Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

Jie Hong; Yifei Zhang; Shenghan Lai; Ankang Lv; Qing Su; Yan Dong; Zhiguang Zhou; Weili Tang; Jiajun Zhao; Lianqun Cui; Dajin Zou; Dawang Wang; Hong Li; Chao Liu; Guoting Wu; Jie Shen; Dalong Zhu; Weiqing Wang; Weifeng Shen; Guang Ning

doi:10.2337/dc12-0719

Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

Hong, Jie; Zhang, Yifei; Lai, Shenghan; Lv, Ankang; Su, Qing; Dong, Yan; Zhou, Zhiguang; Tang, Weili; Zhao, Jiajun; Cui, Lianqun; Zou, Dajin; Wang, Dawang; Li, Hong; Liu, Chao; Wu, Guoting; Shen, Jie; Zhu, Dalong; Wang, Weiqing; Shen, Weifeng; Ning, Guang; , 2013-04-13 00:00:00 Cardiovascular and M etabolic R isk OR IGIN AL AR TIC L E Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease 1 7 JIE HONG, MD DAWANG WANG, MD he prevalence of type 2 diabetes has 1 8 YIFEI ZHANG, MD HONG LI, MD been increasing rapidly throughout 2 9 SHENGHAN LAI, MD CHAO LIU, MD Tthe world during the past decades (1). 1 10 ANKANG LV, MD GUOTING WU, MD Since cardiovascular disease is the 3 11 QING SU, MD JIE SHEN, MD 3 12 major complication of type 2 diabetes, YAN DONG, MD DALONG ZHU, MD 4 1 and cardiovascular mortality accounts ZHIGUANG ZHOU, MD WEIQING WANG, MD 4 1 for the majority of diabetic patient WEILI TANG, MD WEIFENG SHEN, MD 5 1 deaths, there has been growing interest JIAJUN ZHAO, MD GUANG NING, MD, PHD LIANQUN CUI, MD ON BEHALF OF THE SPREAD-DIMCAD in developing strategies for blood glucose DAJIN ZOU, MD INVESTIGATORS* control in type 2 diabetic patients to re- duce cardiovascular risk and mortality (2–6). OBJECTIVEdThe two major classes of antidiabetic drugs, sulfonylureas and metformin, may Among various oral glucose-lowering differentially affect macrovascular complications and mortality in diabetic patients. We com- medications, metformin and sulfonyl- pared the long-term effects of glipizide and metformin on the major cardiovascular events in type ureas have been the mainstay treatments 2 diabetic patients who had a history of coronary artery disease (CAD). for type 2 diabetes. Several studies have RESEARCH DESIGN AND METHODSdThis study is a multicenter, randomized, double- examined the effects of these medications blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = on cardiovascular risk among diabetic 63.3 years (range, 36–80 years), were enrolled. Participants were randomly assigned to receive either patients; the results, however, are incon- glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the sistent (2,7–9). In an early, large-scale, composite of recurrent cardiovascular events, including death from a cardiovascular cause, death randomized trial, an increased risk of car- from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. diovascular mortality was observed in di- RESULTSdAt the end of study drug administration, both groups achieved a signiﬁcant decrease in abetic patients treated with sulfonylurea the level of glycated hemoglobin (7.1% in the glipizidegroup and7.0% inthe metformingroup). At a (tolbutamide) or biguanide (phenformin) median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat medications (7,8). Some other studies analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30–0.90; P = 0.026) for the composites suggest that these two classes of medica- of cardiovascular events among the patients that received metformin, compared with glipizide. The tions might differentially affect cardiovas- secondary end points and adverse events were not signiﬁcantly different between the two groups. cular risk (9–14). For example, in the CONCLUSIONSdTreatment with metformin for 3 years substantially reduced major cardio- open-label UK Prospective Diabetes vascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a Study (UKPDS) (9), it was found that di- potential beneﬁt of metformin therapy on cardiovascular outcomes in high-risk patients. abetic patients with metformin treatment had a reduced risk of macrovascular and Diabetes Care 36:1304–1311, 2013 microvascular complications as well as all-cause mortality compared with those treated with sulfonylurea or insulin. ccccc cccccccc cccccccc cccccccc cccccccc cccccccc ccc c However, the combined treatment of 1 2 From the Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; the Johns metformin and sulfonylurea led to an in- Hopkins University School of Medicine, Baltimore, Maryland; the Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; The Second Xiangya Hospital of Central South University, creased risk of all-cause mortality. Taken 5 6 Changsha, China; the Shandong Provincial Hospital, Shandong University, Jinan, China; the Chang Hai together, how these two major hypogly- Hospital, Second Military Medical University, Shanghai, China; The First Afﬁliated Hospital of Wenzhou cemic agents may affect cardiovascular Medical College, Zhejiang Province, China; the Sir Run Run Shao Hospital, Zhejiang Province, China; the 9 10 risk and mortality among diabetic pa- Jiangsu Province Hospital, Jiangsu Province, China; the Shanghai Ten’sPeople’s Hospital of Tongji Uni- 11 12 versity, Shanghai, China; the Nanfang Hospital, Guangdong Province, China; and the Nanjin Drum Tower tients remains unclear. Hospital, Jiangsu Province, China. Therefore, we performed a random- Corresponding author: Guang Ning, [email protected]. ized, double-blind, placebo-controlled Received 16 April 2012 and accepted 4 October 2012. trial to compare the effects of the two DOI: 10.2337/dc12-0719. Clinical trial reg. no. NCT00513630, clinicaltrials.gov. major classes of blood glucose–lowering This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 .2337/dc12-0719/-/DC1. agents, sulfonylurea (glipizide) and met- J.H. and Y.Z. contributed equally to this study. formin, on the cardiovascular events and *A complete list of the investigators of SPREAD-DIMCAD can be found in the APPENDIX. mortality in 304 Chinese type 2 diabetic © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly patients who had a history of coronary 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. artery disease (CAD). 1304 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates RESEARCH DESIGN AND infarction, nonfatal stroke or arterial re- other treatments for CAD and modiﬁable METHODS vascularization by percutaneous trans- cardiovascular risk factors were identical luminal coronary angioplasty (PTCA) or in both groups through all research cen- Study design and participants by coronary artery bypass graft, death ters according to the recommendation of The Study on the Prognosis and Effect of from a cardiovascular cause, and death the Third Report of the National Choles- Antidiabetic Drugs on Type 2 Diabetes from any cause. The end points were terol Education Program Expert Panel on Mellitus with Coronary Artery Disease obtained and conﬁrmed by the medical Detection, Evaluation, and Treatment of (SPREAD-DIMCAD) was a prospective, records and death certiﬁcates that were High Blood Cholesterol In Adults (Adult randomized, double-blind, placebo- kept in each center. The secondary car- Treatment Panel III) (17). controlled trial that evaluated the differ- diovascular end points included new or The study drug administration was 3 ent effects of glipizide and metformin on worsening angina, new or worsening years for each participant. The follow-up the major cardiovascular events and mor- heart failure, new critical cardiac ar- for primary end points began at random- tality among type 2 diabetic patients rhythmia, and new peripheral vascular ization and continued until the end of the with a history of CAD. The patients were events. Other adverse events, including study. The original protocol invited all recruited from 15 clinical centers in China. hypoglycemia (severe hypoglycemia in participants to continue with the follow- The study was approved by the institu- which the subject required assistance up of primary outcomes until the end of tional review board of Ruijin Hospital, and and/or a plasma glucose level ,56 mg/dL the whole study (last subject ﬁnished the written informed consent was obtained [3.1 mmol/L] was recorded as a hypo- study drug administration) after the ini- from each patient. The study was conduc- glycemic attack and would be reported tial 3-year studydrugadministration. In ted in accordance with the principles of the in this manuscript) and microvascular the postdrug follow-up period, the pri- Declaration of Helsinki. complications, were also monitored. mary end points were obtained and no The targeted participants in the cur- attempts were made to maintain their rent study were patients with both type 2 Randomization and study medication previous therapies. During study drug diabetes and CAD. The eligibility criteria After a 2-week run-in period, the eligible administration, information on adher- included the following: 1)diagnosed as study participants were required to with- ence and tolerability of study drugs, CAD by either having a history of acute draw from all antidiabetic agents and concomitant medication, adverse events, myocardial infarction diagnosed by a rep- were randomly assigned in double-blind and occurrence of study outcomes were resentative set of electrocardiograms, to receive either glipizide plus metformin collected, and physical examination, vital cardiac enzyme values, and typical symp- placebo or metformin plus glipizide pla- signs, and plasma glucose concentrations toms or by angiographically identiﬁed cebo for 3 years. The baseline metabolic were obtained. Glycated hemoglobin lev- stenosis of .50% of lumen diameter in values were obtained immediately after els were measured at 6, 12, 18, 24, 30, at least one major epicardial coronary ar- the withdrawal of previous antidiabetic and 36 months (extra results might be tery (15); 2) diagnosed as type 2 diabetic therapy. The randomization codes were