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Original Article

All-Cause and Cardiovascular Mortality following Treatment

with Metformin or Glyburide in Patients with Type 2
Diabetes Mellitus
Mohammad Reza Raee MD1, Arash Aghajani Nargesi MD MPH1, Behnam Heidari MD MPH1, Mohammad Ali Mansournia MD PHD2,
Mehrdad Larry MD MPH1, Soghra Rabizadeh MD1, Mitra Zarifkar MD1, Alireza Esteghamati MD1, Manouchehr Nakhjavani MDƔ

Abstract
Background: %RWK PHWIRUPLQ and VXOIRQ\OXUHD68GUXJV are DPRQJ WKH PRVW ZLGHO\XVHG antiK\SHUJO\FHPLF PHGLFDWLRQV in SDWLHQWV
ZLWK W\SH  GLDEHWHV PHOOLWXV7'03UHYLRXV VWXGLHV KDYH VKRZQ WKDW WUHDWPHQW ZLWK 68V PLJKW EH DVVRFLDWHG ZLWK GHFUHDVHG VXUYLYDO
FRPSDUHG ZLWK PHWIRUPLQ7KLV VWXG\ DLPHG to HYDOXDWH allFDXVH and FDUGLRYDVFXODU PRUWDOLW\ rates EHWZHHQ JO\EXULGH and PHWIRUPLQ in
SDWLHQWV GLDJQRVHG ZLWK 7'0
Methods: 7KLV ZDV a FRKRUW VWXG\ on  SDWLHQWV ZLWK 7'0 XQGHUJRLQJ PRQRWKHUDS\ ZLWK JO\EXULGH and  ZLWK PHWIRUPLQ'DWD
ZHUH JDWKHUHG IURP  to $OOFDXVH and FDUGLRYDVFXODU PRUWDOLW\ ZHUH endSRLQWV
Results: 'XULQJ WKH IROORZXS GHDWKV ZHUH LGHQWL¿HGRI ZKLFK  ZHUH FDUGLRYDVFXODU in QDWXUH7KH JURXS ZLWK JO\EXULGH PRQRWKHUDS\
KDG JUHDWHU allFDXVH PRUWDOLW\in JO\EXULGH vs7in PHWIRUPLQP and FDUGLRYDVFXODU PRUWDOLW\in
JO\EXULGH vs. in PHWIRUPLQ; P 0HWIRUPLQ ZDV PRUH SURWHFWLYH WKDQ JO\EXULGH IRU ERWK allFDXVH+5 [±]
PYDOXH and FDUGLRYDVFXODU PRUWDOLW\+5 [±@PYDOXH DIWHU PXOWLSOH DGMXVWPHQWV IRU FDUGLRYDVFXODU ULVN
IDFWRUV$PRQJ DGYHUVH FDUGLRYDVFXODU HYHQWVnonIDWDO 0, ZDV KLJKHU in JO\EXULGH FRPSDUHG to PHWIRUPLQ PRQRWKHUDS\ JURXS vs.
; PYDOXH EXW not FRURQDU\ DUWHU\ E\SDVV JUDIWLQJPYDOXH VWHQWLQJPYDOXH need IRU DQJLRJUDSK\PYDOXH 
&&8 DGPLVVLRQPYDOXH or FHUHEURYDVFXODU DFFLGHQWPYDOXH 
Conclusion: 7UHDWPHQW ZLWK JO\EXULGH is DVVRFLDWHG ZLWK LQFUHDVHG allFDXVH and FDUGLRYDVFXODU PRUWDOLW\ in SDWLHQWV ZLWK 7'0

Keywords: &DUGLRYDVFXODU diseasesGLDEHWHV PHOOLWXVJO\EXULGHPHWIRUPLQPRUWDOLW\

Cite this article as: Raee MR, Nargesi AA, Heidari B, Mansournia MA, Larry M, Rabizadeh S, Zarifkar M, Esteghamati A, Nakhjavani M. All-cause and
cardiovascular mortality following treatment with metformin or glyburide in patients with type 2 diabetes mellitus. Arch Iran Med. 2017; 141 – 146.

