Opinion Review
Copyright ©The Author(s) 2022.
World J Cardiol. Jun 26, 2022; 14(6): 329-342
Published online Jun 26, 2022. doi: 10.4330/wjc.v14.i6.329
Table 1 Studies with GLP-1 receptor agonists plus SGLT-2 inhibitors vs SGLT-2 inhibitors or GLP-1 receptor agonists
Type of study
Ref.
Comparator agent
n
Duration
∆HbA1c (%), (95%CI or mean ± SD)
∆Weight (kg), (95%CI)
∆SBP (mmHg), (95%CI)
OR for severe Hypo’s (95%CI)
GI S/E
GTI
Simultaneous initiation of GLP-1RA plus SGLT-2I vs SGLT-2I
RCT, DB/ DURATION-8Frías et al[16], 2016EXE QW + DAPA vs DAPA69528 wk-0.6 (-0.8; -0.3)-1.22 (-2.00; -0.44)-2.4 (-4.5; -0.3)1.00 (0.02; 50.61)EXENA + DAPA-16%; DAPA-12%EXENA + DAPA- 4%; DAPA- 6%
RCTIkonomodis et al[19], 2018LIRA + EMPA vs EMPA4012 wk-0.70 (-2.55; 1.15)NR0.00 (-5.70; 5.70)NRNRNR
RCT, OLAli et al[12], 2020LIRA + CANA vs CANA4516 wk-0.78 (-1.52; -0.04)-2.50 (-4.35; -0.65)-8.90 (-16.19; -1.61)1.00 (0.02; 53.66)NRNR
Sequential addition of GLP-1RA to SGLT-2I vs SGLT-2I
RCT, DB/AWARD-10Ludvik et al[20], 2018DULA + SGLT-2I vs PBO + SGLT-2I42424 wk-0.73 (-0.88; -0.58)-0.75 (-1.47; -0.03)-2.45 (-4.78; -0.12)2.50 (0.06; 104.85)DULA + SGLT-2I- 26.5%; PBO-17%DULA + SGLT-2I- 0%; PBO-1%
RCT, DB/SUSTAIN-9Zinman et al[21], 2019SEMA + SGLT-2I vs PBO + SGLT-2I30230 wk-1.40 (-1.58; -1.22)-3.80 (-4.67; -2.93)-6.30 (-9.07; -3.53)9.27 (0.50; 173.02)SEMA + SGLT-2I- 37.3%; PBO-13.2%NR
RCT, DB/LIRA-ADD2SGLT2iBlonde et al[22], 2020LIRA + SGLT-2I vs PBO + SGLT-2I30326 wk-0.68 (-0.89; -0.47)-0.82 (-1.67; 0.03)1.40 (-1.65; 4.45)1.00 (0.02; 64.81)LIRA + SGLT-2I- 26%1; PBO-6.0%1NR
Simultaneous initiation of SGLT-2I plus GLP-1RA vs GLP-1RA
RCT/DURATION-8Frías et al[16], 2016DAPA + EXE QW vs EXE QW69528 wk-0.4 (-0.6; -0.1)-1.87 (-2.66; -1.08)-2.9 (-5.0; -0.8)1.00 (0.02; 50.61)EXENA + DAPA-16%; DAPA-15%EXENA + DAPA-4%; EXENA-2%
RCTIkonomodis et al[19], 2018EMPA + LIRA vs LIRA4012 wk-0.20 (-2.16; 1.76)NR-1.00 (-6.57; 4.57)NRNRNR
RCTAli et al[12], 2020CANA + LIRA vs LIRA4516 wk-0.23 (-1.18; 0.72)-4.10 (-6.32; -1.88)-9.00 (-18.49; 0.49)1.00 (0.02; 53.66)NRNR
Sequential addition of SGLT-2I to GLP-1RA vs GLP-1RA
RCT, DB/CANVASFulcher et al[23], 2016CANA + GLP-1RA vs PBO + GLP-1RA9518 wk-1.03 (-1.34; -0.72)-2.72 (-3.70; -1.74)-8.05 (-14.13; -1.97)2.5 (0.05; 114.6)NRCANA + GLP-1RA-12.3%; PBO-5.3%
Non-randomized studies (all ∆ from baseline)
Simultaneous initiation of SGLT-2I plus GLP-1RA
ObsGoncalves et al[28,29], 2017SGLT-2I with LIRA3362-2.0-10.0-13.0NRNRNR
Sequential addition of SGLT-2I to GLP-1RA
ObsSaroka et al[24], 2015CANA added to GLP-1RA75 (60 on insulin)10.7 mo (mean)-0.39 ± 0.88-4.6 ± 4.3-4.0 ± 12NR1.3%GTI: 8%
Retro, ObsCurtis et al[25], 2016DAPA added to GLP-1RA14 (10 on insulin)48 wk-4.4 (-5.7; -2.7)-5.47 (-22.9; -5)NRNRNRNR
