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Background Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. Objective The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. Methods A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. Results We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e′ (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. Conclusion LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. Trial Registration UMIN000006504. Registered 7 October 2011. other hand, the severity of HF is associated with a slightly 1 Introduction increased risk of developing DM [5]. Metformin is the most widely used oral antihypergly- The prevalence of type 2 diabetes mellitus (T2DM) among cemic agent in patients with T2DM. It has been shown to patients with heart failure (HF) continues to increase, improve insulin sensitivity, mainly in the skeletal mus- approaching 40% in recent clinical trials [1, 2]. Studies cles and liver, and reduces blood glucose by decreasing have reported that diabetes mellitus (DM) is the second gluconeogenesis in the liver. It also appears to have car- most common pathology related to HF, after coronary dioprotective potential. Various experimental and clinical artery disease, with a doubled risk of HF [3]. It has also studies have demonstrated that metformin has a beneficial been shown that HF is usually an initial manifestation of effect on lipid, atherosclerotic, and inflammatory profiles cardiovascular disease in patients with T2DM [4]. On the as well as on endothelial function [6, 7]. In dogs with pacing-induced HF, metformin also significantly reduced * Koh Ono pulmonary capillary wedge pressure and left ventricu- kohono@kuhp.kyoto-u.ac.jp lar (LV) end-diastolic pressure versus control [8]. The Extended author information available on the last page of the article Vol.:(0123456789) 284 K. Ono et al. females). Key exclusion criteria included a diagnosis of Key Points type 1 or secondary DM; severe liver dysfunction or cir- rhosis; acute coronary syndrome, severe coronary heart In addition to lowering blood glucose levels, metformin disease (left main trunk disease or triple vessel disease); has been reported to exert cardio-protective effects. atrial fibrillation or implanted pacemaker; and shock, congestive HF, or pulmonary embolism with hypoxia. One year of treatment with metformin did not affect the Additional exclusion criteria were as follows: a history LV mass or diastolic function in patients with type 2 of lactic acidosis; alcohol abuse or dehydration with gas- diabetes mellitus and hypertension. trointestinal dysfunction; severe ketosis, diabetic coma, Treatment with metformin was associated with a reduc- or pre-coma; severe infection or perioperative condition tion of body mass index and serum LDL-C levels, and or severe trauma; malnutrition, weakness, dysfunction in preservation of renal function. pituitary or adrenal gland; history of allergic reaction to metformin; pregnancy or plans to become pregnant; and individuals recognized as inappropriate by the physician. mechanisms underlying these beneficial effects have been Following initial screening, eligible patients were rand- linked to the activation of 5′ adenosine monophosphate- omized 1:1 into one of the following groups: to be treated activated protein kinase (AMPK) [9]. A recent study indi- with metformin (metformin-treated group) or other hypo- cated that metformin also has AMPK-independent effects, glycemic agents without metformin (control group). Both including hepatic glucagon-signaling inhibition following groups received therapy for 1 year. Since earlier studies decreased production of cyclic AMP [10]. Despite these have shown that thiazolidinediones affect cardiac hypertro- possible benefits of metformin on DM and HF, Japan’s phy [12], they were not used in this trial for either group. Ministry of Health, Labour and Welfare classifies HF as Patients were allocated using a secure web response a contraindication to metformin therapy because of the system, in accordance with the sequence from the rand- risk of developing lactic acidosis [11]. The US FDA has omization list. We adjusted the following factors as con- removed HF as a contraindication to metformin use, but founding for randomization: age, sex, blood pressure, and acute or unstable HF remains a precaution. HbA