required according to the investigator’s according to the 1999 World Health Or- generated by the study’s biostatistician at judgment), and lipid concentration, bio- ganization criteria (fasting plasma glucose Shanghai Jiao Tong University School of chemical safety laboratory analysis, elec- $7mmol/Land/or2-h oral glucose tol- Medicine. Study sites did not have access trocardiograms, and echocardiographic erance test $11.1 mmol/L (16) and fast- to the codes. results were obtained. ing plasma glucose ,15 mmol/L); and 3) For both groups, the targeted glyca- Ruijin Hospital served as the coordi- no more than 80 years of age (both men ted hemoglobin level was ,7.0%, the nating center. There was no central labo- and women). The exclusion criteria in- fasting blood glucose concentration was ratory for biochemical analysis for the cluded the following: 1) severe liver dys- ,7 mmol/L, and the postload 2-h blood study. function, including serum alanine glucose concentration was ,10 mmol/L. aminotransferase concentration .2.5 The study drugs and the matched placebo Statistical analysis times above the upper limit of normal were prepared in indistinguishable tab- This study was designed in accordance range and abnormal renal function (se- lets. For the glipizide group, the initial with a predetermined statistical analysis rum creatinine .132 mmol/L); 2) severe dose was 15 mg daily (5 mg per one plan. Given a constant rate of events of dysfunction of the heart (New York Heart pill, three times daily) and titrated to 30 10% per year, a sample size of 150 Association class .phase III); 3) psychi- mg (10 mg per two pills, three times patients in each of the two study groups atric disease, severe infection, severe ane- daily) within 3 months, if not to target. would provide an 85% power at a type 1 mia, or neutropenia; 4)other severe The mean daily dose of glipizide was error rate of 0.05 to detect a 30% re- organic heart diseases, including, but 28.36 3.9 mg. For the metformin group, duction in the relative risk of the com- not limited to, congenital heart disease, the initial dose was 0.75 g daily (0.25 g posite primary outcomes during the rheumatic heart disease, and hypertro- per one pill, three times daily), and ti- follow-up. This analysis was designed to phic or dilated cardiomyopathy; 5) preg- trated to 1.5 g (0.5 g per two pills, three test the primary hypothesis that glipizide nant or lactating; 6) allergic to study times daily) within 3 months, if not to and metformin would have a different drugs; 7) using insulin therapy for type target. The mean daily dose of metformin effect on the recurrence of composite 2 diabetes and could not be changed to was 1.4 6 0.2g.After 3months, insulin cardiovascular events. The follow-up for oral glucose-lowering drugs; and 8)re- was added for patients with the maxi- primary end points began at randomiza- cent drug or alcohol abuse. mum dose of study drug administration tion and continued until the end of the The primary study end points were in either group who did not achieve tar- study (last subject ﬁnished the study drug the composite of recurrent cardiovascu- geted glucose control level (see Supple- administration) after the initial 3-year lar events, including nonfatal myocardial mentary Data). Lifestyle intervention and study drug administration. care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1305 Metformin, glipizide, and cardiovascular outcomes Statistical analysis was performed with SAS (version 9.2; SAS Institute, Cary, NC). Data were expressed as means and SDs or as medians with IQRs when speciﬁed. Logarithmic transformation was used for variables that were not normally distributed. Within-group com- parisons were performed with paired- sample Student t tests to evaluate the differences from baseline in each group. A Student t test (for data that were normally distributed) or a Mann-Whitney U test (not normally distributed) and an ANCOVA analysis with a model that in- cluded the baseline value of the dependent variable as a covariate were also used for comparison between groups. A x test was used to analyze the differences in categor- ical variables. The primary end point of this trial was time to recurrent events. Multiple event analysis was performed with the use of the proportional means re- gression model (18). A multivariate pro- portional means regression model was used to control for the duration of diabe- tes, duration of CAD, age, sex, and smok- ing history at baseline. For all analyses, glipizide use was treated as the reference group. The intention-to-treat principle was used for end point analyses. All reported P values are two sided, Figure 1dSPREAD-DIMCAD trial proﬁle. and P values ,0.05 were considered to be statistically signiﬁcant. At the end of the 3-year study drug for 25 patients in the glipizide group and RESULTSdRecruitment ran from 1 administration, the glycated hemoglobin 30 patients in the metformin group, re- June 2004 to 30 July 2007. Of 565 levels were signiﬁcantly improved in both spectively (P = 0.259). The percentage of patients who were screened, a total of groups, and no difference was found patients using insulin between the two 304 patients were enrolled in the study, between the two groups (Table 1). The groups at each visit was not signiﬁcantly with follow-up ending in July 2010. Fig- mean glycated hemoglobin values had different (all P . 0.05). Furthermore, the ure 1 showed the process of screening and fallen from 7.6% at baseline to 7.1% in dose used per person who was added with randomization. The 31 patients in the gli- the glipizide group and from 7.6 to insulin in both groups increased but with pizide group and 32 in the metformin 7.0% in the metformin group within 6 no difference between the two groups group that terminated early with the months after randomization and re- (Table 1 and Supplementary Fig. 1). study drug administration were still en- mained stable thereafter (Fig. 2A). Both Drugs prescribed for other risk factors couraged to continue the follow-up of pri- groups showed a signiﬁcant decrease in did not differ signiﬁcantly at the end of mary outcomes. The median follow-up fasting and 2-h plasma glucose concentra- the follow-up between the two groups, period was 5.0 years (range, 3.7–5.7 tions after treatment, and no difference except for statins, which were used less years). The mean age of the participants was found between the two groups (Table in the metformin group compared with was 63.3 years (range, 36–80 years). Type 1 and Fig. 2B). At baseline, no difference the glipizide group (P = 0.013) (Table 1). 2 diabetes had been diagnosed for a was found in the BMI between the groups. A total of 103 composite primary end mean of 5.6 years and CAD for a mean However, after treatment, it was signiﬁ- points occurred in 91 patients (52 of 2.9 years before recruitment. The dis- cantly lower in the metformin group [35.1%] in the glipizide group and 39 tribution and doses of glucose-lowering than in the glipizide group (Table 1 and [25.0%] in the metformin group) (char- agents at baseline (Table 1 and Supple- Fig. 2C). Similar differences were ob- acteristics of these patients are shown in mentary Table 1) and the other baseline served for body weight and waist circum- Supplementary Table 2) during the whole characteristics of the participants in the ference between these two groups (Table study period: 60 events in the glipizide glipizide and metformin groups were 1). Detailed changes and a comparison of group (14 deaths from any causes [in- generally similar except for the 2-h the other clinical and biochemical charac- cluding 11 deaths from cardiovascular plasma glucose levels. There was no sig- teristics of the two groups are shown in events and 3 from sudden death; unfor- niﬁcant differences between the two Table 1 and Fig. 2. tunately autopsies were not performed to groups in the concomitant medication In order to reach the targeted glycated conﬁrm the 3 patients’ precise causes of (Table 1). hemoglobin level, insulin was prescribed death], 6 nonfatal myocardial infarctions, 1306 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates Table 1dCharacteristics of the patients at baseline and end of follow-up Baseline End of follow-up Glipizide Metformin Glipizide Metformin Characteristic (n = 148) (n = 156) P value* (n =97) (n = 111) P value* P valuex Age (years) 63.8 6 9.4 62.8 6 8.5 0.302 Sex, n (%) 0.805 Male 114 (77.0%) 122 (78.2%) Female 34 (23.0%) 34 (21.8%) Time since diagnosis of diabetes (years) 5.6 6 4.9 5.6 6 5.3 0.947 Time since diagnosis of CAD (years) 3.0 6 5.1 2.9 6 4.8 0.837 History of myocardial infarction, n (%) 94 (63.5%) 84 (53.8%) 0.103 History of arterial revascularization, n (%) 95 (64.2%) 98 (62.8%) 0.813 History of nonfatal stroke, n (%) 13 (9.0%) 18 (11.5%) 0.428 Patients with hypertension, n (%) 106 (71.6%) 105 (67.3%) 0.408 Current smokers, n (%) 53 (35.8%) 61 (39.1%) 0.726 Alcohol use, n (%) 19 (12.8%) 36 (23.1%) 0.068 Body weight (kg) 68.7 6 10.6 69.6 6 10.1 0.465 69.6 6 11.0 68.6 6 10.4 0.554 0.002 BMI (kg/m ) 25.1 6 2.9 25.2 6 3.0 0.675 25.7 6 2.9 24.7 6 2.8 0.026 ,0.001 Waist circumference (cm) 90 6991 690.317 92 6990 6 9 0.118 0.001 Blood glucose control Glycated hemoglobin level (%) Mean 6 SD 7.6 6 1.7 7.6 6 1.7 0.847 7.1 6 1.1 7.0 6 1.3 0.662 0.419 Median 7.3 7.3 7.0 6.8 IQR 6.5–8.4 6.6–8.4 6.3–7.8 6.2–7.4 Fasting plasma glucose (mmol/L) Mean 6 SD 7.77 6 2.22 8.21 6 2.28 0.075 6.91 6 1.52 7.21 6 2.24 0.297 0.405 Median 7.4 7.8 7.0 6.8 IQR 6.4–8.4 6.6–9.0 6.0–7.7 6.2–7.7 Postload 2-h plasma glucose (mmol/L) Mean 6 SD 12.56 6 4.20 13.61 6 4.05 0.014 11.34 6 3.58 10.84 6 3.41 0.370 0.207 Median 12.0 13.0 10.5 10.3 IQR 9.6–15.1 10.5–16.3 8.8–13.0 8.5–12.7 Blood pressure (mmHg) Systolic 129.1 6 18.4 130.1 6 17.6 0.667 128.6 6 15.1 128.0 6 15.5 0.804 0.737 Diastolic 78.3 6 9.7 