Retro, ObsDeol et al[26], 2016SGLT-2I added to GLP-1RA37 (DAPA = 36, CANA = 1)3-6 mo 139 d (mean)-1.05 (-1.41; -0.69)-3.07 (-4.36; -1.78)-1.16 (-6.01; 8.42)NRNRNR
Non-R, OL, PMSHarashima et al[27], 2017CANA added to LIRA7152 wk-0.7 (-0.89; -0.51)-3.29 (-3.86; -2.72)-7.9 (-10.7; -5.1)9.9% (mild)NR7.1%
ObsGoncalves et al[28,29], 2017SGLT-2I added to LIRA4676 wk-0.9-4.0-7.0NRNRNR
Non-RSeino et al[30], 2018LUSEO added to LIRA7652 wk-0.68 (-0.87; -0.49)-2.71 (-3.18; -2.23)-7.1 (-10.4; -3.9)6.6% (mild)13.2%3.9%
1Nausea. CANA: Canagliflozin; DAPA: Dapagliflozin; DB: Double blind; EMPA: Empagliflozin; EX QW: Exenatide once weekly; GI: Gastrointestinal; GLP-1RA: GLP-1 receptor agonists; GTI: Genital tract infections; Hypo’s: Hypoglycemia; LIRA: Liraglutide; LUSEO: Luseogliflozin; Non-R: Non-randomized; NR: Not reported/retrievable; Obs: Observational; OL: Open label; OR: Odds ratio; PBO: Placebo; PMS: Post marketing study; RCT: Randomized controlled trial; Retro: Retrospective; SBP: Systolic blood pressure; SGLT-2I: SGLT-2 inhibitors; S/E: Side effect; SEMA: Semaglutide.
Table 2 Meta-analysis of randomized controlled trials comparing GLP-1 receptor agonists + SGLT-2I vs SGLT-2I or GLP-1 receptor agonists
Ref.
Types of studies included, n
Comparator arm
N
∆HbA1c (%), (95%CI)
∆Weight (kg), (95%CI)
∆SBP (mmHg), (95%CI)
Adverse events (GI, GTI, Hypo’s) with SGLT-2I + GLP-1RA vs SGLT-2I
Zhou et al[31], 2019RCT, 3GLP-1RA + SGLT-2I vs SGLT-2I1421-0.80 (-1.14; -0.45)-1.46 (-2.38; -0.54)-2.88 (-4.52; -1.25)Increased risk of GI S/E (RR: 1.68; 95%CI: 1.14-2.47) but similar GTI (RR: 0.82; 95%CI: 0.39-1.75) and hypo’s (RR: 2.10; 95%CI: 0.75-5.90) in combo arm
Castellana et al[32], 2019RCT, 4GLP-1RA + SGLT-2I vs SGLT-2I1610-0.74 (-1.15; -0.33)-1.61 (-2.83; -0.38)-3.32 (-4.96; -1.68)Similar hypo’s (RR: 1.43; 95%CI: 0.46-4.52). GTI and GI S/E not reported
Patoulias et al[33], 2019RCT, 3GLP-1RA + SGLT-2I vs SGLT-2I1042-0.91 (-1.41; -0.42)-1.95 (-3.83; -0.07)-3.64 (-6.24; -1.03)Increased risk of nausea (RR: 3.21; 95%CI: 1.36-7.54) and hypo’s (RR: 2.62; 95%CI: 1.15-5.96) in combo arm. GTI not reported
Mantsiou et al[34], 2020RCT, 7GLP-1RA + SGLT-2I vs SGLT-2I1913-0.85 (-1.19; -0.52)-1.46 (-2.94; +0.03)-2.66 (-5.26; -0.06)No difference in severe hypo’s (OR: 2.39; 95%CI: 0.47-12.27). GTI and GI S/E not reported
GLP-1RA + SGLT-2I vs GLP-1RA-0.61 (-1.09; -0.14)-2.59 (-3.68; -1.51)-4.13 (-7.28; -0.99)No difference in severe hypo’s (OR: 1.38; 95%CI: 0.14-13.14). GTI and GI S/E not reported
GI: Gastrointestinal; GLP-1RA: GLP-1 receptor agonists; GTI: Genital tract infections; Hypo’s: Hypoglycemia; OR: Odds ratio; RR: Risk ratio; RCT: Randomized controlled trial; SBP: Systolic blood pressure; S/E: Side effect; SGLT-2I: SGLT-2 inhibitors.