levels. All patients received diabetes education at 1c The aim of the present prospective randomized con- enrollment and reinforcement of this throughout the study. trolled trial was to assess whether metformin treatment has Specifically, the latter consisted of routine clinical prac- beneficial effects on patients with T2DM and hypertension tice, including dietary and exercise suggestions according without overt HF. To this end, we analyzed the effects of to Japanese guidelines. Metformin was initiated at 500 mg/ metformin on LV mass (LVM) and diastolic function in day and titrated up to 2250 mg/day. If required, antihyper- patients with T2DM with a history of hypertension. glycemic agents were added to the therapeutic protocol, with the exception of thiazolidinediones. At baseline, eligible patients underwent the following procedures: physical examination, urine test (including 2 Methods urine albumin and creatinine concentration), and fasting blood sampling for biological measurements (including 2.1 Study Population brain natriuretic peptide [BNP], liver enzyme, plasma lipids, and H bA ). Plasma BNP was measured with a 1c This multicenter, prospective, randomized controlled trial chemiluminescent enzyme immunoassay. We also per- was conducted at 26 centers in Japan between September formed chest X-ray examination, electrocardiogram, and 2011 and December 2017. This trial (UMIN000006504) echocardiography. Similar examinations were also per- conformed to the Declaration of Helsinki and good clini- formed at 6 months and 1 year post-randomization. cal practice guidelines and was approved by independent ethics committees. All patients provided written informed consent before participating in trial-related activities. 2.2 Echocardiography Key inclusion criteria were as follows: (1) patients aged 30–75 years with a history of hypertension; (2) blood pres- Echocardiography was performed at rest. During the test, sure < 140/90 mmHg and stable for at least 1 month; (3) patients were in the partial left decubitus position, and T2DM with glycated hemoglobin (HbA ) levels > 6.5% in we used standard parasternal and apical views. M-mode 1c the absence of metformin, thiazolidinediones, or insulin echocardiograms of the LV chamber were recorded under treatment; and (4) absence of renal dysfunction (serum two-dimensional control. We followed the recommendations cr eatinine < 1.3 mg/dL in males and < 1.2 mg/dL in of the American Society of Echocardiography in performing Effects of Metformin on the Heart in Patients with Diabetes 285 the measurements of the interventricular septal thickness at (see Fig. 1). As Table 1 shows, despite randomization, we end-diastole (IVSd), LV end-diastolic dimension (LVEDD), observed significant differences in body mass index (BMI) and posterior wall thickness at end-diastole (PWd). LVM within the baseline characteristics of the metformin-treated was measured according to the following formula: and control groups (p < 0.01). LVM = 0.8 1.04 (IVSd + LVEDD + PWd) + 0.6. 3.2 Primary Efficacy Endpoint LVM index (LVMI) was calculated by dividing LVM with body surface area (BSA) using weight (W) and height We observed no difference in serial changes in LVMI in (H), defined as follows: both groups during the 1-year treatment period. BNP levels were significantly changed in the control group (p < 0.017) 0.425 0.725 BSA = W × H × 0.007184. (Table 2) but were unchanged in the metformin-treated We measured the peak flow velocity of early diastole (E group (Table 3). Comparing BNP changes between two wave). Color tissue Doppler imaging loops were obtained timepoints showed no statistical significance following in the apical four-chamber view. Peak early diastolic mitral Bonferroni correction in the control group (Table 3). When annulus velocity (e′) was measured at the base of the septum, percentage change between baseline and 1 year in each and the E/e′ ratio was calculated. parameter between control and metformin-treated groups was compared, no difference in changes in BNP levels was found (Table 4). E/e′, which indicates LV diastolic function, 2.3 Definitions was unchanged during the treatment period in both groups. The primary endpoints for the current analysis were as fol- 3.3 Other Evaluation Data lows: changes in LVMI, plasma BNP levels, and echocar- diographic parameters that indicate