Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access
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Review

Volume 14, Number 3, June 2024, pages 128-148

Dapagliflozin-Saxagliptin Combination - The Quest for Optimal Glycemic Control With Cardio-Renal Protection in Type 2 Diabetes Mellitus: An Expert Consensus in Indian Settings

Figures

Figure 1.
Figure 1. Combination therapy in T2DM. T2DM: type 2 diabetes mellitus.
Figure 2.
Figure 2. The ominous octet. DPP4i: dipeptidyl peptidase-4 inhibitor; SGLT2i: sodium-glucose cotransporter-2 inhibitor.
Figure 3.
Figure 3. Clinical evidence for improved glycemic control with DAPA + SAXA. aDifferences in the change in total body weight between DAPA + SAXA + MET and DAPA + MET were not available. DAPA: dapagliflozin; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; MET: metformin; SAXA: saxagliptin.
Figure 4.
Figure 4. Glycemic efficacy of DAPA + SAXA. DAPA: dapagliflozin; SAXA: saxagliptin.
Figure 5.
Figure 5. Safety of DAPA + SAXA. DAPA: dapagliflozin; SAXA: saxagliptin.
Figure 6.
Figure 6. Summary of results from SAVOR-TIMI 53. CKD: chronic kidney disease; hHF: hospitalization for heart failure; MACE: major adverse cardiovascular event; NT-proBNP: N-terminal pro-B-type natriuretic peptides; PBO: placebo; SAXA: saxagliptin.
Figure 7.
Figure 7. Cardiovascular safety of SAXA. SAXA: saxagliptin.
Figure 8.
Figure 8. Cardiorenal protection with DAPA + SAXA. DAPA: dapagliflozin; SAXA: saxagliptin.
Figure 9.
Figure 9. Summary of recommendations for the DAPA + SAXA FDC in Indian patients with T2DM. DAPA: dapagliflozin; FDC: fixed-dose combination; SAXA: saxagliptin; T2DM: type 2 diabetes mellitus.

Tables

Table 1. Summary of Recommendation of T2DM Management Pertaining to Pharmacologic Agents by ADA, AACE and RSSDI
 
ADA [25]AACE [26]RSSDI [27]
ADA: American Diabetes Association; AACE: American Association of Clinical Endocrinology; AGi: alpha-glucosidase inhibitors; DPP4i: dipeptidyl peptidase-4 inhibitor; GLP-1 RA: glucagon-like peptide-1 receptor agonist; GIP: gastric inhibitory polypeptide; GLP-1: glucagon-like peptide-1; HbA1c: glycated hemoglobin; NASH: nonalcoholic steatohepatitis; RSSDI: Research Society for the Study of Diabetes in India; SGLT2i: sodium-glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; TZD: thiazolidinediones.
  • Metformin should be continued upon initiation of insulin therapy (unless contraindicated or not tolerated) for ongoing glycemic and metabolic benefits.
  • Pharmacologic therapy should be guided by person-centered treatment factors, including comorbidities and treatment goals. Consider effects on cardiovascular and renal comorbidities, efficacy, hypoglycemia risk, impact on weight, cost and access, risk for side effects, and individual preferences.
  • Early combination therapy can be considered in some individuals at treatment initiation to extend the time to treatment failure.
  • Among individuals with T2DM who have established atherosclerotic cardiovascular disease or indicators of high cardiovascular risk, established kidney disease, or heart failure, SGLT2i and/or GLP-1 RA with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen and comprehensive cardiovascular risk reduction, independent of A1c and in consideration of person-specific factors.
  • Metformin should be initiated if there is no contraindication.
  • Clinicians should consider multiple factors when selecting the second agent, including presence of overweight or obesity, hypoglycemia risk, access/cost, and presence of severe hyperglycemia.
  • In drug naive persons with newly diagnosed T2DM, prospective studies support the initiation of combination therapy to achieve glycemic targets more quickly as compared with a stepwise approach.
  • For overweight/obese patients GLP-1RA or SGLT2i is preferred, alternately DPP4i can be used.
  • For patients at risk of hypoglycemia, GLP-1RA or SGLT2i is preferred, alternately, DPP4i can be used.
  • In those patients with overweight or obesity and the additional goal of weight loss, dual GIP/GLP-1 RA, GLP-1 RA, or SGLT2i class are preferred options. Persons with a history of hypoglycemia, at high risk of hypoglycemia. and/or at risk for severe complications from hypoglycemia should preferentially be initiated with an agent associated with low risk for hypoglycemia, including GLP-1 RA, SGLT2i, dual GIP/GLP-1 RA, TZD, or DPP4i.
  • Metformin can be initiated in combination with lifestyle interventions at the time of diagnosis.
  • Other options: sulfonylureas (or glinides), TZD, DPP4i, SGLT2i, AGi or oral GLP1-RA can be used initially for cases where metformin is contraindicated or not tolerated.
  • Consider cardiovascular/heart failure risk, renal/hepatic (NASH) risk and other comorbidities while deciding therapy.
  • Consider initiating combination therapy if the HbA1c > 1.5 above the target.
  • If glucose control targets are not achieved: Add SGLT2i, or DPP4i or sulfonylurea or TZD or AGi or oral GLP1-RA.
  • For patients with established or having high-risk for atherosclerotic cardiovascular disease, heart failure, diabetic kidney disease or in need of weight reduction consider using SGLT2i or oral GLP-1RA.
  • If glucose targets are not achieved with two agents: start third oral agent-AGI, DPP4i, SGLT2i, or TZD or oral GLP-1 RA (depending on the second-line agent used).

