retrospectivedatabase analyses. In addition, thereferencegroup varied among the studies. For in-stance, some studies used diet as the refer-ence group, while othersusedsulfonylureasor metformin monotherapy as the referencegroup. Finally, we observed substantialquantitative heterogeneity across the stud-ies, but the small number of studies limitedourabilityto explorepossible sourcesof thisvariability. Additionally, findings from the

subgroup analyses should be interpretedcautiously, as the number of studies exam-ined was small.

Overall, our results provide a mix ofreassurance and concern to prescribers ofdiabetes medications who use combina-tion therapies to achieve good glycemiccontrol. Since sulfonylurea and met-formin are likely the most widely usedcombination, it is possible that such useleads to early improvement in glycemiccontrol, which, in itself, may lead to bettermicrovascular outcomes. Although diet

alone is associated with lower mortalityrisk, in the UKPDS, diet alone was asso-ciated with increased microvascularcomplications (2). Therefore, one mustbalance the risks and benefits of medica-tions used while making treatmentdecisions.

We emphasize that this meta-analysishas limitations and serves to examinepublished data to generate hypotheses.Such analysis should not be used as a ba-sis for clinical decisions. We hope that ouranalysis will prompt the planning of fu-ture clinical trials to determine not only

the value of good glycemic control, butalso the safest and most cost effective wayto achieve glycemic goals. Clearly, weneed further studies to assess the associa-tion of combination therapy of metforminand sulfonylurea with all-cause and/orcardiovascular mortality as well as to un-derstand the potential mechanism of its

deleterious effects.

Acknowledgments This study was notfunded. K.R. was partially supported by grantP20-RR17659 from the National Center forResearch Resources (National Institutes ofHealth [NIH]). Diabetes research and educa-tion at Tulane University Health Sciences Cen-ter is supported in part by the Tullis-TulaneAlumni Chair in Diabetes and the Earl Madi-son Ellis fund. V.F. is supported in part by theAmerican Diabetes Association (ADA) and theNIH (ACCORD and TINSAL T2D trials). V.F.has also received research support (to Tulane)

from Glaxo Smith Kline, Novartis, Takeda, As-tra Zeneca, Pfizer, sanofi-aventis, Eli Lilly,NIH, and ADA; and honoraria from GlaxoSmith Kline, Novartis, Takeda, Pfizer, sanofi-aventis, and Eli Lilly.

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