LV diastolic function, Over the study period, the median HbA significantly 1c including the E/e′ ratio. Other evaluation items included reduced in both groups (p < 0.001). Of note, the median clinical findings and blood laboratory examination data. BMI was significantly reduced only in the metformin-treated group (p = 0.001). A post-hoc analysis of the Friedman test indicated that BMI changes were statistically significant 2.4 Statistical Analysis between the baseline versus 6 months and baseline ver- sus 1 year, even after Bonferroni correction. When com- Data are presented as numbers and percentages, mean paring percentage change between baseline and 1 year in value ± standard deviation, or median and interquartile range each parameter, only BMI was significantly reduced in the (IQR). We used Fisher’s exact test to compare categorical metformin-treated versus the control group (p < 0.01). We variables. Continuous two variables were compared using observed that serum creatinine and estimated glomerular the Student’s t test or the Mann–Whitney U test, according to their distributions. We compared continuous three variables using repeated-measures analysis of variance (ANOVA), the Friedman test, the paired t test with Bonferroni correction, ABLE-MET or the Wilcoxon signed-rank test with Bonferroni correction 231paents with inadequately controlled T2DM without treatment with meormin according to their distributions. We used JMP 10.0 (SAS Institute Inc, Cary, NC, USA) to perform all analyses. We Excluded due to lack considered all p values < 0.05 to be statistically significant. of E/e’ or BNP data 67 paents 3 Results 164paents 3.1 Baseline Characteristics A total of 231 patients with T2DM with a history of hyper- Control group Meormin-treated group tension without metformin treatment were included in the 81 paents 83 paents study (randomized 1:1 into metformin-treated and con- trol groups). Serial echocardiography and BNP data were Fig. 1 Flow chart of study process. BNP brain natriuretic peptide, missing in 64 and 52 patients, respectively, and a further E/e′ early diastolic transmitral flow velocity/early diastolic mitral 67 patients were excluded, leaving 164 patients for analysis annular velocity, T2DM type 2 diabetes mellitus 286 K. Ono et al. a significant reduction between baseline and 6 months and Table 1 Patients’ baseline characteristics between baseline and 1 year. The reduction in non-HDL-C Characteristics Control group Metformin-treated p value was significant only between baseline and 6 months. Com- group paring percentage change between baseline and 1 year in Sex, M/F 81; 46/35 83; 46/37 0.876 each parameter between control and metformin-treated Age, (years) 81; 66 (60–70) 83; 66 (61–70) 0.936 groups showed no changes in creatinine, eGFR, LDL-C, or BMI 80; 24.8 (22.8–28.4) 83; 26.8 (24.0–30.1) 0.008 non-HDL-C (Table 4). Mean metformin doses at 6 months SBP 81; 129 (123–135) 83; 130 (122–138) 0.235 and 1 year were 857 and 909 mg/day, respectively. Table 5 DBP 81; 74.7 ± 10.5 83; 75.4 ± 9.0 0.634 summarizes the changes of metformin doses. Oral hypo- PR 81; 71.5 ± 11.6 83; 74.7 ± 11.8 0.075 glycemic agents used at baseline included sulfonylureas, LVDd 81; 46.2 ± 4.5 83; 45.9 ± 4.6 0.693 dipeptidyl peptidase-4 (DPP-4) inhibitors, and α-glucosidase LVEF 81; 69.0 ± 7.9 83; 68.9 ± 6.7 0.937 inhibitors (Table 5). Tables 6, 7 and 8 summarize the serial LAD 81; 38.2 ± 5.0 83; 38.7 ± 5.4 0.550 changes of other medications. No differences were observed E/e′ (septal) 81; 10.5 (9.0–13.1) 83; 10.8 (8.1–14.8) 0.781 in the use of lipid-lowering agents between the two groups LVM 81; 155 (125–184) 83; 147 (127–188) 0.713 in the course of the treatment period. LVMI 80; 93.4 (77.6– 83; 88.2 (75.6– 0.414 108.7) 108.3) BNP 81; 14.2 (6.9–27.2) 83; 15.8 (7.3–24.8) 0.652 4 Discussion Cre 81; 0.7 (0.6–0.9) 83; 0.7 (0.6–0.8) 0.329 eGFR 81; 73.0 (62.6–85.0) 83; 76.5 (66.2–89.2) 0.276 The main finding of this study was that 1 year of metformin TC 80; 190 (161–216) 82; 183 (165–208) 0.442 treatment in patients with T2DM did not affect LVM or LV TG 81; 124 (91–164) 83; 133 (99–197) 0.252 diastolic function versus treatments with other hypoglycemic HDL-C 81; 53 (46–61) 83; 51 (43–61) 0.295 agents. However, it significantly reduced BMI and LDL-C LDL-C 80; 113 (96–134) 82; 110 (96–128) 0.374 levels and preserved renal