 

Table 2. Summary of the Studies Investigating the Outcomes of DAPA, DAPA + SAXA, and SAXA in Patients With T2DM
 
Author and trial nameType of trialCountryPatients and interventionKey outcomes
ACR: albumin to creatinine ratio; AE: adverse event, BSA: body surface area; BW: body weight; BMI: body mass index; CI: confidence interval; CVD: cardiovascular disease; DAPA: dapagliflozin; DBP: diastolic blood pressure; DPP4i: dipeptidyl peptidase-4 inhibitor; DKA: diabetic ketoacidosis; ESRD: end-stage renal disease; FPG: fasting plasma glucose; GLIM: glimepiride; HF: heart failure; hHF: hospitalization for heart failure; HR: hazard ratio; HOMA-IR: homeostatic model assessment of insulin resistance; eGFR: estimated glomerular filtration rate; MET: metformin; NYHA: New York heart association; LINA: linagliptin; PPG: post-prandial plasma glucose; INS: insulin; ITT: intent to treat; MI: myocardial infraction; oGLD: other glucose lowering drugs; UTI: urinary tract infection; LDL: low-density lipoprotein; MACE: major adverse cardiovascular event; RWE: real-world evidence; RCT: randomized controlled trial; SGLT2i: sodium-glucose cotransporter-2 inhibitor; PBO: placebo; SAXA: saxagliptin; SBP: systolic blood pressure; SITA: sitagliptin; VILD: vildagliptin; SU: sulfonylurea; SCAT: subcutaneous adipose tissue; TEAE: treatment emergent adverse events; UTI: urinary tract infection; VAT: visceral adipose tissue.
Wiviott et al, 2019 [62] (DECLARE TIMI 58)RCTMultinationalPatients with T2DM (n = 17,160; n = 10,186 without atherosclerotic CVD) treated with DAPA 10 mg vs. PBO
  • MACE: 8.8%, DAPA; 9.4%, PBO; HR: 0.93; 95% CI: 0.84 to 1.03; P = 0.17
  • CVD death or hHF: 4.9% DAPA; 5.8% PBO; HR: -0.83; 95% CI: 0.73 to 0.95; P = 0.005
  • Risk of hHF: HR: 0.73; 95% CI: 0.61 to 0.88
  • Renal composite outcome: 4.3%, DAPA; 5.6%, PBO; HR: 0.76; 95% CI: 0.67 to 0.87
  • Genital infections: 0.9%, DAPA; 0.1%, PBO, P < 0.01
McGurnaghan et al, 2019 [44]RWEScotland, UKPatients with T2DM (n = 8,566) treated with DAPA as per recommended dose
  • HbA1c: -1.19%
  • SBP: -4.32 mm Hg, 95% CI: -4.84, -3.79
  • BMI: -0.82 kg/m2, 95% CI: -0.87, -0.77
  • Body weight: -2.20 kg, 95% CI: -2.34, -2.06
  • CVD in 111, DKA in 13 and LLA in 28
  • CVD significantly low in ever-users vs. never-users (HR: 0.71, P = 0.02)
Viswanathan et al, 2019 [47] (FOREFRONT)RWEIndiaPatients with T2DM (n = 1,941, treated with DAPA) as per recommended dose
  • HbA1c: -1.00% at 3 months; 1.49% at 6 months (P < 0.001)
  • Body weight reduction: 1.14 ± 2.21 kg, 3 months; 1.86 ± 3.04 kg, 6 months, P < 0.001
  • Vulvovaginitis: 9 (0.5%); fungal infection and UTI: 4 (0.2%) each
McMurray et al, 2019 [59] (DAPA-HF)RCTUnited Kingdom (UK)Patients with T2DM and NYHA class II, III, or IV HF and an ejection fraction of 40%, treated with DAPA 10 mg (n = 2,373) vs. PBO (n = 2,371)