Table 3 Effect of simultaneous application of GLP-1 receptor agonists + SGLT-2I therapy on HbA1c (%), body weight (kg), and systolic blood pressure (mmHg) in randomized controlled trialx
Ref.Parameters studied
Duration (wk)
(A) ∆GLP-1 RA
(B) ∆SGLT-2I
(C) ∆GLP-1 RA + SGLT-2I
(A + B) ∆Sum of GLP-1 RA and SGLT2i
Effect of (C) compared to (A + B)
Frías et al[16], 2016; Jabbour et al[17], 2018; Birnbaum et al[18], 2018HbA1c28-1.60-1.40-2.00-3.00Less than additive
52-1.38-1.23-1.75-2.61Less than additive
104-1.29-1.06-1.70-2.35Less than additive
Ikonomidis et al[19], 2018HbA1c12-1.30-0.80-1.50-2.10Less than additive
Ali et al[12], 2020HbA1c16-1.44-0.89-1.67-2.33Less than additive
Frías et al[16], 2016; Jabbour et al[17], 2018; Birnbaum et al[18], 2018Body weight28-1.56-2.22-3.55-3.78Nearly additive
52-1.51-2.28-3.31-3.79Nearly additive
104-0.80-3.00-2.50-3.80Less than additive
Ikonomidis et al[19], 2018Body weight12NRNRNRNRNR
Ali et al[12], 2020Body weight16-1.90-3.50-6.00-5.40More than additive
Frías et al[16], 2016; Jabbour et al[17], 2018; Birnbaum et al[18], 2018SBP28-1.20-1.80-4.30-3.00More than additive
52-0.70-2.70-4.50-3.40More than additive
104-0.10-1.10-3.10-1.20More than additive
Ikonomidis et al[19], 2018SBP12-3.00-4.00-4.00-7.00Less than additive
Ali et al[12], 2020SBP16-5.10-5.20-14.10-10.30More than additive
GLP-1RA: GLP-1 receptor agonists; HbA1c: Glycated haemoglobin; NR: Not reported; SBP: Systolic blood pressure; SGLT-2I: SGLT-2 inhibitors.
Table 4 Meta-data of three-point composite of major adverse cardiovascular events, heart failure hospitalization, and renal outcome in cardiovascular outcome trials of SGLT-2 inhibitors and GLP-1 receptor agonists
Trial eponym, drugs
Background GLP-1RA + SGLT-2I therapy; n
Active arm (n/N), % or rate-per 100-patient-yr1
Placebo arm (n/N), % or rate-per 100-patient-yr1
HR, (95%CI)
P value of interaction
3-point composite of major adverse cardiovascular events outcome
CANVAS[46], CanagliflozinYes; 407NRNR0.73 (0.36-1.46)0.94
No; 9735NRNR0.86 (0.76-0.98)
DECLARE-TIMI[47], DapagliflozinYes; 75031/397, 7.8%31/353, 8.8%0.87 (0.53-1.43)0.84
No; 16410725/8185, 8.9%772/8225, 9.4%0.94 (0.85-1.04)
VERTIS-CV[48], ErtugliflozinYes; 27721/192, 3.5419/85, 3.7910.94 (0.43-2.05)NR
No; 7961632/5301, 3.911318/2660, 4.0210.97 (0.85-1.11)
EXSCEL[43], Exenatide QWYes; 11442NR/572, 3.291NR/572, 4.8110.68 (0.39-1.17)NR
NoNRNRNR
AMPLITUDE-O[45], EfpeglenatideYes; 61825/412, 6.1%, 3.4117/206, 8.3%, 5.010.70 (0.37-1.30)0.68
No; 3458164/2305, 7.1%, 4.01108/1153, 9.4%, 5.410.74 (0.58-0.94)
Heart failure hospitalization outcome
DECLARE-TIMI[47], DapagliflozinYes; 7504/397, 1.0%18/353, 5.1%0.20 (0.07-0.60)0.01
No; 16410208/8185, 2.5%268/8225, 3.3%0.77 (0.64-0.92)
AMPLITUDE-O[45], EfpeglenatideYes; 6183/412, 0.7%; 0.416/206, 2.9%, 1.610.23 (0.05-0.97)0.35
No; 345837/2305, 1.6%, 0.9125/1153, 2.2%, 1.210.70 (0.42-1.17)
Renal outcome
DECLARE-TIMI[47], Dapagliflozin3Yes; 7504/397, 1.0%10/353, 2.8%0.36 (0.11-1.15)0.49
No; 16410123/8185, 1.5%228/8225, 2.8%0.54 (0.43-0.67)
AMPLITUDE-O[45], Efpeglenatide4Yes; 61837/412, 9.0%, 5.1134/206, 16.5%, 10.010.52 (0.33-0.83)0.38
No; 3458316/2305, 13.7%, 8.21216/1153, 18.7%, 11.910.70 (0.59-0.83)
1Rate-per 100-patient-yr.
2Open-label, propensity-matched.
3Renal composite outcome consist of sustained decrease of 40% or more in eGFR to less than 60 mL/min/1.73 m2, new end-stage renal disease, or death from renal causes.
4Renal composite outcome consists of incident macroalbuminuria (UACR > 300 mg/g or 33.9 mg/mmol) plus ≥ 30% rise of UACR from baseline, a sustained ≥ 30 d decrease in eGFR by ≥ 40%, renal replacement therapy, and a sustained (≥ 30 d) eGFR < 15 mL/min/1.73 m2.
3P-MACE: Three-point composite of major adverse cardiovascular events; CVOTs: Cardiovascular outcome trials; HHF: Heart failure hospitalization; GLP-1RA: Glucagon-like petide-1 receptor agonists; HR: Hazard ratio; n: Number of events; N: Total number of patients; NR: Not reported/retrievable; PBO: Placebo; SGLT-2I: Sodium glucose transporter-2 inhibitors.