function. Non-HDL-C 80; 132 (109–158) 82; 132 (113–152) 0.782 Metformin is an oral hypoglycemic drug of the biguanide HbA 81; 7.0 (6.7–7.6) 83; 7.2 (6.7–7.9) 0.167 1c class that lowers blood glucose levels by decreasing hepatic glucose production and improving the insulin sensitivity of Data are presented as N; mean ± standard deviation and median (interquartile range) unless otherwise indicated the peripheral tissues by increasing glucose uptake. It is cur- BMI body mass index, BNP brain natriuretic peptide, Cre creatinine, rently used as a first-line treatment for T2DM. The drug is DBP diastolic blood pressure, E/e′ early diastolic transmitral flow recommended during all stages of therapy as monotherapy velocity/early diastolic mitral annular velocity, eGFR estimated glo- and in combination with other oral antihyperglycemic drugs merular filtration rate, F female, HbA glycated hemoglobin, HDL-C 1c as well as insulin. Such guidelines are due to its low cost, high-density lipoprotein cholesterol, LAD left atrial diameter, LDL- C low-density lipoprotein cholesterol, LVDd left ventricular diastolic safety, and association with a reduction in the risk of cardio- diameter, LVEF left ventricular ejection fraction, LVM left ventricular vascular events [13–15]. mass, LVMI left ventricular mass index, M male, PR pulse rate, SBP T2DM is an independent risk factor for cardiovascular systolic blood pressure, TC total cholesterol, TG triglyceride disease and is associated with a higher incidence of HF, as Fisher’s exact test first reported in the Framingham study [16]. The risk of HF Mann–Whitney U test in patients with T2DM is almost two times higher for men Unpaired t test and five times higher for women than in the general popula - tion, and patients with T2DM account for one-third of all HF filtration rate (eGFR) levels were significantly changed in cases [17]. However, concerns regarding the development of the control group (p < 0.0074 for creatinine; p < 0.0074, for lactic acidosis with the use of phenformin led the US FDA to eGFR) (Table 2) but not in the metformin-treated group apply a black box warning to metformin cautioning against (Table 3). A comparison of changes in creatinine and eGFR using it in the setting of chronic kidney disease because of between two time points showed a statistically significant possible impaired drug excretion. It also recommended cau- difference between baseline versus 6 months and baseline tion in patients with conditions that may promote lactate versus 1 year in the control group. Conversely, low-density accumulation. Examples of the latter include congestive HF lipoprotein cholesterol (LDL-C) and non-high-density and chronic liver disease. The FDA has removed congestive lipoprotein cholesterol (HDL-C) levels were significantly HF as a contraindication to metformin use. However, acute changed in the metformin-treated group (p < 0.00016 for or unstable congestive HF remains a precaution. In Japan, LDL-C; p < 0.0012 for non-HDL-C) (Table 3). However, to date, HF is classified as a contraindication to metformin no changes were found in the control group. Comparing therapy because of the risk of lactic acidosis [11]. There- changes in LDL-C between the two time points identified fore, we aimed to verify the effects of metformin on cardiac Effects of Metformin on the Heart in Patients with Diabetes 287 Table 2 Changes in primary and secondary endpoints (control group) Endpoint n Baseline (time1; T1) 6 months (time2; T2) 1 year (time3; T3) p value (time) p value (Bonferroni correction) T1 vs. T2 T1 vs. T3 T2 vs. T3 a b BMI 80 24.8 (22.8–28.4) 24.7 (22.7–27.0) 25.2 (22.7–27.6) 0.699 > 0.999 > 0.999 0.952 a b SBP 79 129 (123–135) 130 (121–138) 131 (120–140) 0.696 0.982 > 0.999 > 0.999 c d DBP 79 75.0 ± 10.3 73.4 ± 10.1 74.1 ± 11.7 0.360 0.429 > 0.999 > 0.999 c d PR 79 71.5 ± 11.6 73.1 ± 11.6 73.4 ± 13.0 0.213 0.496 0.349 > 0.999 c d LVDd 80 46.3 ± 4.5 46.4 ± 4.9 46.3 ± 4.5 0.971 > 0.999 > 0.999 > 0.999 c d LVEF 80 68.9 ± 8.0 68.3 ± 7.1 68.3 ± 6.8 0.593 > 0.999 > 0.999 > 0.999 c d LAD 80 38.3 ± 5.0 38.2 ± 5.0 38.0 ± 4.6 0.831 > 0.999 > 0.999 > 0.999 a b E/e′ (septal) 77 10.7 (9.0–13.1) 11.4 (9.2–14.1) 11.5 (9.4–13.2) 0.200 0.334 0.176 > 0.999 a b LVM 80 156.8 (124.0–184.3) 158.8 (124.1–183.2) 158.2 (133.6–175.8) 0.857 > 0.999 > 0.999 > 0.999 a b LVMI 79 94.0 (76.9–109.3) 