  • First worsening HF event: 237 (10.0%), DAPA; 326 (13.7%), PBO; HR: 0.70; 95% CI: 0.59 to 0.83
  • Death from CV: 227 (9.6%), DAPA; 273 (11.5%), PBO; HR: 0.82; 95% CI: 0.69 to 0.98
  • Death from any cause: 276 (11.6%), DAPA; 329 (13.9%), PBO; HR: 0.83; 95% CI: 0.71 to 0.97
Fuchigami et al, 2020 [63] (DIVERSITY-CVR)RCTJapanPatients with T2DM treated with DAPA 5 - 10 mg (n = 170) vs. SITA 50 - 100 mg (n = 170)
  • Achievement ratio of composite endpoint: (HbA1c ≤ 7.0%, maintenance of sensor glucose > 54 mg/dL, body weight loss ≥ 3.0%) higher in DAPA vs. SITA: 24.4% vs. 13.8% (P < 0.05)
  • Higher in DAPA vs. SITA: 24.4% vs. 13.8% (P < 0.05)
  • Hypoglycemia: 88.7 vs. 92.3%, DAPA vs. SITA
  • Body weight: ≥ -3.0%, DAPA (P < 0.001)
Brown et al, 2020 [54] (DAPA-LVH)RCTScotland, UKPatients with T2DM and LVH, treated with DAPA 10 mg (n = 66)
  • LVM reduction: -2.82 g (95% CI: -5.13 to -0.51, P = 0.018), DAPA vs. SITA
  • Reduction in 24 h SBP (P = 0.012), nocturnal SBP (P = 0.017), body weight (P < 0.001), VAT (P < 0.001), SCAT (P = 0.001), HOMA-IR (P = 0.017), DAPA vs. SITA
Khunti et al, 2021 [57] (CVD REAL)RWEMultinationalT2DM patients who were new users of SGLT2i (n = 440,599); DAPA contributed 60% of total exposure time
  • Lower risk of all-cause death: ITT-unadjusted pooled HR: 0.52, 95% CI: 0.45 - 0.60; P < 0.001
  • hHF or all-cause death: 6932 and 10,275 events of in SGLT-2i and oGLD
  • Lower risk of composite of hHF or all-cause death: ITT-unadjusted pooled HR: 0.60, 95% CI: 0.53 - 0.68; P < 0.001
  • MI events: 2,203 and 2,677 in the SGLT2i and oGLD group
  • Lower risk of MI: ITT-unadjusted pooled HR: 0.85, 95% CI: 0.78 - 0.92; P < 0.001
Hassoun et al, 2022 [43] (REWARD)RWEUAE and KuwaitPatients with T2DM treated with DAPA 10 mg (n = 511)
  • HbA1c: -0.9±0.3% (P < 0.001)
  • SBP: -1.9 mm Hg (P = 0.003)
  • BMI: 29.9 to EOS 29.7 (P < 0.001)
  • Reduction in cholesterol (P = 0.005); LDL (P = 0.001), and HDL (P = 0.005)
  • Hypoglycemic episodes: n = 90, 0 severe
  • UTIs: 1.96%
Morales et al, 2022 [64] (DAPA-RWE)RWESpainPatients with T2DM treated with DAPA (n = 594) and SITA (n = 452)
  • HbA1c: -1.63%
  • body weight: -2.88 kg
  • SBP/DBP: -4.82/-2.70 mm Hg, P < 0.05
  • UACR: -17.38 mg/g (P < 0.05), LDL cholesterol: -4.1 mg/dL (P < 0.05), uric acid: -0.30 mg/dL (P < 0.05)
  • No hypoglycemia, DKA, Fournier gangrene, fractures or amputations reported
Sethi et al, 2022 [48]RWEIndiaPatients with T2DM treated with DAPA as an add-on to other antihyperglycemic agents with or without INS (n = 1,935)
  • HbA1c: -1.1% (P < 0.001)
  • FPG: -30.5 mg/dL (P < 0.001)
  • PPG: -57.5 mg/dL (P < 0.001)
  • SBP: -12.1 mm Hg (P < 0.001), DBP: -5.8 mm Hg (P < 0.001)
  • Cholesterol: -20.9 mg/dL (P < 0.001)
  • BMI: -1.1 kg/m2 (P < 0.001)
Solomon et al, 2022 [61] (DELIVER)RCTMultinationalPatients with T2DM with HF and LVEF of more than 40% treated with DAPA 10 mg (n = 3,131) and PBO (n = 3,132)