Introduction infarction in patients with diabetes mellitus is equal to non-

diabetic subjects with previous history of myocardial infarction.5
ype 2 diabetes mellitus is one of the most common chronic Therefore, prevention of adverse cardiovascular outcomes is at the
T diseases with a worldwide prevalence of about 8.3%
among adults.1 During the past decades, its prevalence has
center of strategies to reduce the burden of this disease. Although
intensive control of plasma glucose is associated with decreased
been on the rise and is estimated to increase to 9.9% until the year microvascular complications, the EHQH¿W of intensive control of
2030.1 Diabetes and elevated plasma glucose are directly plasma glucose level (with insulin or sulfonylureas) for reducing
associated with all-cause and cardiovascular mortality.2 cardiovascular and all-cause mortality is open to debate.6–9
Hyperglycemic state of diabetes mediates various destructive Although sulfonylureas (SUs) are more potent glycemic
pathways and is at least partially responsible for chronic diabetes controllers, current treatment guidelines mostly recommend the
complications.3 Intensive control of plasma glucose has been use of metformin as the ¿UVW-line medication in patients with type
shown to slow down the progression of diabetic microvascular 2 diabetes mellitus.10,11 Observational and experimental studies
complications, including nephropathy, neuropathy, and have shown that treatment with SUs may increase mortality and
retinopathy,4 and the current therapeutic strategies in diabetes adverse cardiovascular events in comparison with metformin.12–16
mellitus are mainly directed against lowering plasma glucose to Some other studies have suggested that combination therapy
slow down its micro- and macro-vascular complications.3 with SUs and metformin is also associated with higher all-
About one half of all deaths in diabetic patients are estimated cause and cardiovascular mortality compared to metformin
to be due to cardiovascular diseases.5 The risk of myocardial alone.17 However, not all previous studies have reached the same
conclusion.18–21
$XWKRUV¶ DI¿OLDWLRQV 1Endocrinology and Metabolism Research Center
(EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Both SUs and metformin are among the most available (and
Sciences, Tehran, Iran, 2Department of Epidemiology and Biostatistics, School of ¿QDQFLDOO\ affordable) ¿UVW-line medications for treatment of
Public Health, Tehran University of Medical Sciences, Tehran, Iran. diabetes mellitus and are widely used alone or in combination
•Corresponding author and reprints: Manouchehr Nakhjavani MD,
Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, with other hypoglycemic agents.10,11 This study aimed to compare
Tehran University of Medical Sciences, Tehran, Iran , P. O. Box: 13145-784, Fax: all-cause mortality, cardiovascular mortality and VSHFL¿F cardiac
+98-21-64432466, Tel: +98-21-88841791, E-mail: nakhjavanim@tums.ac.ir. related events between ¿UVW-line monotherapy with glyburide and
Accepted for publication: 25 January 2017
metformin in patients with type 2 diabetes mellitus.