78.4 6 10.0 0.921 75.8 6 9.8 75.9 6 8.3 0.933 0.950 Fasting serum cholesterol (mmol/L) Total 4.55 6 1.32 4.93 6 3.00 0.159 4.36 6 1.30 4.52 6 1.23 0.442 0.667 LDL 2.73 6 0.90 2.79 6 0.89 0.544 2.40 6 0.83 2.60 6 0.83 0.132 0.248 HDL 1.16 6 0.32 1.15 6 0.32 0.748 1.28 6 0.38 1.23 6 0.33 0.339 0.958 Fasting serum triglyceride (mmol/L) 2.07 6 1.65 2.44 6 1.96 0.080 2.10 6 2.49 2.10 6 1.71 1.000 0.537 Serum creatinine (mmol/L) 86.7 6 18.9 83.8 6 17.6 0.165 86.3 6 22.0 83.3 6 25.2 0.433 0.302 Medications, n (%) Glucose-lowering drug Sulfonylurea 80 (54.1%) 76 (48.7%) 0.349 Metformin 81 (54.7%) 74 (47.4%) 0.201 Thiazolidinedione 3 (2.0%) 3 (1.9%) 0.948 Acarbose 30 (20.3%) 37 (23.7%) 0.469 Glinide 4 (2.7%) 5 (3.2%) 0.797 Insulin 15 (10.1%) 13 (8.3%) 0.586 25 (26.3%) 30 (27.0%) 0.908 0.259 None 24 (16.2%) 37 (23.7%) 0.103 Other drugs Aspirin 122 (82.4%) 132 (84.6%) 0.703 77 (81.1%) 99 (89.2%) 0.067 0.287 ACE inhibitor 76 (51.4%) 79 (50.6%) 0.893 53 (55.8%) 54 (48.6%) 0.338 0.492 Continued on p. 1308 care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1307 Metformin, glipizide, and cardiovascular outcomes Table 1dContinued Baseline End of follow-up Glipizide Metformin Glipizide Metformin Characteristic (n = 148) (n = 156) P value* (n =97) (n = 111) P value* P valuex Angiotensin receptor blocker 11 (7.4%) 17 (10.9%) 0.297 5 (5.3%) 10 (9.0%) 0.294 0.456 Beta-blocker 80 (54.1%) 90 (57.7%) 0.524 60 (63.2%) 73 (65.8%) 0.632 0.625 Calcium-channel blocker 47 (31.8%) 48 (30.8%) 0.910 34 (35.8%) 35 (31.5%) 0.580 0.901 Diuretic 22 (14.9%) 16 (10.3%) 0.223 11 (11.6%) 10 (9.0%) 0.558 0.726 Statin 97 (65.5%) 97 (62.2%) 0.582 70 (73.7%) 66 (59.5%) 0.039 0.013 Data are means 6 SD for data normally distributed, n (%), or median and IQR for data not normally distributed. Statistical signiﬁcances were determined using a Student t test (for data normally distributed) or a Mann-Whitney U test (for data not normally distributed) and x test (for categorical variable data). *P values are for the difference between the groups at baseline or at the end of follow-up. xP value refers to comparison between the glipizide and the metformin groups after treatment using the ANCOVA analysis. 15 nonfatal strokes, and 25 arterial revas- CONCLUSIONSdSPREAD-DIMCAD effects of sulfonylureas and metformin cularizations), as compared with 43 was the ﬁrst double-blind, randomized, on cardiovascular events, and the evi- events in the metformin group (7 deaths controlled trial to compare the different dence from randomized clinical trials is from any causes [all were deaths from car- effects of glipizide and metformin on the sparse (12). diovascular events], 5 nonfatal myocardial major cardiovascular events among pa- Our study was the ﬁrst to compare infarctions, 10 nonfatal strokes, and 21 ar- tients with type 2 diabetes and CAD. the effects of sulfonylureas (glipizide) and terial revascularizations). As compared After a median of 5.0 years of follow-up, metformin on the recurrence of major with the patients treated with glipizide, treatmentwithmetformin showed a signif- cardiovascular events in a prospective, the HR for the composite cardiovascular icant reduction of the recurrence of com- randomized, double-blind, placebo- events for metformin treatment was 0.54 posite cardiovascular events compared controlled trial. We found that, compared (95% CI 0.30–0.90; P = 0.026) after adjust- with glipizide, which indicated a protective with glipizide, metformin showed a sig- ment for the duration of diabetes, duration effect of metformin on cardiovascular niﬁcant reduction in composite cardiovas- of CAD, age, sex, and smoking history at events in high-risk patients. Such a pro- cular end points. Furthermore, since the baseline (Supplementary Table 3). No sig- tective effect of metformin may also be primary outcome occurring within 1 year niﬁcant difference in the mortality rate be- present in a later stage of type 2 diabetes (nine patients in the glipizide group and tween the two groups was found; P =0.55. during insulin therapy (19). eight patients in the metformin group) During the study drug administra- Cardiovascular disease is the most seems unlikely to have been caused by tion, the following secondary end points common complication and the leading the effects of glipizide or metformin treat- occurred: new or worsening heart failure cause of mortality in patients with type 2 ment, we performed a stratiﬁed analysis developed in 10 (6.8%) patients in the diabetes (20,21). Sulfonylureas and met- and only looked at the events after 1 year glipizide group and 9 (5.8%) patients in formin have been the cornerstone of drug (HR 0.48 [95% CI 0.31–0.72]; P , the metformin group (adjusted HR 0.82 therapy for type 2 diabetes, either alone or 0.001), showing a better effect of metfor- [95% CI 0.31–2.13]; P = 0.677); new crit- in combination, for a quarter of a century min on the primary outcome. Several lines ical cardiac arrhythmia occurred in 27 (22). Experimental studies have shown of evidence may explain the different ef- (18.2%) patients in the glipizide group different effects of these two kinds of an- fects of sulfonylureas and metformin on and 30 (19.2%) patients in the metformin tidiabetic drugs on cardiovascular disease cardiovascular and all-cause mortality. group (1.01 [0.60–1.72]; P = 0.958); new besides their glucose-lowering effect (23– Sulfonylureas can increase pancreatic or worsening angina occurred in 71 29). However, studies comparing these b-cell insulin release by inhibiting the (48%) patients in the glipizide group two classes of medications on cardiovas- ATP-sensitive potassium (K )channel ATP and 77 (49.4%) patients in the metformin cular risk in humans generated highly in- through binding to b-cell sulfonylurea re- group (1.07 [0.77–1.48]; P = 0.696); and consistent results (7–14). Several reasons ceptor 1. While binding to sulfonylurea 6 (4.1%) patients in the glipizide group may account for the discrepancies among receptor 2 on cardiac myocytes, sulfony- and 1 (0.6%) patient in the metformin these studies. First, most of the previous lureas inhibit cardiac K channels and ATP group developed peripheral vascular studies are retrospective and observa- reduce the protective effects of myocardial events (0.13 [0.02–1.08]; P = 0.059). tional in design. The patients included preconditioning (14,23–25). On the Furthermore, the two groups did not in different studies varied in the severity other hand, metformin reduces hepatic differ signiﬁcantly with respect to the of diabetes and cardiovascular disorders gluconeogenesis and increases insulin- number of patients who reported one as well as other characteristics, such as stimulated glucose uptake in skeletal mus- or more hypoglycemic attacks during BMI and glucose levels, which might in- cle and fat tissue (26). Recent evidence study drug administration (four in the ﬂuence drug choice. Second, the uses of shows that metformin has antiatherogenic glipizide group and three in the metfor- cardiovascular medications were not well effects through the reduction of inﬂamma- min group, P = 0.651; when excluding controlled in some studies and might also tory markers, vascular adhesion molecules, insulin users, three in glipizide group contribute to the diverse associations with and coagulation parameters, as well as the and zero in metformin group, P = cardiovascular events. Moreover, few pre- reduction of endothelial dysfunction 0.080). vious studies directly compared the (27–29). In addition, sulfonylureas are 1308 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates Figure 2dChanges of major clinical and biochemical characteristics at baseline and during follow-up in different groups. HbA (A), fasting 1c plasma glucose (B), BMI (C), triglycerides (D), total cholesterol (E), LDL cholesterol (F), HDL cholesterol (G), and estimated glomerular ﬁltration rate (eGFR) (H). Data displayed as means 6 SD. P value refers to comparison between the groups. care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1309 Metformin, glipizide, and cardiovascular outcomes Foundation of China (30971077, 81170784), associated with weight gain, whereas met- (Department of Endocrinology, The Second theShanghaiShenkang HospitalDevelopment formin is associated with weight loss. Xiangya Hospital of Central South Univer- Center (Shdc12007309), the Key Laboratory for Weight gain may negate the beneﬁcial ef- sity); Jiajun Zhao, MD, PHD; Qingbo Guan, Endocrine and Metabolic Diseases of Ministry fects of sulfonylureas on glucose and in- MD; Xu Zhang, MD (Department of Endo- of Chinese Public Health (1994DP131044), crease mortality (30). Moreover, in our crinology, Shandong Provincial Hospital); the National Key New Drug Creation and present study, statin use was signiﬁcantly Lianqun Cui, MD, PHD; Liming Chen, MD Manufacturing Program (2008ZX09312/019), lower in the metformin group as compared (Department of Cardiology, Shandong the Shanghai Committee on Science and Tech- with the glipizide group (59.5 vs. 73.7%; Provincial Hospital); Dajin Zou, MD, PHD; nology (10dz1920802), the Program for In- P = 0.013) at the end of the study. How- Juan Li, MD; Yue Chen, PHD (Department novative Research Team of Shanghai Municipal ever, no signiﬁcant difference was found in Education Commission, the Sector Funds of of Endocrinology, Chang Hai Hospital); Ministry of Health (No. 201002002), and the the lipid levels between the two groups af- Dawang Wang, MD, PHD; Feixia Shen, National Key New Drug Creation and Manu- ter treatment, even with a tendency of MD, PHD; Wenjun Wu, MD (Department facturing Program of Ministry of Science and slightly higher triglyceride levels during of Endocrinology, The First Afﬁliated Technology (No. 2012ZX09303006-001). Both the ﬁrst part (18 months) in the metformin Hospital of Wenzhou Medical College); glipizide and