  • Worsening HF: 368 (11.8%) vs. 455 (14.5%); HR: 0.79; 95% CI: 0.69 to 0.91, DAPA vs. PBO
  • SAE including death: 43.5% vs. 45.5%, DAPA vs. PBO
  • CV deaths: 7.4% vs. 8.3%; HR: 0.88; 95% CI: 0.74 to 1.05, DAPA vs. PBO
Rosenstock et al, 2015 [53]RCTMultinationalPatients with T2DM treated with DAPA (10 mg) + SAXA (5 mg) + MET (n = 179) vs. SAXA + MET or PBO (n = 176) vs. DAPA + MET or PBO (n = 179)
  • HbA1c: -1.5%, DAPA + SAXA + MET vs. -0.9%, SAXA + MET vs. -1.2%, DAPA + MET
  • FPG: -38 ± 2.8 mg/dL, SAXA + DAPA + MET vs. -14 ± 2.9 mg/dL, SAXA + MET group vs. -32 ± 2.8 mg/dL, DAPA + MET
  • Body weight: -2.1 kg, SAXA + DAPA + MET vs. -2.4 kg, DAPA + MET vs. no change, SAXA + MET
  • Genital infections: 0, SAXA + DAPA + MET; 6%, DAPA + MET; 0.6%, SAXA + MET
  • SBP: -1.9 mm Hg, SAXA + DAPA + MET; -3.5 mm Hg, DAPA + MET; 0, SAXA + MET
  • DBP: -1.0 mm Hg, SAXA + DAPA + MET; -0.4, SAXA + MET; -1.4 mm Hg, DAPA + MET
Mathieu et al, 2016 [21]RCTMultinationalPatients with T2DM treated with PBO + SAXA + MET (n = 158) vs. DAPA 10 mg + SAXA + MET (n = 158)
  • HbA1c: -0.74% vs. 0.07%, DAPA + SAXA + MET vs. PBO + SAXA + MET
  • FPG: -27 vs. 10 mg/dL, DAPA + SAXA + MET vs. PBO + SAXA + MET
  • Body weight: -2.1 vs. -0.4 kg, DAPA + SAXA + MET vs. PBO + SAXA + MET
  • AE events: 66% vs. 71% DAPA + SAXA + MET vs. PBO + SAXA + MET
  • Genital infections: 6% vs. 1% for DAPA + SAXA + MET vs. PBO + SAXA + MET
Matthaei et al, 2016 [58]RCTMultinationalPatients with T2DM treated with DAPA 10 mg + MET + SAXA 5 mg (n = 153) vs. DAPA 10 mg + MET + PBO (n = 162)
  • HbA1c: -0.38% vs. -0.05%; difference (95% CI): -0.42% (-0.64, -0.20), DAPA + MET + SAXA vs. DAPA + MET + PBO
  • Genital infections: 3.3% vs. 6.2%, DAPA + MET + SAXA vs. DAPA + MET + PBO
Muller et al, 2018 [51]RCT, DapaZu studyGermany, Czech Republic, Hungary, Poland and SlovakiaPatients with T2DM treated with MET + DAPA 10 mg (n = 314) vs. MET + DAPA 10 mg + SAXA 5 mg (n = 312) vs. MET + GLIM 1 to 6 mg (titrated) (n = 313)
  • HbA1c: -1.20% vs. 0.82% vs. 0.99%, DAPA + SAXA vs. DAPA vs. GLIM
  • Body weight: -3.2 kg vs. -3.5 kg vs. +1.8 kg, DAPA + SAXA vs. DAPA vs. GLIM
  • SBP: -6.4 mm Hg vs. -5.6 mm Hg vs. -1.6 mm Hg in DAPA + SAXA vs. DAPA vs. GLIM
  • PPG: -37.8 mg/dL vs. -27 mg/dL vs. -28.8 mg/dL, DAPA + SAXA vs. GLIM vs. DAPA
Vilsboll et al, 2020 [24]RCTMultinationalPatients with T2DM treated with DAPA 10 mg + SAXA 5 mg (n = 306) vs. INS 100 U/mL (n = 294)
  • HbA1c: -1.5% vs. -1.3% in DAPA + SAXA vs. INS
  • Body weight: -1.8 kg (95% CI: -2.4, -1.3), DAPA + SAXA vs. +2.8 kg (95% CI: 2.2, 3.3)
  • Hypoglycemia: < 7.0% vs. 9.1%, DAPA + SAXA vs. INS
  • UTI infections: 6.2% in DAPA + SAXA vs. 5% in INS
  • Genital infections: 4.9% in DAPA + SAXA vs. 0.6% in INS
Frias et al, 2020 [22]RCTMultinationalPatients with T2DM treated with DAPA 10 mg + SAXA 5 mg (n = 227) vs. GLIM 1 - 6 mg (titrated; n = 217)