Archives of Iranian Medicine, Volume 20, Number 3, March 2017 141

 Metformin vs*O\EXULGHLQ7\SH'LDEHWHV0HOOLWXV

Methods for both men and women) plus at least two of the following: 1)
Plasma TG•150 mg/dL or taking TG lowering drugs; 2) HDL
Study population cholesterol < 40 mg/dL for men and < 50 mg/dL for women
The study design was historical cohort. We used a sample of or alternatively taking HDL-increasing medications; 3) Blood
patients diagnosed with type 2 diabetes mellitus in diabetes clinic pressure•130/85 mmHg or alternatively taking anti-hypertensive
of Vali-Asr hospital DI¿OLDWHG with Tehran University of Medical medications; 4) FPG • 110 mg/dL.23 To calculate body mass
Sciences. Patients’ follow up began in April 2001 and continued index (BMI), weight (in kilograms) was divided by height in
to December 2014. Recorded data in the patients’ ¿OHV was used meters squared (kg/m2). Glomerular filtration rate (mL/min/1.73 m2 of
for data collection. Type 2 diabetic men and women aged 20 years body surface area) was estimated as 175 × standardized
or higher were enrolled in the study. Treatment regimen for all Cr í1.154 (mg/dL) × ageí0.203 × 0.742 (for female patients).24
included patients was lifestyle PRGL¿FDWLRQ plus monotherapy
with metformin or glyburide. Written informed consents were Statistical Analysis
taken from participants as they were included in the study. The To express primary characteristics of the study population,
ethics committee of Endocrinology and Metabolism Research continuous variables were presented as mean ± standard
Center of Tehran University of Medical Sciences approved the deviation (SD) and dichotomous variables were presented as
study protocol. number and percent. T-test and Mann-Whitney U-test were used
for comparing means between the two groups for normally and
Clinical and laboratory measurements non-normally distributed variables, respectively. To compare
Age, sex, smoking status, drug history, family history of coronary dichotomous variables between the two groups, Ȥ2 -test was used.
heart disease, and duration of diabetes and other concomitant Cox proportional hazard regression test was used for survival
diseases were obtained through interview and checking medical analysis. The glyburide monotherapy group was considered as the
records. Patients’ reporting of cigarette smoking during the referent. Hazard ratios for all-cause and cardiovascular mortality
preceding year of inclusion was considered as positive cigarette were obtained for metformin monotherapy group compared to
smoking status. Height and weight were measured with light the referent. Stepwise adjustment was performed for age, gender,
clothing without shoes. Waist circumference was measured at metabolic syndrome, waist circumference, BMI, systolic blood
midline between the costal margin and the iliac crest in standing pressure, smoking status, history of CAD, family history of CAD,
position following expiration. Systolic and diastolic blood HbA1c, duration of diabetes, and plasma Cr. Two-sided P-values
pressures were measured twice on each arm after 10 minutes < 0.05 were considered statistically VLJQL¿FDQW. SPSS software for
of resting in sitting position. The greatest value of the four windows (version 20) was used to perform statistical analyses.
measurements was considered as the subject’s blood pressure.
After 10 hours of overnight fasting, venous blood samples Results
were obtained for biochemical measurements. Fasting plasma
glucose (FPG) and 2-hours post-prandial glucose were measured A total number of 717 type 2 DM patients (56% females and
by glucose oxidase method. HbA1c was measured by high- 44% males) with a mean age of 56.3 ± 11.1 years participated
performance liquid chromatography (DS5 Pink kit; Drew, in our study. Glyburide and metformin monotherapy groups
Marseille, France). To measure triglyceride (TG), total cholesterol, consisted of 271 and 446 patients, respectively. The patients were
low-density lipoprotein cholesterol (LDL-C), and high density followed for a median of 3 years>interquartile range: 1 – 5 years].
lipoprotein cholesterol (HDL-C) direct enzymatic methods were Table 1 presents the principal characteristics of the study
used (Parsazmun kit, Karaj, Iran). Serum creatinine was measured population. Both all-cause (6.3% vs. 1.6%) and cardiovascular
by Jaffe method (Parsazmun kit). (4.1% vs. 0.4%) mortality were higher in patients undergoing
monotherapy with glyburide compared to metformin monotherapy
2XWFRPHPHDVXUHVDQGGH¿QLWLRQV group (P = 0.001). Age, duration of diabetes, glycemic SUR¿OH,
The primary endpoint of the study was GH¿QHG as death of and systolic blood pressure values were higher in glyburide
any cause. Mortality was divided into two arms: all-cause and group (P-value < 0.001). Plasma Cr was also slightly elevated
cardiovascular. The exact date of death was considered as the end of in glyburide monotherapy group (P = 0.023). We observed no
follow-up for patients with events. For surviving patients, the date VLJQL¿FDQW difference between the two groups regarding past
of the last visit, the date of changing their monotherapy regimen history or family history of CAD, lipid SUR¿OH, lipid-lowering
to any other anti-hyperglycemic drug, or the time of addition of medications, diastolic blood pressure, past history of hypertension,
any other anti-hyperglycemic medication to their monotherapy anti-hypertensive medications, smoking, and estimated GFR. The
regimen was considered as the end of follow-up time. Patients presence of metabolic syndrome was more probable and BMI
were visited regularly every 3 months by an endocrinologist and and waist circumference were greater in metformin monotherapy
the type and dosage of treatment (including anti-hyperglycemic, group compared to the glyburide.
anti-platelet, anti-hypertensive, and lipid-lowering medications) Table 2 shows detailed adverse cardiovascular events during
were changed, as indicated. In each visit, the dosage and duration the years of follow-up. Patients taking glyburide experienced
of administration of each medication were updated. more non-fatal myocardial infarction (3.2% vs. 0.8%, P = 0.03).
The 2008 American Diabetes Association guideline was used for There was no VLJQL¿FDQW difference between the two study groups
diagnosis of diabetes mellitus.22 To diagnose metabolic syndrome, regarding need for angiography, coronary artery bypass grafting,
nationally PRGL¿HG version of National Cholesterol Education stenting, CCU admission, or cerebrovascular accidents.
Program’s Adult Treatment Panel III guideline was used. It was In Cox regression model, metformin was more protective
GH¿QHG as positive abdominal obesity (waist circumference•90 cm than glyburide for both all-cause (HR: 0.22 >0.09 – 0.52]; P =