metformin were provided by Xinyi group. These ﬁndings further strengthened Hong Li, MD, PHD; Jiaqiang Zhou, MD Pharmaceutical Co. (Shanghai, China). All the the beneﬁcial long-term effects of metfor- (Department of Endocrinology, Sir Run funding sources of the study had no role in min, which might be associated with the Run Shao Hospital); Chao Liu, MD, PHD; study design, data collection, data analysis, data antiatherosclerotic properties beyond glu- Tao Yang, MD, PHD; Bei Shen, MD (De- interpretation, or writing of the manuscript. No cose lowering (31,32). partment of Endocrinology, Jiangsu Prov- other potential conﬂicts of interest relevant to The prospective, randomized, and ince Hospital); Guoting Wu, MD, PHD; this article were reported. controlled design of our study minimizes J.H. and Y.Z. contributed to the implemen- Shen Qu, MD, PHD; Chunjun Sheng, tation of the protocol and to writing the RESEARCH the potential bias and confounding. How- MD; Xiaoyun Cheng, MD (Department of DESIGN AND METHODS, RESULTS,and CONCLUSIONS. ever, several limitations need to be consid- Endocrinology, Shanghai Ten’sPeople’s S.L. performed the statistical analysis and re- ered. First, we used glipizide to represent Hospital of Tongji University); Jie Shen, viewed the manuscript. A.L., D.Zh., W.W., and the sulfonylureas because it is one of the MD, PHD; Yaoming Xue, MD, PHD; Min W.S. contributed to the design and im- most commonly used sulfonylureas in Wang, MD; Xiangrong Luo (Department of plementation of the protocol and to writing the China. However, various sulfonylureas Endocrinology, Nanfang Hospital); Dalong CONCLUSIONS. Q.S., Y.D., Z.Z., W.T., J.Z., L.C., may differ in their effects on glucose control Zhu, MD, PHD; Shanmei Shen, MD (De- D.Zo., D.W., H.L., C.L., G.W., and J.S. contrib- and cardiovascular risk in diabetic patients partment of Endocrinology, Nanjin Drum uted to the implementation of the protocol and (14–16). Second, the secondary end points coordinated preparation of the CONCLUSIONS. Tower Hospital); Shenghua Yao, MD; G.N. designed and implemented the protocol and adverse events were recorded only dur- Xiuhua Yu, MD (Department of Endocri- and was lead author. All authors approved the ing the 3-year period of study drug admin- nology, Putuo Hospital, Shanghai, China); ﬁnal manuscript. G.N. is the guarantor of this istration, which might decrease the power Huigen Jin, MD; Jia Shi, MD (Department work and, as such, had full access to all the data in of analysis. Third, we did not have a wash- of Cardiology, Putuo Hospital); Bo Feng, the study and takes responsibility for the integrity out period in the current study due to safety MD, PHD; Yafang Ni, MD (Department of of the data and the accuracy of the data analysis. concerns. Moreover, although the training Endocrinology, East Hospital, Shanghai, of a lifestyle approach was implemented to China); Shengli Yan, MD; Yangang Wang, reduce the risk for cardiovascular outcome MD; and Xingji Gong, MD (Department of APPENDIX in both groups and through all research Endocrinology, The Afﬁliated Hospital centers according to the National Choles- of Qindao University Medical College, terol Education Program Adult Treatment SPREAD-DIMCAD CLINICAL Shandong Province, China). Panel III recommendation, we did not SITES monitor and record the change of diet and The investigators and coordinators of this References exercise during the study. However, the study are as follows: Guang Ning, MD, 1. Yang W, Lu J, Weng J, et al.; China Na- double-blind, randomized study design PHD; Jie Hong, PHD; Yifei Zhang, PHD; tional Diabetes and Metabolic Disorders and the intent-to-treat approach might min- Weiqing Wang, MD, PHD; Minghui Gui, Study Group. Prevalence of diabetes imize these limitations. Therefore, we would PHD; Ying Chen, MD; Zhenni Chi, MD; among men and women in China. N Engl be cautious in interpreting the ﬁndings. Qun Yan, MD; Ying Zhai, MD (Shanghai J Med 2010;362:1090–1101 In summary, metformin therapy for 3 Clinical Center for Endocrine and Meta- 2. UK Prospective Diabetes Study (UKPDS) years substantially reduced major cardio- bolic Diseases, Ruijin Hospital); Weifeng Group. Intensive blood-glucose control vascular events in high-risk patients Shen, MD, PHD; Ankang Lv, MD; Ruiyan with sulphonylureas or insulin compared compared with glipizide, one of the com- Zhang, MD, PHD (Department of Cardi- with conventional treatment and risk of complications in patients with type 2 di- monly used sulfonylureas. Our results, ology, Ruijin Hospital); Jialin Yang, PHD; abetes (UKPDS 33). Lancet 1998;352: taken in conjunction with recent re- Yu Zhang, MD; Xiaofang Fan, MD (De- 837–853 search, indicated a potential beneﬁtof partment of Endocrinology, Min Hang 3. Holman RR, Paul SK, Bethel MA, metformin therapy on cardiovascular out- Center Hospital, Shanghai, China); Da- Matthews DR, Neil HA. 10-year follow-up comes in diabetic patients. dong Zhang, MD, PHD (Department of of intensive glucose control in type 2 di- Cardiology, Min Hang Center Hospital); abetes. N Engl J Med 2008;359:1577– Qing Su, PHD; Yan Dong, PHD; Huili Xing, MD (Department of Endocrinology, AcknowledgmentsdThis study was sup- 4. Patel A, MacMahon S, Chalmers J, et al.; Xinhua Hospital); Zhiguang Zhou, MD, ported by grants from the 863 Project (2006 ADVANCE Collaborative Group. Inten- PHD; Xing Li, MD; Weili Tang, PHD AA 02A409), the National Natural Science sive blood glucose control and vascular 1310 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates outcomes in patients with type 2 diabetes. infarction not treated with emergent per- 22. DeFronzo RA. Pharmacologic therapy for N Engl J Med 2008;358:2560–2572 cutaneous coronary interventionda ret- type 2 diabetes mellitus. Ann Intern Med 5. Gaede P, Vedel P, Larsen N, Jensen GV, rospective nationwide cohort study. 1999;131:281–303 Parving HH, Pedersen O. Multifactorial Cardiovasc Diabetol 2010;9:54 23. O’Rourke B. Evidence for mitochondrial intervention and cardiovascular disease in 14. Schramm TK, Gislason GH, Vaag A, et al. K channels and their role in cardio- patients with type 2 diabetes. N Engl J Mortality and cardiovascular risk associ- protection. Circ Res 2004;94:420–432 Med 2003;348:383–393 ated with different insulin secretagogues 24. Yellon DM, Downey JM. Preconditioning 6. Gaede P, Lund-Andersen H, Parving HH, compared with metformin in type 2 di- the myocardium: from cellular physiology Pedersen O. Effect of a multifactorial in- abetes, with or without a previous myo- to clinical cardiology. Physiol Rev 2003; tervention on mortality in type 2 diabetes. cardial infarction: a nationwide study. Eur 83:1113–1151 N Engl J Med 2008;358:580–591 Heart J 2011;32:1900–1908 25. Riveline JP, Danchin N, Ledru F, Varroud- 7. Meinert CL, Knatterud GL, Prout TE, 15. Fiévet C, Nuttens MC, Ducimetière P, Vial M, Charpentier G. Sulfonylureas and Klimt CR. A study of the effects of hypo- Fruchart JC, Bertrand M, Salomez JL. Re- cardiovascular effects: from experimental glycemic agents on vascular complica- lation of arteriographically deﬁned coro- data to clinical use. Available data in hu- tions in patients with adult-onset diabetes. nary artery disease to serum lipoprotein mans and clinical applications. Diabetes II. Mortality results. 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UK Prospective Diabetes Study (UKPDS) and Treatment of High Blood Cholesterol protein 90 and endothelial nitric oxide Group. Effect of intensive blood-glucose in Adults. Executive Summary of the synthase. Diabetes 2006;55:496–505 control with metformin on complications Third Report of the National Cholesterol 28. Mather KJ, Verma S, Anderson TJ. Im- in overweight patients with type 2 di- Education Program (NCEP) Expert Panel proved endothelial function with metfor- abetes (UKPDS 34). Lancet 1998;352: on Detection, Evaluation, and Treatment min in type 2 diabetes mellitus. J Am Coll 854–865 of High Blood Cholesterol in Adults Cardiol 2001;37:1344–1350 10. Johnson JA, Majumdar SR, Simpson SH, (Adult Treatment Panel III). JAMA 2001; 29. De Jager J, Kooy A, Lehert P, et al. Effects Toth EL. Decreased mortality associated 285:2486–2497 of short-term treatment with metformin with the use of metformin compared with 18. Lin DY, Wei LJ, Yang I, Ying Z. 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A meta-analysis of observational betologia 2006;49:930–936 625 studies. Diabetes Care 2008;31:1672–1678 12. Kahn SE, Haffner SM, Heise MA, et al.; 20. Gu K, Cowie CC, Harris MI. Mortality in 31. Fidan E, Onder Ersoz H, Yilmaz M, et al. ADOPT Study Group. Glycemic durabil- adults with and without diabetes in a na- The effects of rosiglitazone and metformin ity of rosiglitazone, metformin, or gly- tional cohort of the U.S. population, on inﬂammation and endothelial dys- buride monotherapy. N Engl J Med 2006; 1971-1993. Diabetes Care 1998;21: function in patients with type 2 diabetes 355:2427–2443 1138–1145 mellitus. Acta Diabetol 2011;48:297–302 13. Jørgensen CH, Gislason GH, Andersson 21. Bertoni AG, Krop JS, Anderson GF, 32. Papanas N, Maltezos E. Oral antidiabetic C, et al. Effects of oral glucose-lowering Brancati FL. Diabetes-related morbidity agents: anti-atherosclerotic properties be- drugs on long term outcomes in patients and mortality in a national sample of U.S. yond glucose lowering? Curr Pharm Des with diabetes mellitus following myocardial elders. Diabetes Care 2002;25:471–475 2009;15:3179–3192 care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1311 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Care Pubmed Central http://www.deepdyve.com/lp/pubmed-central/effects-of-metformin-versus-glipizide-on-cardiovascular-outcomes-in-q0hyiMIAp0

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Publisher: Pubmed Central
Copyright: © 2013 by the American Diabetes Association.