  • HbA1c: -1.35%, DAPA + SAXA vs. -0.98%, GLIM (P < 0.001)
  • Body weight: -3.1 kg, DAPA + SAXA vs. 1.0 kg (P < 0.001), GLIM
  • SBP: -2.6 mm Hg, DAPA + SAXA; +1.0 mm Hg (P = 0.007), GLIM
  • UTI: 6.2%, DAPA + SAXA vs. 4.2% in GLIM
  • Genital infections: 5.3%, DAPA + SAXA vs. and 1.9%, GLIM
  • Renal impairment: 4% vs. 1.4%, DAPA + SAXA vs. GLIM
Johansson et al, 2020 [56]RCTMultinationalPatients with T2DM treated with DAPA 10 mg + SAXA 5 mg + MET (n = 46) vs. GLIM + MET (n = 36)> 30% reduction in liver fat (P = 0.007) and > 10% reduction in adipose tissue volumes (P < 0.01) with DAPA + SAXA + MET vs. GLIM + MET
Nowicki et al, 2011 [52]RCTMultinationalPatients with T2DM and renal impairment (moderate, severe or ESRD on hemodialysis) treated with SAXA 2.5 mg (n = 85) vs. PBO (n = 85)
  • HbA1c: -1.35% (95% CI: 1.69 - 1.00) vs. -0.53% (95% CI: -0.83 to -0.23), P < 0.001, SAXA vs. PBO
  • FPG: -14.76 mg/dL vs. -2.7 mg/dL, SAXA vs. PBO
  • HbA1c w.r.t to renal impairment: SAXA vs. PBO moderate (-0.94% vs. 0.19%), severe (-0.81% vs. -0.49%), ESRD (-1.13% vs. -0.99%)
Kumar et al, 2014 [50]RCTIndiaTreatment-naive pts with T2DM treated with SAXA (n = 107) vs. PBO (n = 106)
  • HbA1c: -0.51% vs. -0.05%, SAXA vs. PBO, P = 0.0011
  • FPG: -10.44 ± 3.78 vs. -0.00 ± 3.78 mg/dL; P = 0.06, SAXA vs. PBO
  • Body weight change: +0.75 kg vs. -0.27 kg, SAXA vs. PBO
  • TEAEs: 5.6% vs. 7.5%, SAXA vs. PBO
Scirica et al, 2014 [60] (SAVOR-TIMI)RCTMultinationalPatients with T2DM and a history of, or at risk of, cardiovascular events treated with SAXA 5 mg or 2.5 mg (n = 8,280) vs. PBO (n = 8,212)
  • hHF: 3.5% vs. 2.8%; HR: 1.27; 95% CI: 1.07 - 1.51; P = 0.007, SAXA vs. PBO
  • Body weight: 87.6 ± 18.4 vs. 87.9 ± 19.4 kg; P = 0.87, SAXA vs. PBO
Mosenzon et al 2016 [65] (SAVOR-TIMI)RCTMultinationalPatients with T2DM and history of established CVD or multiple risk factors for CVD (n = 16,492) treated with SAXA 5 mg or 2.5 mg vs. PBO
  • SAXA improves/reduces deterioration in ACR categories, P = 0.021, P < 0.001, and P = 0.049 in pts with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria
  • ACR change in SAXA vs. PBO: -19.3 mg/g (P = 0.033) for eGFR > 50 mL/min/BSA/1.73 m2, -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR < 30 mL/min/BSA
Ha et al, 2018 [55]RWEKoreaPatients with T2DM who are newly prescribed DPP4i, SITA (n = 167,157), VILD (n = 67,412), SAXA (n = 29,479), LINA (n = 220,672), or GEMI (n = 49,607)CVD risk: HR (95% CI); VILD, 0.97 (0.94 - 1.01), P = 0.163; SAXA, 0.76 (0.71 - 0.81), P < 0.001; LINA, 0.95 (0.92 - 0.98), P < 0.001; GEMI, 0.84 (0.80 - 0.88), P < 0.001
Kalra et al, 2019 [49] (ONTARGET-INDIA)RWEIndiaPatients with T2DM inadequately controlled on MET treated with SAXA 5 mg (n = 1,109)
  • HbA1c: -0.86% ± 1.76 (P < 0.0001)
  • UTI and genital tract infection: 13.35% and 5.23% each