142 Archives of Iranian Medicine, Volume 20, Number 3, March 2017

 055DHH$$1DUJHVL%+HLGDULHWDO

Table 1. 3ULQFLSDO&KDUDFWHULVWLFV2I6WXG\3RSXODWLRQ

*O\EXULGHQ  0HWIRUPLQQ  P-value

Age (years) 58.7 ± 10.8 55 ± 11.1 < 0.001
Gender (female/male)Į 140/131 260/186 0.08
Height (cm) 161.6 ± 8.6 161.9 ± 8.8 0.68
Weight (kg) 71.6 ± 13.2 78.9 ± 14.5 < 0.001
Waist circumference (cm) 95.6 ± 10.9 99.6 ± 11.1 < 0.001
2
BMI (kg/m ) 27.4 ± 4.8 30.1 ± 5.2 < 0.001
Smoking n (%)Į 11 (4%) 8 (1.8%) 0.07
Į
Metabolic Syndrome n (%) 171 (64%) 336 (76%) < 0.001
CAD n (%)Į 32 (12%) 47 (11%) 0.11
Family History of CAD n (%)Į 52 (19%) 89 (20%) 0.69
Duration of diabetes (years)ȕ 11.0 ± 7.6 7.4 ± 4.9 < 0.001
FPG (mg/dL)ȕ 175.1 ± 63.6 156.1 ± 47.0 < 0.001
PPPG (mg/dL)ȕ 259.2 ± 102.2 204.5 ± 78.6 < 0.001
HbA1C (%) 8.1 ± 1.9 7.4 ± 1.4 < 0.001
Total Cholesterol (mg/dL) 196.7 ± 46.9 192.2 ± 45.6 0.23
HDL-C (mg/dL) 44.3 ± 11.5 46 ± 12.2 0.09
LDL-C (mg/dL) 113.1 ± 36.4 109.2 ± 35.4 0.19
ȕ
Triglycerides (mg/dL) 189.8 ± 94.2 180.4 ± 104.8 0.10
Anti-hyperlipidemic drugs (%)Į 110 (40%) 201 (45%) 0.22
Statins (%)Į 103 (37%) 180 (40%) 0.50
*HP¿EUR]LOĮ 19 (7%) 37 (8%) 0.52
SBP (mmHg) 132.3 ± 19.9 126.6 ± 17.6 < 0.001
DBP (mmHg) 80.2 ± 11.2 79.9 ± 9.7 0.73
Hypertension n (%)Į 117 (43%) 182 (40%) 0.56
Duration of Hypertension (years)ȕ 9.19 ± 5.98 10.29 ± 6.81 0.85
Į
Anti-hypertensive drugs (%) 89 (32%) 155 (34%) 0.57
ACEI/ARB (%)Į 64 (23%) 100 (22.4%) 0.73
Beta blocker (%)Į 27 (10%) 47 (10%) 0.79
Į
CCB (%) 14 (5%) 34 (8%) 0.19
Creatinine (mg/dL) 1.03 ± 0.28 0.98 ± 0.23 0.023
eGFR (ml/min/1.73 m2) 73.9 ± 20.9 75.8 ± 19.9 0.25
All-cause mortalityĮ 17 (6%) 7 (2%) 0.001
Cardiovascular mortalityĮ 11 (4%) 2 (0.4%) 0.001

BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; PPPG: post-prandial plasma glucose;
+'/&KLJKGHQVLW\OLSRSURWHLQFKROHVWHURO/'/&ORZGHQVLW\OLSRSURWHLQFKROHVWHUROH*)5HVWLPDWHGJORPHUXODU¿OWUDWLRQUDWH&$'FRURQDU\DUWHU\
disease; ACEI: angiotensin converting enzyme inhibitor; ARB: aldosterone receptor blocker; CCB: calcium channel blocker. ĮVariables are compared using
Ȥ2-test; ȕVariables are compared using Mann-Whitney U-test.
Note: Data are presented as mean ± standard deviation (SD) or number (percent). Groups were compared using independent samples t-test.