96.6 (82.1–108.4) 93.9 (84.6–108.6) 0.987 > 0.999 > 0.999 > 0.999 a b BNP 80 14.5 (6.8–28.1) 16.6 (9.7–28.4) 17.0 (8.7–29.2) 0.017 0.138 0.114 > 0.999 a b Cre 81 0.7 (0.6–0.9) 0.7 (0.7–0.9) 0.8 (0.7–0.9) 0.007 0.013 0.019 > 0.999 a b eGFR 81 73.0 (62.6–85.0) 69.6 (61.6–81.4) 70.4 (60.5–81.9) 0.007 0.002 0.016 > 0.999 a b TC 79 190 (161–217) 180 (163–208) 186 (159–210) 0.540 0.359 > 0.999 0.879 a b TG 81 124 (91–164) 112 (87–180) 119 (87–153) 0.634 > 0.999 0.421 0.941 a b HDL-C 81 53 (46–61) 52 (45–63) 55 (44–66) 0.331 > 0.999 > 0.999 0.084 a b LDL-C 80 113 (96–134) 108 (91.3–125.5) 113 (92–137) 0.419 0.188 > 0.999 0.515 a b Non-HDL-C 79 133 (108–158) 130 (105–148) 133 (110–153) 0.451 0.584 > 0.999 > 0.999 a b HbA 81 7.0 (6.7–7.6) 6.4 (6.1–7.1) 6.4 (6.0–6.9) 0.000 0.000 0.000 > 0.999 1c Data are presented as N, mean ± standard deviation and median (interquartile range) unless otherwise indicated ANOVA analysis of variance, BMI body mass index, BNP brain natriuretic peptide, Cre creatinine, DBP diastolic blood pressure, E/e′ early diastolic transmitral flow velocity/early diastolic mitral annular velocity, eGFR estimated glomerular filtration rate, HbA glycated hemoglobin, 1c HDL-C high-density lipoprotein cholesterol, LAD left atrial diameter, LDL-C low-density lipoprotein cholesterol, LVDd left ventricular diastolic diameter, LVEF left ventricular ejection fraction, LVM left ventricular mass, LVMI left ventricular mass index, PR pulse rate, SBP systolic blood pressure, TC total cholesterol, TG triglyceride The Friedman test The Wilcoxon signed-rank test (Bonferroni correction) Repeated-measures ANOV A Paired t test (Bonferroni correction) morphology and function in patients with hypertension who [20]. A meta-analysis [21] of randomized controlled trials were at risk for HF development. investigating the effects of hypoglycemic agents on LVM Our study showed no clear changes in the indicators of recently showed that gliclazide was the only medication to LV diastolic function and LVM. There are various reasons significantly reduce LVM in patients with T2DM. Addition- for not having proved our working hypothesis. First, the pre- ally, metformin exhibited negative effects on the prevention viously observed effects of metformin on the reduction of of cardiac hypertrophy. Our results are in line with this cardiovascular events differ from the prevention of cardiac report. Sodium–glucose co-transporter 2 (SGLT2) inhibi- hypertrophy and/or diastolic dysfunction observed in the tors have proven effective in reducing HF hospitalization early phase of hypertension. Several events are associated in patients with DM, and glucagon-like peptide-1 (GLP-1) with HF development, and additional factors may be asso- receptor agonists are beneficial for patients with ischemic ciated with metformin treatment. Second, the use of DPP-4 heart disease [22, 23]. However, GLP-1 receptor agonists inhibitors increased in the control group over the treat- were not used in either of our groups in this study. The use ment period. Several reports have shown beneficial effects of SGLT2 inhibitors had not been approved by the Japan from DPP-4 inhibitors on cardiac hypertrophy in animal Ministry of Health, Labor, and Welfare when this study was experiments. They act by suppressing sodium-proton pump conducted. exchanger type 1 or insulin-like growth factor-I [18, 19]. We observed several beneficial effects of metformin in However, several clinical studies have reported that the use our study population. Like previous reports, we observed a of DDP-4 inhibitors was associated with worsening of HF significant decrease in BMI following metformin treatment, 288 K. Ono et al. Table 3 Changes in primary and secondary endpoints (metformin-treated group) Endpoint n Baseline (time1; T1) 6 months (time2; T2) 1 year (time3; T3) p value (time) p value (Bonferroni correction) T1 vs. T2 T1 vs. T3 T2 vs. T3 a b BMI 78 27.2 (24.5–30.5) 26.5 (24.1–30.6) 26.1 (23.7–30.1) 0.001 0.014 0.003 0.562 a b SBP 82 131 (122–138) 131 (121–141) 134 (124–143) 0.821 > 0.999 0.354 0.294 c d DBP 82 75.5 ± 9.1 74.3 ± 9.9 75.2 ± 9.9 0.575 0.905 > 0.999 > 0.999 c d PR 80 74.8 ± 12.0 76.0 ± 11.0 75.1 ± 12.0 0.453 0.616 > 0.999 > 0.999 c d LVDd 83 45.9 ± 4.6 45.4 ± 5.5 45.6 ± 4.8 0.470 0.759 > 0.999 > 0.999 c d LVEF 83 68.9 ± 6.7 69.3 ± 7.0 68.9 ± 6.4 0.763 > 0.999 > 0.999 > 0.999 c d LAD 83 38.7 ± 5.4 38.8 ± 5.1 38.5 ± 5.3 0.655 > 0.999 > 0.999 > 0.999 a b E/e′ (septal) 81 10.8 (8.1–14.7) 11.5 (9.2–15.0) 10.9 (9.4–14.0) 0.013 0.119 0.962 0.482 a b LVM 83 146.8 (127.1–188.4) 147.8 (128.0–188.0) 149.9 (127.8–188.0) 0.701 > 0.999 > 0.999 > 0.999 a b LVMI 78 88.4 (76.9–108.6) 88.8 (76.8–107.7) 88.7 (76.4–104.4) 0.905 > 0.999 > 0.999 > 0.999 a b BNP 82 15.7 (7.2–23.9) 15.4 (7.7–29.0) 15.8 (8.8–28.9) 0.520 0.100 0.064 > 0.999 a b Cre 83 0.7 (0.6–0.8) 0.7 (0.6–0.9) 0.7 (0.6–0.8) 0.627 0.727 > 0.999 0.407 a b eGFR 83 76.5 (66.2–89.2) 76.9 (62.8–87.4) 76.3 (63.6–89.3) 0.627 0.478 > 0.999 0.486 a b TC 82 183 (165–208) 174 (156–196) 180 (161–200) 0.059 0.039 0.417 0.650 a b TG 83 133 (99–197) 132 (88–191) 130 (104–188) 0.918 > 0.999 > 0.999 > 0.999 a b HDL-C 83 51 (43–61) 50 (43–60) 51 (44–63) 0.167 > 0.999 0.445 0.609 a b LDL-C 81 110 (96–129) 96 (82–115) 103 (86–122) 0.000 0.000 0.027 0.063 a b Non-HDL-C 82 132 (113–152) 120 (101–144) 125 (107–146) 0.012 0.035 0.153 > 0.999 a b HbA 82 7.2 (6.7–7.9) 6.4 (6.0–6.9) 6.4 (6.2–7.1) 0.000 0.000 0.000 > 0.999 1c Data are presented as N, mean ± standard deviation and median (interquartile range) unless otherwise indicated ANOVA analysis of variance, BMI body mass index, BNP brain natriuretic peptide, Cre creatinine, DBP diastolic blood pressure, E/e′ early diastolic transmitral flow velocity/early diastolic mitral annular velocity, eGFR estimate glomerular filtration rate, HbA glycated hemoglobin, 1c HDL-C high-density lipoprotein cholesterol, LAD left atrial diameter, LDL-C low-density lipoprotein cholesterol, LVDd left ventricular diastolic diameter, LVEF left ventricular ejection fraction, LVM left ventricular mass, LVMI left ventricular mass index, PR pulse rate, SBP systolic blood pressure, TC total cholesterol, TG triglyceride The Friedman test The Wilcoxon signed-rank test (Bonferroni correction) Repeated-measures ANOV A Paired t test (Bonferroni correction) and its effect was more evident in the first 6 months of treat- Health) registry suggested that the proposed cardiovascu- ment [24–26]. A possible explanation for this effect is the lar benefits of metformin may include patients with estab- higher usage of sulfonylureas in the control group than in lished atherosclerosis and moderate chronic kidney disease the metformin-treated group. However, other explanations [31]. However, the abovementioned reports do not support for the mechanisms of metformin-induced weight loss may the hypothesis of a renoprotective effect. Metformin has be considered. An earlier study suggested that metformin previously been shown to attenuate renal fibrosis in both reduces weight by affecting appetite signals in the brain, fat AMPKα2-dependent and -independent manners [32]. In our oxidation, and fat storage in the liver [27]. An additional study group, kidney function may have been preserved by report suggested that metformin-induced weight loss, secre- such antifibrotic effects. Hypertension causes renal dam- tion of GLP-1 and peptide YY, and increases in conjugated age, which in turn further increases blood pressure. Con- bile acid are associated with alterations of the gut microbiota sequently, patients with DM and hypertension may be good [28, 29]. candidates for metformin treatment. Renal function in the control group deteriorated during In the metformin-treated group, LDL-C significantly the 1-year study but was unchanged in the metformin-treated decreased in the study period. This was more evident dur- group. Uncertainty remains about the underlying mecha- ing the first half of the study than the last. It has been nisms. Recently published data support the use of met- recently shown in patients with T2DM that metformin formin in patients with renal diseases [30]. An analysis by treatment reduces the levels of three acyl-alkyl-phos- the REACH (Reduction of Atherothrombosis for Continued phatidylcholine metabolites [33]. The reduction of LDL-C Effects of Metformin on the Heart in Patients with Diabetes 289 Table 4 Percent changes of primary and secondary endpoints 1 year post-treatment with or without metformin Endpoint (%) Control group Metformin-treated group p value BMI 80; 0.6 (− 2.2 to 2.8) 79; − 1.9 (− 4.6 to 1.5) 0.006 SBP 80; 0.7 (− 7.8 to 10.6) 82; 1.1 (− 6.3 to 12.5) 0.685 DBP 80; − 0.4 ± 13.7 82; 0.7 ± 15.6 0.654 PR 80; 3.5 ± 13.8 