 

Table 3. Comparison of Key Outcomes for SGLT2i + DPP4i Fixed-Dose Combinations Approved in India
 
OutcomesDAPA + SAXA [22, 24, 53, 80]Empagliflozin + linagliptin [75, 76, 78]Remogliflozin + vildagliptin [74, 79, 81]DAPA + sitagliptin [77]
CARMELINA: Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; CARLINA: Cardiovascular Outcome Study of Linagliptin; CVOT: Cardiovascular Outcome Trial; CVD REAL: Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors; DAPA: dapagliflozin; DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DAPA-LVH: Dapagliflozin on Left Ventricular Hypertrophy; DECLARE-TIMI: Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction; DELIVER: Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; EMA: European Medicines Agency; EMPA-REG: Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose; FDA: Food and Drug Administration; FDC: fixed-dose combination; NA: not available; SAXA: saxagliptin; SAVOR-TIMI: Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction; TECOS: Trial Evaluating Cardiovascular Outcomes With Sitagliptin; VIVIDD: Vildagliptin in Ventricular Dysfunction Diabetes.
Mean reduction in HbA1c, %-1.37 to -1.5-0.93 to -1.19-1.2 to -1.80.0 to -0.4
Mean reduction in FPG, mg/dL-35.8 to -38-35.3 to -47.11-32.5 to -47.37-23.2 to -25.7
Mean reduction in body weight, kg-1.9 to -3.1-1.53 to -3.0NA-1.4 to -2.5
Genital infections, %0 to 5.301.1 to 8.6NA9.8
Urinary tract infections, %0.6 to 6.50 to 10.2NA6.7
Hypoglycemia, %1 to 6.20 to 3.6None5.3
CVOT trialsSAVOR-TIMI [65], DECLARE-TIMI [62], DAPA-HF [59], DAPA-LVH [54], CVD REAL [57, 84], DELIVER [61]EMPA-REG [88], CARMELINA [87], CAROLINA [89], EMPEROR-Preserved [82], EMPEROR-Reduced [86]VIVIDD [85]TECOS [83]
FDC US/EU approval status
  US FDA approvalYesYesNoNo
  EMA approvalYesYesNoNo