ISSN: 0149-5992
eISSN: 1935-5548
DOI: 10.2337/dc12-0719
Publisher site: See Article on Publisher Site

Abstract

Cardiovascular and M etabolic R isk OR IGIN AL AR TIC L E Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease 1 7 JIE HONG, MD DAWANG WANG, MD he prevalence of type 2 diabetes has 1 8 YIFEI ZHANG, MD HONG LI, MD been increasing rapidly throughout 2 9 SHENGHAN LAI, MD CHAO LIU, MD Tthe world during the past decades (1). 1 10 ANKANG LV, MD GUOTING WU, MD Since cardiovascular disease is the 3 11 QING SU, MD JIE SHEN, MD 3 12 major complication of type 2 diabetes, YAN DONG, MD DALONG ZHU, MD 4 1 and cardiovascular mortality accounts ZHIGUANG ZHOU, MD WEIQING WANG, MD 4 1 for the majority of diabetic patient WEILI TANG, MD WEIFENG SHEN, MD 5 1 deaths, there has been growing interest JIAJUN ZHAO, MD GUANG NING, MD, PHD LIANQUN CUI, MD ON BEHALF OF THE SPREAD-DIMCAD in developing strategies for blood glucose DAJIN ZOU, MD INVESTIGATORS* control in type 2 diabetic patients to re- duce cardiovascular risk and mortality (2–6). OBJECTIVEdThe two major classes of antidiabetic drugs, sulfonylureas and metformin, may Among various oral glucose-lowering differentially affect macrovascular complications and mortality in diabetic patients. We com- medications, metformin and sulfonyl- pared the long-term effects of glipizide and metformin on the major cardiovascular events in type ureas have been the mainstay treatments 2 diabetic patients who had a history of coronary artery disease (CAD). for type 2 diabetes. Several studies have RESEARCH DESIGN AND METHODSdThis study is a multicenter, randomized, double- examined the effects of these medications blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = on cardiovascular risk among diabetic 63.3 years (range, 36–80 years), were enrolled. Participants were randomly assigned to receive either patients; the results, however, are incon- glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the sistent (2,7–9). In an early, large-scale, composite of recurrent cardiovascular events, including death from a cardiovascular cause, death randomized trial, an increased risk of car- from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. diovascular mortality was observed in di- RESULTSdAt the end of study drug administration, both groups achieved a signiﬁcant decrease in abetic patients treated with sulfonylurea the level of glycated hemoglobin (7.1% in the glipizidegroup and7.0% inthe metformingroup). At a (tolbutamide) or biguanide (phenformin) median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat medications (7,8). Some other studies analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30–0.90; P = 0.026) for the composites suggest that these two classes of medica- of cardiovascular events among the patients that received metformin, compared with glipizide. The tions might differentially affect cardiovas- secondary end points and adverse events were not signiﬁcantly different between the two groups. cular risk (9–14). For example, in the CONCLUSIONSdTreatment with metformin for 3 years substantially reduced major cardio- open-label UK Prospective Diabetes vascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a Study (UKPDS) (9), it was found that di- potential beneﬁt of metformin therapy on cardiovascular outcomes in high-risk patients. abetic patients with metformin treatment had a reduced risk of macrovascular and Diabetes Care 36:1304–1311, 2013 microvascular complications as well as all-cause mortality compared with those treated with sulfonylurea or insulin. ccccc cccccccc cccccccc cccccccc cccccccc cccccccc ccc c However, the combined treatment of 1 2 From the Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; the Johns metformin and sulfonylurea led to an in- Hopkins University School of Medicine, Baltimore, Maryland; the Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; The Second Xiangya Hospital of Central South University, creased risk of all-cause mortality. Taken 5 6 Changsha, China; the Shandong Provincial Hospital, Shandong University, Jinan, China; the Chang Hai together, how these two major hypogly- Hospital, Second Military Medical University, Shanghai, China; The First Afﬁliated Hospital of Wenzhou cemic agents may affect cardiovascular Medical College, Zhejiang Province, China; the Sir Run Run Shao Hospital, Zhejiang Province, China; the 9 10 risk and mortality among diabetic pa- Jiangsu Province Hospital, Jiangsu Province, China; the Shanghai Ten’sPeople’s Hospital of Tongji Uni- 11 12 versity, Shanghai, China; the Nanfang Hospital, Guangdong Province, China; and the Nanjin Drum Tower tients remains unclear. Hospital, Jiangsu Province, China. Therefore, we performed a random- Corresponding author: Guang Ning, [email protected]. ized, double-blind, placebo-controlled Received 16 April 2012 and accepted 4 October 2012. trial to compare the effects of the two DOI: 10.2337/dc12-0719. Clinical trial reg. no. NCT00513630, clinicaltrials.gov. major classes of blood glucose–lowering This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 .2337/dc12-0719/-/DC1. agents, sulfonylurea (glipizide) and met- J.H. and Y.Z. contributed equally to this study. formin, on the cardiovascular events and *A complete list of the investigators of SPREAD-DIMCAD can be found in the APPENDIX. mortality in 304 Chinese type 2 diabetic © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly patients who had a history of coronary 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. artery disease (CAD). 1304 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates RESEARCH DESIGN AND infarction, nonfatal stroke or arterial re- other treatments for CAD and modiﬁable METHODS vascularization by percutaneous trans- cardiovascular risk factors were identical luminal coronary angioplasty (PTCA) or in both groups through all research cen- Study design and participants by coronary artery bypass graft, death ters according to the recommendation of The Study on the Prognosis and Effect of from a cardiovascular cause, and death the Third Report of the National Choles- Antidiabetic Drugs on Type 2 Diabetes from any cause. The end points were terol Education Program Expert Panel on Mellitus with Coronary Artery Disease obtained and conﬁrmed by the medical Detection, Evaluation, and Treatment of (SPREAD-DIMCAD) was a prospective, records and death certiﬁcates that were High Blood Cholesterol In Adults (Adult randomized, double-blind, placebo- kept in each center. The secondary car- Treatment Panel III) (17). controlled trial that evaluated the differ- diovascular end points included new or The study drug administration was 3 ent effects of glipizide and metformin on worsening angina, new or worsening years for each participant. The follow-up the major cardiovascular events and mor- heart failure, new critical cardiac ar- for primary end points began at random- tality among type 2 diabetic patients rhythmia, and new peripheral vascular ization and continued until the end of the with a history of CAD. The patients were events. Other adverse events, including study. The original protocol invited all recruited from 15 clinical centers in China. hypoglycemia (severe hypoglycemia in participants to continue with the follow- The study was approved by the institu- which the subject required assistance up of primary outcomes until the end of tional review board of Ruijin Hospital, and and/or a plasma glucose level ,56 mg/dL the whole study (last subject ﬁnished the written informed consent was obtained [3.1 mmol/L] was recorded as a hypo- study drug administration) after the ini- from each patient. The study was conduc- glycemic attack and would be reported tial 3-year studydrugadministration. In ted in accordance with the principles of the in this manuscript) and microvascular the postdrug follow-up period, the pri- Declaration of Helsinki. complications, were also monitored. mary end points were obtained and no The targeted participants in the cur- attempts were made to maintain their rent study were patients with both type 2 Randomization and study medication previous therapies. During study drug diabetes and CAD. The eligibility criteria After a 2-week run-in period, the eligible administration, information on adher- included the following: 1)diagnosed as study participants were required to with- ence and tolerability of study drugs, CAD by either having a history of acute draw from all antidiabetic agents and concomitant medication, adverse events, myocardial infarction diagnosed by a rep- were randomly assigned in double-blind and occurrence of study outcomes were resentative set of electrocardiograms, to receive either glipizide plus metformin collected, and physical examination, vital cardiac enzyme values, and typical symp- placebo or metformin plus glipizide pla- signs, and plasma glucose concentrations toms or by angiographically identiﬁed cebo for 3 years. The baseline metabolic were obtained. Glycated hemoglobin lev- stenosis of .50% of lumen diameter in values were obtained immediately after els were measured at 6, 12, 18, 24, 30, at least one major epicardial coronary ar- the withdrawal of previous antidiabetic and 36 months (extra results might be tery (15); 2) diagnosed as type 2 diabetic therapy. The randomization codes were required according to the investigator’s according to the 1999 World Health Or- generated by the study’s biostatistician at judgment), and lipid concentration, bio- ganization criteria (fasting plasma glucose Shanghai Jiao Tong University School of chemical safety laboratory analysis, elec- $7mmol/Land/or2-h oral glucose tol- Medicine. Study sites did not have access trocardiograms, and echocardiographic erance test $11.1 mmol/L (16) and fast- to the codes. results were obtained. ing plasma glucose ,15 mmol/L); and 3) For both groups, the targeted glyca- Ruijin Hospital served as the coordi- no more than 80 years of age (both men ted hemoglobin level was ,7.0%, the nating center. There was no central labo- and women). The exclusion criteria in- fasting blood glucose concentration was ratory for biochemical analysis for the cluded the following: 1) severe