www.nature.com/scientificreports OPEN Systematic review and meta‑analysis for prevention of cardiovascular complications using GLP‑1 receptor agonists and SGLT‑2 inhibitors in obese diabetic patients Kazushi Uneda1,2,4, Yuki Kawai1,4, Takayuki Yamada1,3, Sho Kinguchi1, Kengo Azushima1, Tomohiko Kanaoka1, Yoshiyuki Toya1, Hiromichi Wakui1* & Kouichi Tamura1 Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs) and sodium‑glucose cotransporter (SGLT‑2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more efective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta‑analysis to compare the efcacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP‑1 RAs signifcantly reduced the risk of MACE versus placebo (relative risk, RR [95% confdence interval, CI]: 0.88 [0.81– 0.96]), whereas SGLT‑2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83–1.00]). In an indirect comparison, GLP‑1 RAs were not associated with a signifcant diference in MACE compared with SGLT‑2 inhibitors (RR [95% CI]: 0.97 [0.85–1.09]). Thus, GLP‑1 RAs are efective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT‑2 inhibitors. Type 2 diabetes mellitus (T2DM) is an important risk factor for cardiovascular disease (CVD), chronic kidney disease, and mortality. In clinical settings, patients with T2DM ofen have other cardiometabolic comorbidities, such as hypertension, dyslipidemia, atherosclerotic disease, and obesity 1,2. Indeed, more than half of patients with T2DM have been reported to be obese2,3. Furthermore, because obesity in T2DM increases the risks of CVD and all-cause mortality, the presence of obesity is an important determinant of the prognosis of patients with T2DM3,4. Te mechanism of this link involves abnormal secretion of adipocytokines, which exacerbates the other CVD risk factors, including hypertension, hyperlipidemia, and insulin resistance 1,5,6. Terefore, intensive therapy for patients with T2DM and obesity is crucial. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors are novel glucose-lowering agents. GLP-1 RAs act as mimetics of the endogenous incretin hormone GLP-1, promote glucose-dependent insulin secretion, and inhibit hepatic glucose production 7. SGLT-2 inhibitors suppress glucose reabsorption by the renal proximal tubules and exhibit insulin-independent glucose-lowering efects8. Moreover, both GLP-1 RAs and SGLT-2 inhibitors have pleiotropic efects that include natriuresis, reductions in blood pressure, and cardiovascular protection 9,10. Recent randomized controlled studies have shown that GLP-1 RAs and SGLT-2 inhibitors reduce the risks of CVD events 11–14, and therefore the American 1Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. 2Department of Kampo Medicine, Aizu Medical Center, Fukushima Medical University School of Medicine, Aizuwakamatsu, Japan. 3Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine, Mount Sinai, NY, USA. 4These authors contributed equally: Kazushi Uneda and Yuki Kawai. *email: [email protected] Scientifc Reports | (2021) 11:10166 | https://doi.org/10.1038/s41598-021-89620-7 1 Vol.:(0123456789) www.nature.com/scientificreports/ Records identified through Additional records identified on database searching through references a (n = 4,188) (n = 9) Idenfic Records after duplicates removed (n = 3,188) ning ree Records excluded from Sc Records screened title and abstract (n = 3,188) (n = 3,097) Full-text articles Full-text articles excluded, y assessed for eligibility with insufficient data (n = 91) (n = 79) Eligibilit Studies included in qualitative synthesis (n = 12) d Studies included in Include quantitative synthesis (meta-analysis) (n =12) Figure 1. Flow diagram for the study. Diabetes Association (ADA) recommends the use of GLP-1 RAs and SGLT-2 inhibitors as frst-line treatments for patients with T2DM and established or a high risk of atherosclerotic CVD15. Furthermore, both GLP-1 RAs and SGLT-2 inhibitors have anti-obesity efects, in contrast to the efects of some other anti-glycemic agents, such as insulin, the use of which tends to be associated with increases in the body mass of patients. Terefore, these two drugs are also recommended for use in overweight patients with T2DM by the