Table 2. $GYHUVH&DUGLRYDVFXODU(YHQWV,Q3DWLHQWV8QGHU7UHDWPHQW:LWK*O\EXULGH$QG0HWIRUPLQ

Glyburide Metformin P-value

Non-fatal MI 7 (3.2%) 3 (0.8%) 0.03

Angiography 22 (10%) 27 (7.2%) 0.24
CABG 4 (1.8%) 6 (1.6%) 0.85
Stenting 2 (2.2%) 4 (3.6%) 0.69
CCU admission 9 (9.9%) 7 (6.3%) 0.34
CVA 5 (2.3%) 2 (0.5%) 0.10
MI: myocardial infarction; CABG: coronary artery bypass graft; CCU: cardiac care unit; CVA: cerebrovascular accident.
Note:'DWDDUHSUHVHQWHGDVQXPEHUSHUFHQW9DULDEOHVZHUHFRPSDUHGXVLQJȤ2-test.

Archives of Iranian Medicine, Volume 20, Number 3, March 2017 143

 Metformin vs*O\EXULGHLQ7\SH'LDEHWHV0HOOLWXV

Figure 1. .DSODQ0HLHUSORWRIFDUGLRYDVFXODUPRUWDOLW\LQPHWIRUPLQDQGJO\EXULGHJURXSV

Figure 2. .DSODQ0HLHUVXUYLYDOSORWRIDOOFDXVHPRUWDOLW\LQPHWIRUPLQDQGJO\EXULGHJURXSV

0.001) and cardiovascular mortality (HR: 0.10>0.02 – 0.45]; P = cause and cardiovascular mortality in comparison with glyburide.
0.003). This effect remained VLJQL¿FDQW after multiple adjustments Potential confounders which could LQÀXHQFH the choice of the
for cardiovascular risk-factors (HR: 0.27 >0.10 – 0.73] P-value initial assignment of the medication (metformin or glyburide)
= 0.01 for all-cause and 0.12 >0.20 – 0.66], P-value = 0.01 for were adjusted. The full-adjusted HR (CI) for all-cause and
cardiovascular mortality). Figures 1 and 2 illustrate Kaplan- cardiovascular mortality were 0.27>0.10 – 0.73] and 0.12>0.20 –
Meier survival plots for all-cause and cardiovascular mortality in 0.66] respectively, for metformin compared with glyburide.
glyburide and metformin monotherapy groups. Since the release of United Kingdom Prospective Diabetes Study
(UKPDS 34) results in 1998, metformin was recommended as the
Discussion ¿UVW-line anti-hyperglycemic medication for overweight patients
with type 2 diabetes mellitus.25 The mentioned study suggested
In the present study, we showed that monotherapy with that metformin monotherapy could decrease any diabetes-related
metformin in type 2 diabetic patients is associated with lower all- endpoint, as well as mortality, in overweight type 2 diabetic

144 Archives of Iranian Medicine, Volume 20, Number 3, March 2017

 055DHH$$1DUJHVL%+HLGDULHWDO

Table 3. +D]DUG5DWLRV)RU&DUGLRYDVFXODU$QG$OOFDXVH0RUWDOLW\,Q3DWLHQWV8QGHU7UHDWPHQW:LWK0HWIRUPLQ&RPSDUHG:LWK*O\EXULGH

All-cause Mortality Cardiovascular Mortality

Models
+5>&,@ P-value +5>&,@ P-value

Model 1 0.22 (0.09 – 0.52) 0.001 0.10 (0.02 – 0.45) 0.003

Model 2 0.27 (0.11 – 0.66) 0.004 0.10 (0.02 – 0.48) 0.004

Model 3 0.31 (0.12 – 0.79) 0.01 0.15 (0.03 – 0.73) 0.01

Model 4 0.28 (0.11 – 0.75) 0.01 0.13 (0.03 – 0.68) 0.01

Model 5 0.27 (0.10 – 0.73) 0.01 0.12 (0.20 – 0.66) 0.01

Model 1 is unadjusted; Model 2 is adjusted for age and gender; Model 3 is additionally adjusted for systolic blood pressure, metabolic syndrome, BMI,
smoking, past history of CAD and family history of CAD; Model 4 is additionally adjusted for HbA1c and duration of diabetes; Model 5 is further adjusted
for plasma creatinine.