82; 1.7 ± 12.8 0.407 LVDd 81; 0.42 ± 7.47 83; − 0.46 ± 8.80 0.492 LVEF 81; − 0.2 ± 10.3 83; 0.5 ± 10.3 0.642 LAD 81; 0.1 ± 10.4 83; 0.0 ± 9.9 0.945 E/e′ (septal) 81; 2.7 (− 7.5 to 25.5) 83; 5.1 (− 15.8 to 19.3) 0.611 LVM 81; 0.0 (− 9.7 to 14.8) 83; 0.0 (− 13.4 to 12.2) 0.343 LVMI 80; 0.6 (− 9.4 to 13.3) 79; 0.4 (− 12.0 to 13.0) 0.608 BNP 81; 13.3 (− 23.0 to 65.5) 83; 0.0 (− 19.6 to 76.7) 0.951 Cre 81; 2.9 (− 3.0 to 10.3) 83; 0.0 (− 5.6 to 8.9) 0.142 eGFR 81; − 3.0 (− 10.2 to 3.4) 83; 0.0 (− 8.9 to 6.5) 0.142 TC 79; − 1.1 (− 8.4 to 7.5) 82; − 2.5 (− 14.0 to 9.0) 0.420 TG 81; − 3.9 (− 30.8 to 26.3) 83; 0.0 (− 22.1 to 26.3) 0.387 HDL-C 81; 1.7 (− 6.4 to 9.0) 83; 3.8 (− 8.3 to 14.5) 0.497 LDL-C 80; − 3.1 (− 10.7 to 10.3) 81; − 5.4 (− 23.1 to 4.4) 0.139 Non-HDL-C 79; − 0.8 (− 7.7 to 7.1) 82; − 4.2 (− 17.5 to 7.3) 0.238 HbA 81; − 8.2 (− 13.0 to − 1.5) 82; − 9.1 (− 17.1 to − 4.5) 0.083 1c Data are presented as N; mean ± standard deviation and median (interquartile range) unless otherwise indicated BMI body mass index, BNP brain natriuretic peptide, Cre creatinine, DBP diastolic blood pressure, E/e′ early diastolic transmitral flow velocity/ early diastolic mitral annular velocity, eGFR estimate glomerular filtration rate, HbA glycated hemoglobin, HDL-C high-density lipoprotein 1c cholesterol, LAD left atrial diameter, LDL-C low-density lipoprotein cholesterol, LVDd left ventricular diastolic diameter, LVEF left ventricular ejection fraction, LVM left ventricular mass, LVMI left ventricular mass index, PR pulse rate, SBP systolic blood pressure, TC total cholesterol, TG triglyceride Unpaired t test Mann–Whitney U test fatty acid desaturation [33]. These findings suggest that Table 5 Changes in metformin doses metformin may have a beneficial effect on lipid metabo - Metformin 6 months (time2) 1 year (time3) p value lism for the prevention of atherosclerosis in patients with dose (mg) hypertension. The present study has several limitations. First, 250 2 (2.44) 2 (2.44) 0.040636 our protocol set the target sample size at 440 patients 500 33 (40.2) 27 (32.9) (UMIN000006504). We assumed the annual LV weight 750 16 (19.5) 20 (24.4) reduction with metformin treatment would be 6 g [34]. To 1000 11 (13.4) 10 (12.2) determine the superiority of these values with 80% power 1250 1 (1.22) 1 (1.22) and a two-sided overall significance level of 5% required 1500 18 (22.0) 20 (24.4) 185 patients per arm. To allow for a loss-to-follow-up rate 2000 1 (1.22) 1 (1.22) of 15%, we determined that we would need to enroll 220 2250 0 (0) 1 (1.22) patients in each study arm. However, slow recruitment meant Data are presented as n (%) unless otherwise indicated we only recruited 231 patients, which reduced the power of The Wilcoxon signed-rank test this trial. Second, our findings are subject to confounding factors because the two study groups had different BMI val- ues at baseline. Finally, the metformin dose was relatively levels may be due to such changes in metabolic profiles. small compared with that used in other countries, which may The latter is most likely induced by metformin-induced have limited the effects of metformin. activation of AMPK and consequent suppression of sterol regulatory element-binding protein 1c (SREBP1c) and 290 K. Ono et al. Table 6 Other medications at baseline Medications Control group Metformin-treated group p value Oral hypoglycemic agents Sulfonylureas 32 (39.5) 22 (26.5) 0.0967 DPP-4 inhibitor 47 (58.0) 29 (34.9) 0.0047 GLP-1 receptor agonist 0 (0.0) 0 (0.0) – α-Glucosidase inhibitor 23 (28.4) 14 (16.9) 0.0936 Lipid-lowering agents Statins 46 (56.8) 54 (65.1) 0.3371 Ezetimibe 1 (1.2) 4 (4.8) 0.3675 Antihypertensive agents Angiotensin II receptor antagonists 38 (46.9) 43 (51.8) 0.5371 Angiotensin-converting enzyme inhibitors 7 ((8.6) 7 (8.4) > 0.999 Aldosterone antagonists 3 (3.7) 1 (1.2) 0.3643 Calcium channel inhibitors 50 (61.7) 52 (62.7) > 0.999 β-Blockers 18 (22.2) 14 (16.9) 0.4341 Others 9 (11.1) 12 (14.5) 0.6417 Data are presented as n (%) unless otherwise indicated DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1 Fisher’s exact test Table 7 Other medications at 6 months Medications Control group Metformin-treated group p value Oral hypoglycemic agents Sulfonylureas 32 (39.5) 21 (25.3) 0.0662 DPP-4 inhibitor 58 (71.6) 30 (36.1) 0.0000 GLP-1 receptor agonist 0 (0.0) 0 (0.0) – α-Glucosidase