liver dys- ,7 mmol/L, and the postload 2-h blood study. function, including serum alanine glucose concentration was ,10 mmol/L. aminotransferase concentration .2.5 The study drugs and the matched placebo Statistical analysis times above the upper limit of normal were prepared in indistinguishable tab- This study was designed in accordance range and abnormal renal function (se- lets. For the glipizide group, the initial with a predetermined statistical analysis rum creatinine .132 mmol/L); 2) severe dose was 15 mg daily (5 mg per one plan. Given a constant rate of events of dysfunction of the heart (New York Heart pill, three times daily) and titrated to 30 10% per year, a sample size of 150 Association class .phase III); 3) psychi- mg (10 mg per two pills, three times patients in each of the two study groups atric disease, severe infection, severe ane- daily) within 3 months, if not to target. would provide an 85% power at a type 1 mia, or neutropenia; 4)other severe The mean daily dose of glipizide was error rate of 0.05 to detect a 30% re- organic heart diseases, including, but 28.36 3.9 mg. For the metformin group, duction in the relative risk of the com- not limited to, congenital heart disease, the initial dose was 0.75 g daily (0.25 g posite primary outcomes during the rheumatic heart disease, and hypertro- per one pill, three times daily), and ti- follow-up. This analysis was designed to phic or dilated cardiomyopathy; 5) preg- trated to 1.5 g (0.5 g per two pills, three test the primary hypothesis that glipizide nant or lactating; 6) allergic to study times daily) within 3 months, if not to and metformin would have a different drugs; 7) using insulin therapy for type target. The mean daily dose of metformin effect on the recurrence of composite 2 diabetes and could not be changed to was 1.4 6 0.2g.After 3months, insulin cardiovascular events. The follow-up for oral glucose-lowering drugs; and 8)re- was added for patients with the maxi- primary end points began at randomiza- cent drug or alcohol abuse. mum dose of study drug administration tion and continued until the end of the The primary study end points were in either group who did not achieve tar- study (last subject ﬁnished the study drug the composite of recurrent cardiovascu- geted glucose control level (see Supple- administration) after the initial 3-year lar events, including nonfatal myocardial mentary Data). Lifestyle intervention and study drug administration. care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1305 Metformin, glipizide, and cardiovascular outcomes Statistical analysis was performed with SAS (version 9.2; SAS Institute, Cary, NC). Data were expressed as means and SDs or as medians with IQRs when speciﬁed. Logarithmic transformation was used for variables that were not normally distributed. Within-group com- parisons were performed with paired- sample Student t tests to evaluate the differences from baseline in each group. A Student t test (for data that were normally distributed) or a Mann-Whitney U test (not normally distributed) and an ANCOVA analysis with a model that in- cluded the baseline value of the dependent variable as a covariate were also used for comparison between groups. A x test was used to analyze the differences in categor- ical variables. The primary end point of this trial was time to recurrent events. Multiple event analysis was performed with the use of the proportional means re- gression model (18). A multivariate pro- portional means regression model was used to control for the duration of diabe- tes, duration of CAD, age, sex, and smok- ing history at baseline. For all analyses, glipizide use was treated as the reference group. The intention-to-treat principle was used for end point analyses. All reported P values are two sided, Figure 1dSPREAD-DIMCAD trial proﬁle. and P values ,0.05 were considered to be statistically signiﬁcant. At the end of the 3-year study drug for 25 patients in the glipizide group and RESULTSdRecruitment ran from 1 administration, the glycated hemoglobin 30 patients in the metformin group, re- June 2004 to 30 July 2007. Of 565 levels were signiﬁcantly improved in both spectively (P = 0.259). The percentage of patients who were screened, a total of groups, and no difference was found patients using insulin between the two 304 patients were enrolled in the study, between the two groups (Table 1). The groups at each visit was not signiﬁcantly with follow-up ending in July 2010. Fig- mean glycated hemoglobin values had different (all P . 0.05). Furthermore, the ure 1 showed the process of screening and fallen from 7.6% at baseline to 7.1% in dose used per person who was added with randomization. The 31 patients in the gli- the glipizide group and from 7.6 to insulin in both groups increased but with pizide group and 32 in the metformin 7.0% in the metformin group within 6 no difference between the two groups group that terminated early with the months after randomization and re- (Table 1 and Supplementary Fig. 1). study drug administration were still en- mained stable thereafter (Fig. 2A). Both Drugs prescribed for other risk factors couraged to continue the follow-up of pri- groups showed a signiﬁcant decrease in did not differ signiﬁcantly at the end of mary outcomes. The median follow-up fasting and 2-h plasma glucose concentra- the follow-up between the two groups, period was 5.0 years (range, 3.7–5.7 tions after treatment, and no difference except for statins, which were used less years). The mean age of the participants was found between the two groups (Table in the metformin group compared with was 63.3 years (range, 36–80 years). Type 1 and Fig. 2B). At baseline, no difference the glipizide group (P = 0.013) (Table 1). 2 diabetes had been diagnosed for a was found in the BMI between the groups. A total of 103 composite primary end mean of 5.6 years and CAD for a mean However, after treatment, it was signiﬁ- points occurred in 91 patients (52 of 2.9 years before recruitment. The dis- cantly lower in the metformin group [35.1%] in the glipizide group and 39 tribution and doses of glucose-lowering than in the glipizide group (Table 1 and [25.0%] in the metformin group) (char- agents at baseline (Table 1 and Supple- Fig. 2C). Similar differences were ob- acteristics of these patients are shown in mentary Table 1) and the other baseline served for body weight and waist circum- Supplementary Table 2) during the whole characteristics of the participants in the ference between these two groups (Table study period: 60 events in the glipizide glipizide and metformin groups were 1). Detailed changes and a comparison of group (14 deaths from any causes [in- generally similar except for the 2-h the other clinical and biochemical charac- cluding 11 deaths from cardiovascular plasma glucose levels. There was no sig- teristics of the two groups are shown in events and 3 from sudden death; unfor- niﬁcant differences between the two Table 1 and Fig. 2. tunately autopsies were not performed to groups in the concomitant medication In order to reach the targeted glycated conﬁrm the 3 patients’ precise causes of (Table 1). hemoglobin level, insulin was prescribed death], 6 nonfatal myocardial infarctions, 1306 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates Table 1dCharacteristics of the patients at baseline and end of follow-up Baseline End of follow-up Glipizide Metformin Glipizide Metformin Characteristic (n = 148) (n = 156) P value* (n =97) (n = 111) P value* P valuex Age (years) 63.8 6 9.4 62.8 6 8.5 0.302 Sex, n (%) 0.805 Male 114 (77.0%) 122 (78.2%) Female 34 (23.0%) 34 (21.8%) Time since diagnosis of diabetes (years) 5.6 6 4.9 5.6 6 5.3 0.947 Time since diagnosis of CAD (years) 3.0 6 5.1 2.9 6 4.8 0.837 History of myocardial infarction, n (%) 94 (63.5%) 84 (53.8%) 0.103 History of arterial revascularization, n (%) 95 (64.2%) 98 (62.8%) 0.813 History of nonfatal stroke, n (%) 13 (9.0%) 18 (11.5%) 0.428 Patients with hypertension, n (%) 106 (71.6%) 105 (67.3%) 0.408 Current smokers, n (%) 53 (35.8%) 61 (39.1%) 0.726 Alcohol use, n (%) 19 (12.8%) 36 (23.1%) 0.068 Body weight (kg) 68.7 6 10.6 69.6 6 10.1 0.465 69.6 6 11.0 68.6 6 10.4 0.554 0.002 BMI (kg/m ) 25.1 6 2.9 25.2 6 3.0 0.675 25.7 6 2.9 24.7 6 2.8 0.026 ,0.001 Waist circumference (cm) 90 6991 690.317 92 6990 6 9 0.118 0.001 Blood glucose control Glycated hemoglobin level (%) Mean 6 SD 7.6 6 1.7 7.6 6 1.7 0.847 7.1 6 1.1 7.0 6 1.3 0.662 0.419 Median 7.3 7.3 7.0 6.8 IQR 6.5–8.4 6.6–8.4 6.3–7.8 6.2–7.4 Fasting plasma glucose (mmol/L) Mean 6 SD 7.77 6 2.22 8.21 6 2.28 0.075 6.91 6 1.52 7.21 6 2.24 0.297 0.405 Median 7.4 7.8 7.0 6.8 IQR 6.4–8.4 6.6–9.0 6.0–7.7 6.2–7.7 Postload 2-h plasma glucose (mmol/L) Mean 6 SD 12.56 6 4.20 13.61 6 4.05 0.014 11.34 6 3.58 10.84 6 3.41 0.370 0.207 Median 12.0 13.0 10.5 10.3 IQR 9.6–15.1 10.5–16.3 8.8–13.0 8.5–12.7 Blood pressure (mmHg) Systolic 129.1 6 18.4 130.1 6 17.6 0.667 128.6 6 15.1 128.0 6 15.5 0.804 0.737 Diastolic 78.3 6 9.7 78.4 6 10.0 0.921 75.8 6 9.8 75.9 6 8.3 0.933 0.950 Fasting serum cholesterol (mmol/L) Total 4.55 6 1.32 4.93 6 3.00 0.159 4.36 6 1.30 4.52 6 1.23 0.442 0.667 LDL 2.73 6 0.90 2.79 6 0.89 0.544 2.40 6 0.83 2.60 6 0.83 0.132 0.248 HDL 1.16 6 0.32 1.15 6 0.32 0.748 1.28 6 0.38 1.23 6 0.33 0.339 0.958 Fasting serum triglyceride (mmol/L) 2.07 6 1.65 2.44 6 1.96 0.080 2.10 6 2.49 2.10 6 1.71 1.000 0.537 Serum creatinine (mmol/L) 86.7 6 18.9 83.8 6 17.6 0.165 86.3 6 22.0 83.3 6 25.2 0.433 0.302 Medications, n (%) Glucose-lowering drug Sulfonylurea 80 (54.1%) 76 (48.7%) 0.349 Metformin 81 (54.7%) 74 (47.4%) 0.201 Thiazolidinedione 3 (2.0%) 3 (1.9%) 0.948 Acarbose 30 (20.3%) 37 (23.7%) 0.469 Glinide 4 (2.7%) 5 (3.2%) 0.797 Insulin 15 (10.1%) 13 (8.3%) 0.586 25 (26.3%) 30 (27.0%) 0.908 0.259 None 24 (16.2%) 37 (23.7%) 0.103 Other drugs Aspirin 122 (82.4%) 132 (84.6%) 0.703 77 (81.1%) 99 (89.2%) 0.067 0.287 ACE inhibitor 76 (51.4%) 79 (50.6%) 0.893 53 (55.8%) 54 (48.6%) 0.338 0.492 Continued on p. 1308 care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1307 Metformin, glipizide, and cardiovascular outcomes Table 1dContinued Baseline End of follow-up Glipizide Metformin Glipizide Metformin Characteristic (n = 148) (n = 156) P value* (n =97) (n = 111) P value* P valuex Angiotensin receptor blocker 11 (7.4%) 17 (10.9%) 0.297 5 (5.3%) 10 (9.0%) 0.294 0.456 Beta-blocker 80 (54.1%) 90 (57.7%) 0.524 60 (63.2%) 73 (65.8%) 0.632 0.625 Calcium-channel blocker 47 (31.8%) 48 (30.8%) 0.910 34 (35.8%) 35 (31.5%) 0.580 0.901 Diuretic 22 (14.9%) 16 (10.3%) 0.223 11 (11.6%) 10 (9.0%) 0.558 0.726 Statin 97 (65.5%) 97 (62.2%) 0.582 70 (73.7%) 66 (59.5%) 0.039 0.013 Data are means 6 SD for data normally distributed, n (%), or median and IQR for data not normally distributed. Statistical signiﬁcances were determined using a Student t test (for data normally distributed) or a Mann-Whitney U test (for data not normally distributed) and x test (for categorical variable data). *P values are for the difference between the groups at baseline or at the end of follow-up. xP value refers to comparison between the glipizide and the metformin groups after treatment using the ANCOVA analysis. 