patients compared with diet control alone, insulin, glyburide, or metformin, glyburide, and the combination of metformin and
chlorpropamide.25 Several studies have subsequently suggested glyburide.19
that metformin has the advantage of decreased mortality and To date, a vast number of studies have supported the protective
lower adverse cardiovascular events over SUs.9,12–16,26–28 Two effects of metformin in patients with diabetes mellitus. Treatment
studies among the mentioned studies also performed propensity with metformin is associated with decreased oxidative stress,
score matched analysis to match the patients for the probability improved lipid SUR¿OH, and improved endothelial and platelet
of metformin use as the initial treatment.15,28 However, most of function.30–31 Therapy with metformin could decrease plasma
the mentioned studies have analyzed SUs as a composite group triglyceride, total cholesterol and LDL-C, while serum HDL-C
and did not compare the effects of different types of SU drugs levels is increased or at least unaffected.31 Metformin could also
compared with metformin separately;9,15,28 as different types of decrease blood pressure, a well-known cardiovascular risk factor.31
SUs may have different effects on survival when compared with Several observational studies have also proposed that treatment
metformin.12,13,16,26 In a large nationwide study, Schramm, et al. with metformin can decrease cancer incidence compared with
showed that treatment with SUs (including glimepiride, glyburide, SUs.32 It was suggested that increased plasma insulin (which
glipizide, and tolbutamide) was associated with increased all- may impose mutagenic effects) following treatment with SUs,
cause mortality compared with metformin.13 The results for could contribute to increased risk of cancer.32 Patients with type
cardiovascular mortality and composite endpoint of myocardial 2 diabetes under treatment with metformin have better survival
infarction, cardiovascular mortality, and stroke were the same after cancer incidence in comparison with those treated with
in this study. In another retrospective cohort on 23,915 type 2 other glucose-lowering agents or even the general population.33
diabetic patients, Pantalone, et al. showed that treatment with However, further randomized clinical trials are still needed to
glipizide, glyburide or glimepiride are associated with increased FRQ¿UP the oncologic EHQH¿WV of metformin compared with SUs
mortality compared with metformin after a median follow-up of in patients with type 2 diabetes.34
2.2 years.12 Interestingly, a recent study on 90,463 patients with The limitations of this study merit consideration. This was
diabetes mellitus and 90,463 healthy subjects showed that patients an observational cohort study in which the patients were not
with diabetes and under treatment with metformin have better randomized for treatment allocation. Some of the baseline
survival than those treated with SUs and even healthy matched characteristics of the participants were different between
controls.27 Bannister, et al. showed that the survival of metformin- metformin and glyburide groups and lack of randomization is
treated patients with type 2 diabetes is at least as long as that of an inherent weakness of such studies. Therefore, to minimize
healthy matched controls.27 Hong, et al. in a randomized double- the confounding effects, the results of the multivariable cox-
blind clinical trial enrolled 304 patients with type 2 diabetes regression analysis were adjusted for confounders which could
mellitus and history of coronary artery disease.14 The patients potentially affect the primary choice of treatment. In addition,
were randomly allocated to metformin or glipizide monotherapy subjects with contraindications for metformin or glyburide (e.g.
for 3 years. After a median follow-up of 5 years, patients treated elevated creatinine for metformin) were excluded from the study
with metformin had a VLJQL¿FDQWO\ lower risk of major adverse and did not enter the other treatment group.
cardiovascular events than those treated with glipizide.14 In conclusion, we observed that patients with type 2 diabetes
The superiority of metformin over SUs, regarding all-cause receiving glyburide for glycemic control are at increased risk
mortality or adverse cardiovascular events, has not been consistent of all-cause and cardiovascular mortality compared with those
among studies.18–20 Kahn, et al. performed a large randomized receiving metformin. According to these results, metformin
double blind clinical trial on 4,360 patients with type 2 diabetes is recommended as ¿UVW-line glucose lowering medication in
mellitus.18 After 4 years of treatment, no difference was observed patients with type 2 diabetes mellitus if no contraindication exists.
between glyburide (1,441 patients) and metformin (1,454 However, as most of previous studies were observational, non-
patients) for either stroke, fatal or non-fatal myocardial infarction, randomized or retrospective,29 future randomized clinical trials
hospitalization, or all-cause death.18 In another study, Kahler, et al. comparing the most widely used types of SUs with metformin
analyzed the data of 39,721 type 2 diabetic patients and found could help to resolve the existing controversies.
no difference in all-cause mortality between patients treated with

Archives of Iranian Medicine, Volume 20, Number 3, March 2017 145

 Metformin vs*O\EXULGHLQ7\SH'LDEHWHV0HOOLWXV

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146 Archives of Iranian Medicine, Volume 20, Number 3, March 2017