inhibitor 27 (33.3) 15 (18.1) 0.0317 Lipid-lowering agents Statins 46 (56.8) 54 (65.1) 0.3371 Ezetimibe 1 (1.2) 4 (4.8) 0.3675 Antihypertensive agents Angiotensin II receptor antagonists 38 (46.9) 42 (50.6) 0.6433 Angiotensin-converting enzyme inhibitors 7 (8.6) 9 (10.8) 0.7936 Aldosterone antagonists 4 (4.9) 1 (1.2) 0.2073 Calcium channel inhibitors 54 (66.7) 53 (63.9) 0.7447 β-Blockers 18 (22.2) 13 (15.7) 0.3223 Others 9 (11.1) 12 (14.5) 0.6417 Data are presented as n (%) unless otherwise indicated DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1 Fisher’s exact test Effects of Metformin on the Heart in Patients with Diabetes 291 Table 8 Other medications at 1 year Medication Control group Metformin-treated group p value Oral hypoglycemic agents Sulfonylureas 32 (39.5) 21 (25.3) 0.0662 DPP-4 inhibitor 57 (70.4) 30 (36.1) 0.0000 GLP-1 receptor agonist 0 (0.0) 0 (0.0) – α-Glucosidase inhibitor 27 (33.3) 16 (19.3) 0.0509 Lipid-lowering agents Statins 48 (59.3) 56 (67.5) 0.3311 Ezetimibe 2 (2.5) 4 (4.8) 0.6818 Antihypertensive agents Angiotensin II receptor antagonists 38 (46.9) 42 (50.6) 0.6433 Angiotensin-converting enzyme inhibitors 7 (8.6) 9 (10.8) 0.7936 Aldosterone antagonists 4 (4.9) 1 (1.2) 0.2073 Calcium channel inhibitors 55 (67.9) 55 (66.3) 0.8689 β-Blockers 18 (22.2) 13 (15.7) 0.3223 Others 10 (12.3) 10 (12.0) > 0.999 Data are presented as n (%) unless otherwise indicated DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1 Fisher’s exact test Conflict of interest Koh Ono, Hiromichi Wada, Noriko Satoh-Asaha- 5 Conclusion ra, Hitoki Inoue, Keita Uehara, Junichi Funada, Atsushi Ogo, Takahiro Horie, Masatoshi Fujita, Akira Shimatsu, and Koji Hasegawa have no Treatment of patients with T2DM with metformin did not conflicts of interest that are directly relevant to the content of this ar - affect LVM or LV diastolic function versus treatments ticle. with other hypoglycemic agents over the course of 1 year. Funding This work was supported by Grants to KO and KH for a However, metformin reduced BMI, lowered LDL-C, and large-scale clinical study for the promotion of evidence-based medical preserved renal function. practices by the National Hospital Organization. Acknowledgements The authors thank the other members, coop- Open Access This article is distributed under the terms of the Crea- erators, and participants of the ABLE-MET study for their valuable tive Commons Attribution-NonCommercial 4.0 International License contributions. (http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, Author Contributions Conception and design: KO and KH; Analysis provided you give appropriate credit to the original author(s) and the and interpretation of the data: KO, HW, NA, HI, KU, JF, AO, TH, MF, source, provide a link to the Creative Commons license, and indicate AS, and KH; Drafting of the article: KO and KH. 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Circulation. 2009;119:2069–77. peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: Effects of Metformin on the Heart in Patients with Diabetes 293 Affiliations 1,2 1 1 3 4 5 Koh Ono · Hiromichi Wada · Noriko Satoh‑Asahara · Hitoki Inoue · Keita Uehara · Junichi Funada · 6 2 7 1 1 Atsushi Ogo · Takahiro Horie · Masatoshi Fujita · Akira Shimatsu · Koji Hasegawa on behalf of the ABLE‑MET Investigators 1 5 Clinical Research Institute, National Hospital Organization Department of Cardiology, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Ehime Medical Center, 366 Yokogawara, Toon, Fushimi-ku, Kyoto 612-8555, Japan Ehime 791-0281, Japan 2 6 Department of Cardiovascular Medicine, Graduate School Department of Metabolism and Endocrinology, Clinical of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Research Institute, National Hospital Organization Kyushu Sakyo-ku, Kyoto 606-8507, Japan Medical Center, Fukuoka, Japan 3 7 Department of Cardiology, National Hospital Organization Department of Cardiovascular Medicine, Uji Hospital, Uji, Hokkaido Cancer Center, 2-3-54, Kikusuishijyo, Kyoto, Japan Shiraishi-ku, Sapporo, Hokkaido 003-0804, Japan Department of Gastroenterology, National Hospital Organization Tochigi Medical Center, 1-10-37, Nakatomatsuri, Utsunomiya, Tochigi 3208580, Japan
American Journal of Cardiovascular Drugs – Springer Journals
Published: Jun 13, 2020
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