15 nonfatal strokes, and 25 arterial revas- CONCLUSIONSdSPREAD-DIMCAD effects of sulfonylureas and metformin cularizations), as compared with 43 was the ﬁrst double-blind, randomized, on cardiovascular events, and the evi- events in the metformin group (7 deaths controlled trial to compare the different dence from randomized clinical trials is from any causes [all were deaths from car- effects of glipizide and metformin on the sparse (12). diovascular events], 5 nonfatal myocardial major cardiovascular events among pa- Our study was the ﬁrst to compare infarctions, 10 nonfatal strokes, and 21 ar- tients with type 2 diabetes and CAD. the effects of sulfonylureas (glipizide) and terial revascularizations). As compared After a median of 5.0 years of follow-up, metformin on the recurrence of major with the patients treated with glipizide, treatmentwithmetformin showed a signif- cardiovascular events in a prospective, the HR for the composite cardiovascular icant reduction of the recurrence of com- randomized, double-blind, placebo- events for metformin treatment was 0.54 posite cardiovascular events compared controlled trial. We found that, compared (95% CI 0.30–0.90; P = 0.026) after adjust- with glipizide, which indicated a protective with glipizide, metformin showed a sig- ment for the duration of diabetes, duration effect of metformin on cardiovascular niﬁcant reduction in composite cardiovas- of CAD, age, sex, and smoking history at events in high-risk patients. Such a pro- cular end points. Furthermore, since the baseline (Supplementary Table 3). No sig- tective effect of metformin may also be primary outcome occurring within 1 year niﬁcant difference in the mortality rate be- present in a later stage of type 2 diabetes (nine patients in the glipizide group and tween the two groups was found; P =0.55. during insulin therapy (19). eight patients in the metformin group) During the study drug administra- Cardiovascular disease is the most seems unlikely to have been caused by tion, the following secondary end points common complication and the leading the effects of glipizide or metformin treat- occurred: new or worsening heart failure cause of mortality in patients with type 2 ment, we performed a stratiﬁed analysis developed in 10 (6.8%) patients in the diabetes (20,21). Sulfonylureas and met- and only looked at the events after 1 year glipizide group and 9 (5.8%) patients in formin have been the cornerstone of drug (HR 0.48 [95% CI 0.31–0.72]; P , the metformin group (adjusted HR 0.82 therapy for type 2 diabetes, either alone or 0.001), showing a better effect of metfor- [95% CI 0.31–2.13]; P = 0.677); new crit- in combination, for a quarter of a century min on the primary outcome. Several lines ical cardiac arrhythmia occurred in 27 (22). Experimental studies have shown of evidence may explain the different ef- (18.2%) patients in the glipizide group different effects of these two kinds of an- fects of sulfonylureas and metformin on and 30 (19.2%) patients in the metformin tidiabetic drugs on cardiovascular disease cardiovascular and all-cause mortality. group (1.01 [0.60–1.72]; P = 0.958); new besides their glucose-lowering effect (23– Sulfonylureas can increase pancreatic or worsening angina occurred in 71 29). However, studies comparing these b-cell insulin release by inhibiting the (48%) patients in the glipizide group two classes of medications on cardiovas- ATP-sensitive potassium (K )channel ATP and 77 (49.4%) patients in the metformin cular risk in humans generated highly in- through binding to b-cell sulfonylurea re- group (1.07 [0.77–1.48]; P = 0.696); and consistent results (7–14). Several reasons ceptor 1. While binding to sulfonylurea 6 (4.1%) patients in the glipizide group may account for the discrepancies among receptor 2 on cardiac myocytes, sulfony- and 1 (0.6%) patient in the metformin these studies. First, most of the previous lureas inhibit cardiac K channels and ATP group developed peripheral vascular studies are retrospective and observa- reduce the protective effects of myocardial events (0.13 [0.02–1.08]; P = 0.059). tional in design. The patients included preconditioning (14,23–25). On the Furthermore, the two groups did not in different studies varied in the severity other hand, metformin reduces hepatic differ signiﬁcantly with respect to the of diabetes and cardiovascular disorders gluconeogenesis and increases insulin- number of patients who reported one as well as other characteristics, such as stimulated glucose uptake in skeletal mus- or more hypoglycemic attacks during BMI and glucose levels, which might in- cle and fat tissue (26). Recent evidence study drug administration (four in the ﬂuence drug choice. Second, the uses of shows that metformin has antiatherogenic glipizide group and three in the metfor- cardiovascular medications were not well effects through the reduction of inﬂamma- min group, P = 0.651; when excluding controlled in some studies and might also tory markers, vascular adhesion molecules, insulin users, three in glipizide group contribute to the diverse associations with and coagulation parameters, as well as the and zero in metformin group, P = cardiovascular events. Moreover, few pre- reduction of endothelial dysfunction 0.080). vious studies directly compared the (27–29). In addition, sulfonylureas are 1308 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates Figure 2dChanges of major clinical and biochemical characteristics at baseline and during follow-up in different groups. HbA (A), fasting 1c plasma glucose (B), BMI (C), triglycerides (D), total cholesterol (E), LDL cholesterol (F), HDL cholesterol (G), and estimated glomerular ﬁltration rate (eGFR) (H). Data displayed as means 6 SD. P value refers to comparison between the groups. care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1309 Metformin, glipizide, and cardiovascular outcomes Foundation of China (30971077, 81170784), associated with weight gain, whereas met- (Department of Endocrinology, The Second theShanghaiShenkang HospitalDevelopment formin is associated with weight loss. Xiangya Hospital of Central South Univer- Center (Shdc12007309), the Key Laboratory for Weight gain may negate the beneﬁcial ef- sity); Jiajun Zhao, MD, PHD; Qingbo Guan, Endocrine and Metabolic Diseases of Ministry fects of sulfonylureas on glucose and in- MD; Xu Zhang, MD (Department of Endo- of Chinese Public Health (1994DP131044), crease mortality (30). Moreover, in our crinology, Shandong Provincial Hospital); the National Key New Drug Creation and present study, statin use was signiﬁcantly Lianqun Cui, MD, PHD; Liming Chen, MD Manufacturing Program (2008ZX09312/019), lower in the metformin group as compared (Department of Cardiology, Shandong the Shanghai Committee on Science and Tech- with the glipizide group (59.5 vs. 73.7%; Provincial Hospital); Dajin Zou, MD, PHD; nology (10dz1920802), the Program for In- P = 0.013) at the end of the study. How- Juan Li, MD; Yue Chen, PHD (Department novative Research Team of Shanghai Municipal ever, no signiﬁcant difference was found in Education Commission, the Sector Funds of of Endocrinology, Chang Hai Hospital); Ministry of Health (No. 201002002), and the the lipid levels between the two groups af- Dawang Wang, MD, PHD; Feixia Shen, National Key New Drug Creation and Manu- ter treatment, even with a tendency of MD, PHD; Wenjun Wu, MD (Department facturing Program of Ministry of Science and slightly higher triglyceride levels during of Endocrinology, The First Afﬁliated Technology (No. 2012ZX09303006-001). Both the ﬁrst part (18 months) in the metformin Hospital of Wenzhou Medical College); glipizide and metformin were provided by Xinyi group. These ﬁndings further strengthened Hong Li, MD, PHD; Jiaqiang Zhou, MD Pharmaceutical Co. (Shanghai, China). All the the beneﬁcial long-term effects of metfor- (Department of Endocrinology, Sir Run funding sources of the study had no role in min, which might be associated with the Run Shao Hospital); Chao Liu, MD, PHD; study design, data collection, data analysis, data antiatherosclerotic properties beyond glu- Tao Yang, MD, PHD; Bei Shen, MD (De- interpretation, or writing of the manuscript. No cose lowering (31,32). partment of Endocrinology, Jiangsu Prov- other potential conﬂicts of interest relevant to The prospective, randomized, and ince Hospital); Guoting Wu, MD, PHD; this article were reported. controlled design of our study minimizes J.H. and Y.Z. contributed to the implemen- Shen Qu, MD, PHD; Chunjun Sheng, tation of the protocol and to writing the RESEARCH the potential bias and confounding. How- MD; Xiaoyun Cheng, MD (Department of DESIGN AND METHODS, RESULTS,and CONCLUSIONS. ever, several limitations need to be consid- Endocrinology, Shanghai Ten’sPeople’s S.L. performed the statistical analysis and re- ered. First, we used glipizide to represent Hospital of Tongji University); Jie Shen, viewed the manuscript. A.L., D.Zh., W.W., and the sulfonylureas because it is one of the MD, PHD; Yaoming Xue, MD, PHD; Min W.S. contributed to the design and im- most commonly used sulfonylureas in Wang, MD; Xiangrong Luo (Department of plementation of the protocol