ADA 15. However, no head-to-head trials have been conducted on the efcacy of these drugs for the prevention of CVD in patients with obesity and T2DM. Terefore, we conducted a network meta-analysis to compare the efects of GLP-1 RAs and SGLT-2 inhibitors to prevent CVD in patients with obesity and T2DM. Results Search results and included studies. Figure 1 shows a fow chart of the study selection procedure. We selected 4,188 studies through database searching and identifed a further nine studies through the searches of the reference lists of these articles. Afer the removal of duplicates, we removed a further 3,097 reports afer screening the titles and abstracts, and another 79 because of missing data for upon inspection of the full-text articles. Terefore, 12 studies remained for inclusion in our meta-analysis. Of these, fve were placebo-controlled randomized controlled trials (RCTs) of SGLT-2 inhibitors (canaglifozin16,17, empaglifozin13, ertuglifozin18, and dapaglifozin14) and seven were placebo-controlled RCTs of GLP-1 RAs (lixisenatide 19, exenatide20, liraglutide11, albiglutide21, subcutaneous and oral semaglutide22,23, and dulaglutide12). All the studies, except CREDENCE, set major adverse cardiovascular events (MACE) as the primary endpoint. Eleven studies11,13,14,16–23 defned the cut- of value of body mass index (BMI) for obesity as 30 kg/m2 and one12 defned this cut-of as 32 kg/m2. Patient characteristics and study quality assessment. Te 12 studies included in the meta-analysis are listed in Table 1. In the GLP-1 RA studies the median follow-up time was 15.9–64.8 months and in the stud- ies of SGLT-2 inhibitors it was 31.4–50.4 months. Te characteristics of the participants in the included studies Scientifc Reports | (2021) 11:10166 | https://doi.org/10.1038/s41598-021-89620-7 2 Vol:.(1234567890) www.nature.com/scientificreports/ Study Study design Setting Drug dose (mg/day) Median follow up (months) Range of HbA1c (%) Primary outcome GLP-1 RA vs. placebo MACE (including unstable ELIXA RCT Multinational Lixisenatide 20 µg 27.0 5.5–11.0 angina) EXSCEL RCT Multinational Exenatide 2 (weekly) 38.4 6.5–10.0 MACE LEADER RCT Multinational Liraglutide 1.8 45.6 ≥ 7.0 MACE HARMONY Outcomes RCT Multinational Albiglutide 30–50 (weekly) 19.2 > 7.0 MACE PIONEER-6 RCT Multinational Semaglutide 14 (oral) 15.9 N/A MACE REWIND RCT Multinational Dulaglutide 1.5 (weekly) 64.8 ≤ 9.5 MACE SUSTAIN-6 RCT Multinational Semaglutide 0.5/1 (weekly) 25.2 ≥ 7.0 MACE SGLT2i vs. placebo EMPA-REG OUTCOME RCT Multinational Empaglifozin 10/25 37.2 7.0–10.0 MACE CANVAS RCT Multinational Canaglifozin (300/100) 47.1* 7.0–10.5 MACE CREDENCE RCT Multinational Canaglifozin 100 31.4 6.5–12.0 Renal outcomes DECLARE-TIMI 58 RCT Multinational Dapaglifozin 10 50.4 6.5–12.0 MACE VERTIS-CV RCT Multinational Ertuglifozin 5/15 36.0 7.0–10.5 MACE Table 1. List of included studies. SGLT2i, sodium-glucose cotransporter-2 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; RCT, randomized control study; HbA1c, hemoglobin A1c; MACE, major adverse cardiovascular events. *Follow-up period was mean for CANVAS Program. Number of Current SBP DBP eGFR (mL/ LDL-C (mg/ TG (mg/ Study participants Age (years) Male (%) BMI (kg/m2) smokers (%) HbA1c (%) (mmHg) (mmHg) min/1.73m2) dL) dL) GLP-1 RA vs. placebo ELIXA 6,068 60.3 69.3 30.2 11.7 7.7 130 N/A 76.0 78.5 164.5 EXSCEL 14,602 61.9 62.0 32.7 11.7 8.1 135* 80* 78.4 88.0* N/A LEADER 9,331 64.3 64.3 32.5 12.1 8.7 136 77 80.4 89.0 N/A HARMONY 9,413 64.1 69.4 32.3 15.7 8.7 135 77 79.0 N/A N/A Outcomes PIONEER-6 3,182 66.0 68.4 32.3 11.0 8.2 136 76 74.0 78.0 N/A REWIND 9,900 66.2 53.7 32.3 14.2 7.4 137 78 76.9 99.1 141.7 SUSTAIN-6 3,290 64.6 60.7 32.8 N/A 8.7 136 77 N/A 82.3 N/A Weighted 63.7 63.2 32.2 12.9 8.2 135 78.0 78.0 88.2 average SGLT2i vs. placebo EMPA-REG 7,020 63.1 71.3 30.6 N/A 8.1 135 77 74.1 85.6 170.6 OUTCOME CANVAS 10,142 63.3 64.2 32.0 17.8 8.2 137 78 76.5 89.0 177.1 CREDENCE 4,392 63.0 66.1 31.3 14.5 8.3 140 78 56.2 96.4 197.9 DECLARE- 17,151 63.9 62.6 32.0 N/A 8.3 135 78 85.2 N/A N/A TIMI 58 VERTIS-CV 8,237 64.4 70.0 31.9 N/A 8.2 133 76 76.0 89.1 180.6 Weighted 63.7 65.9 31.7 8.2 136 77 77.3 89.3 179.6 average Table 2.