and to writing the China. However, various sulfonylureas Endocrinology, Nanfang Hospital); Dalong CONCLUSIONS. Q.S., Y.D., Z.Z., W.T., J.Z., L.C., may differ in their effects on glucose control Zhu, MD, PHD; Shanmei Shen, MD (De- D.Zo., D.W., H.L., C.L., G.W., and J.S. contrib- and cardiovascular risk in diabetic patients partment of Endocrinology, Nanjin Drum uted to the implementation of the protocol and (14–16). Second, the secondary end points coordinated preparation of the CONCLUSIONS. Tower Hospital); Shenghua Yao, MD; G.N. designed and implemented the protocol and adverse events were recorded only dur- Xiuhua Yu, MD (Department of Endocri- and was lead author. All authors approved the ing the 3-year period of study drug admin- nology, Putuo Hospital, Shanghai, China); ﬁnal manuscript. G.N. is the guarantor of this istration, which might decrease the power Huigen Jin, MD; Jia Shi, MD (Department work and, as such, had full access to all the data in of analysis. Third, we did not have a wash- of Cardiology, Putuo Hospital); Bo Feng, the study and takes responsibility for the integrity out period in the current study due to safety MD, PHD; Yafang Ni, MD (Department of of the data and the accuracy of the data analysis. concerns. Moreover, although the training Endocrinology, East Hospital, Shanghai, of a lifestyle approach was implemented to China); Shengli Yan, MD; Yangang Wang, reduce the risk for cardiovascular outcome MD; and Xingji Gong, MD (Department of APPENDIX in both groups and through all research Endocrinology, The Afﬁliated Hospital centers according to the National Choles- of Qindao University Medical College, terol Education Program Adult Treatment SPREAD-DIMCAD CLINICAL Shandong Province, China). Panel III recommendation, we did not SITES monitor and record the change of diet and The investigators and coordinators of this References exercise during the study. However, the study are as follows: Guang Ning, MD, 1. Yang W, Lu J, Weng J, et al.; China Na- double-blind, randomized study design PHD; Jie Hong, PHD; Yifei Zhang, PHD; tional Diabetes and Metabolic Disorders and the intent-to-treat approach might min- Weiqing Wang, MD, PHD; Minghui Gui, Study Group. Prevalence of diabetes imize these limitations. Therefore, we would PHD; Ying Chen, MD; Zhenni Chi, MD; among men and women in China. N Engl be cautious in interpreting the ﬁndings. Qun Yan, MD; Ying Zhai, MD (Shanghai J Med 2010;362:1090–1101 In summary, metformin therapy for 3 Clinical Center for Endocrine and Meta- 2. UK Prospective Diabetes Study (UKPDS) years substantially reduced major cardio- bolic Diseases, Ruijin Hospital); Weifeng Group. Intensive blood-glucose control vascular events in high-risk patients Shen, MD, PHD; Ankang Lv, MD; Ruiyan with sulphonylureas or insulin compared compared with glipizide, one of the com- Zhang, MD, PHD (Department of Cardi- with conventional treatment and risk of complications in patients with type 2 di- monly used sulfonylureas. Our results, ology, Ruijin Hospital); Jialin Yang, PHD; abetes (UKPDS 33). Lancet 1998;352: taken in conjunction with recent re- Yu Zhang, MD; Xiaofang Fan, MD (De- 837–853 search, indicated a potential beneﬁtof partment of Endocrinology, Min Hang 3. Holman RR, Paul SK, Bethel MA, metformin therapy on cardiovascular out- Center Hospital, Shanghai, China); Da- Matthews DR, Neil HA. 10-year follow-up comes in diabetic patients. dong Zhang, MD, PHD (Department of of intensive glucose control in type 2 di- Cardiology, Min Hang Center Hospital); abetes. N Engl J Med 2008;359:1577– Qing Su, PHD; Yan Dong, PHD; Huili Xing, MD (Department of Endocrinology, AcknowledgmentsdThis study was sup- 4. Patel A, MacMahon S, Chalmers J, et al.; Xinhua Hospital); Zhiguang Zhou, MD, ported by grants from the 863 Project (2006 ADVANCE Collaborative Group. Inten- PHD; Xing Li, MD; Weili Tang, PHD AA 02A409), the National Natural Science sive blood glucose control and vascular 1310 DIABETES CARE, VOLUME 36, MAY 2013 care.diabetesjournals.org Hong and Associates outcomes in patients with type 2 diabetes. infarction not treated with emergent per- 22. DeFronzo RA. Pharmacologic therapy for N Engl J Med 2008;358:2560–2572 cutaneous coronary interventionda ret- type 2 diabetes mellitus. Ann Intern Med 5. Gaede P, Vedel P, Larsen N, Jensen GV, rospective nationwide cohort study. 1999;131:281–303 Parving HH, Pedersen O. Multifactorial Cardiovasc Diabetol 2010;9:54 23. O’Rourke B. Evidence for mitochondrial intervention and cardiovascular disease in 14. Schramm TK, Gislason GH, Vaag A, et al. K channels and their role in cardio- patients with type 2 diabetes. N Engl J Mortality and cardiovascular risk associ- protection. Circ Res 2004;94:420–432 Med 2003;348:383–393 ated with different insulin secretagogues 24. Yellon DM, Downey JM. Preconditioning 6. Gaede P, Lund-Andersen H, Parving HH, compared with metformin in type 2 di- the myocardium: from cellular physiology Pedersen O. Effect of a multifactorial in- abetes, with or without a previous myo- to clinical cardiology. Physiol Rev 2003; tervention on mortality in type 2 diabetes. cardial infarction: a nationwide study. Eur 83:1113–1151 N Engl J Med 2008;358:580–591 Heart J 2011;32:1900–1908 25. Riveline JP, Danchin N, Ledru F, Varroud- 7. Meinert CL, Knatterud GL, Prout TE, 15. Fiévet C, Nuttens MC, Ducimetière P, Vial M, Charpentier G. Sulfonylureas and Klimt CR. A study of the effects of hypo- Fruchart JC, Bertrand M, Salomez JL. Re- cardiovascular effects: from experimental glycemic agents on vascular complica- lation of arteriographically deﬁned coro- data to clinical use. Available data in hu- tions in patients with adult-onset diabetes. nary artery disease to serum lipoprotein mans and clinical applications. Diabetes II. Mortality results. Diabetes 1970;19 particles mapped with monoclonal anti- Metab 2003;29:207–222 (Suppl.):789–830 bodies. Circulation 1991;84:153–159 26. Kirpichnikov D, McFarlane SI, Sowers JR. 8. The University Group Diabetes Program. 16. Gabir MM, Hanson RL, Dabelea D, et al. Metformin: an update. Ann Intern Med The University Group Diabetes Program. The 1997 American Diabetes Association 2002;137:25–33 A study of the effects of hypoglycemic and 1999 World Health Organization 27. Davis BJ, Xie Z, Viollet B, Zou MH. Acti- agents on vascular complications in pa- criteria for hyperglycemia in the diagnosis vation of the AMP-activated kinase by tients with adult-onset diabetes. V. Eval- and prediction of diabetes. Diabetes Care antidiabetes drug metformin stimulates uation of pheniformin therapy. Diabetes 2000;23:1108–1112 nitric oxide synthesis in vivo by pro- 1975;24(Suppl. 1):65–184 17. Expert Panel on Detection, Evaluation, moting the association of heat shock 9. UK Prospective Diabetes Study (UKPDS) and Treatment of High Blood Cholesterol protein 90 and endothelial nitric oxide Group. Effect of intensive blood-glucose in Adults. Executive Summary of the synthase. Diabetes 2006;55:496–505 control with metformin on complications Third Report of the National Cholesterol 28. Mather KJ, Verma S, Anderson TJ. Im- in overweight patients with type 2 di- Education Program (NCEP) Expert Panel proved endothelial function with metfor- abetes (UKPDS 34). Lancet 1998;352: on Detection, Evaluation, and Treatment min in type 2 diabetes mellitus. J Am Coll 854–865 of High Blood Cholesterol in Adults Cardiol 2001;37:1344–1350 10. Johnson JA, Majumdar SR, Simpson SH, (Adult Treatment Panel III). JAMA 2001; 29. De Jager J, Kooy A, Lehert P, et al. Effects Toth EL. Decreased mortality associated 285:2486–2497 of short-term treatment with metformin with the use of metformin compared with 18. Lin DY, Wei LJ, Yang I, Ying Z. Semi- on markers of endothelial function and sulfonylurea monotherapy in type 2 di- parametric regression for the mean and rate inﬂammatory activity in type 2 diabetes abetes. Diabetes Care 2002;25:2244– functions of recurrent events. J R Stat Soc mellitus: a randomized, placebo-controlled 2248 Series B Stat Methodol 2000;62:711–730 trial. J Intern Med 2005;257:100–109 11. Evans JM, Ogston SA, Emslie-Smith A, 19. Kooy A, de Jager J, Lehert P, et al. Long- 30. Rao AD, Kuhadiya N, Reynolds K, Fonseca Morris AD. Risk of mortality and adverse term effects of metformin on metabolism VA. Is the combination of sulfonylureas and cardiovascular outcomes in type 2 di- and microvascular and macrovascular metformin associated with an increased risk abetes: a comparison of patients treated disease in patients with type 2 diabetes of cardiovascular disease or all-cause mor- with sulfonylureas and metformin. Dia- mellitus. Arch Intern Med 2009;169:616– tality? A meta-analysis of observational betologia 2006;49:930–936 625 studies. Diabetes Care 2008;31:1672–1678 12. Kahn SE, Haffner SM, Heise MA, et al.; 20. Gu K, Cowie CC, Harris MI. Mortality in 31. Fidan E, Onder Ersoz H, Yilmaz M, et al. ADOPT Study Group. Glycemic durabil- adults with and without diabetes in a na- The effects of rosiglitazone and metformin ity of rosiglitazone, metformin, or gly- tional cohort of the U.S. population, on inﬂammation and endothelial dys- buride monotherapy. N Engl J Med 2006; 1971-1993. Diabetes Care 1998;21: function in patients with type 2 diabetes 355:2427–2443 1138–1145 mellitus. Acta Diabetol 2011;48:297–302 13. Jørgensen CH, Gislason GH, Andersson 21. Bertoni AG, Krop JS, Anderson GF, 32. Papanas N, Maltezos E. Oral antidiabetic C, et al. Effects of oral glucose-lowering Brancati FL. Diabetes-related morbidity agents: anti-atherosclerotic properties be- drugs on long term outcomes in patients and mortality in a national sample of U.S. yond glucose lowering? Curr Pharm Des with diabetes mellitus following myocardial elders. Diabetes Care 2002;25:471–475 2009;15:3179–3192 care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1311

Journal

Diabetes Care – Pubmed Central

Published: Apr 13, 2013

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Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

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Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery Disease

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