5. Markers on timeline represent trial completion (except for VERTIS CV, AMPLITUDE-O and SOUL, for which estimated trial completion dates are provided), all of which
come from ClinicalTrials.gov. Primary endpoint is 3P-MACE unless indicated otherwise
See slide notes for abbreviations and full list of references
TECOS5
Sitagliptin
N=14,671
4P-MACE
ELIXA4
Lixisenatide
N=6068
4P-MACE
EMPA-REG OUTCOME6
Empagliflozin
N=7020
CARMELINA13
Linagliptin
N=6979
EXSCEL12
Exenatide
N=14,752
DECLARE-TIMI 5817
Dapagliflozin
N=17,160
3P-MACE and
CV death or HHF
CANVAS Program11
Canagliflozin
N=10,142
FREEDOM-CVO8,9
ITCA 650
N=4156
4P-MACE
PIONEER 619
Semaglutide (oral)
N=3183
CAROLINA18
Linagliptin
N=6041
Harmony
Outcomes14
Albiglutide
N=9463
REWIND15,16
Dulaglutide
N=9901
LEADER7
Liraglutide
N=9340
SUSTAIN-610
Semaglutide (inj.)
N=3297
VERTIS CV20
Ertugliflozin
N=8000
DPP-4 inhibitor
SGLT2 inhibitor
GLP-1 RA
EXAMINE3
Alogliptin
N=5380
SAVOR-TIMI 532
Saxagliptin
N=16,492
2013 2014 2015 2016 2017 2018 2019 2020 2021
AMPLITUDE-O21
Efpeglenatide
N=4076
SOUL22
Semaglutide (oral)
N=9642
2024
Since the 2008 FDA mandate, more than 190,000 patients have been
enrolled in outcomes trials
6. 3P MACE SGLT2i 與 GLP1 部分藥物表現優於安慰劑
0.25 0.5 1 2
Drug class Trial (study drug) HR (95% CI) p-value
SGLT2 inhibitor EMPA-REG OUTCOME1 (empagliflozin) 0.86 (0.74, 0.99) 0.04
CANVAS Program2 (canagliflozin) 0.86 (0.75, 0.97) 0.02
DECLARE-TIMI 583 (dapagliflozin) 0.93 (0.84, 1.03) 0.17
GLP-1 RA ELIXA4 (lixisenatide) 1.02 (0.89, 1.17) 0.81
LEADER5 (liraglutide) 0.87 (0.78, 0.97) 0.01
SUSTAIN-66 (inj. semaglutide) 0.74 (0.58, 0.95) 0.02
PIONEER 6†7 (oral semaglutide) 0.79 (0.57, 1.11) 0.17
EXSCEL8 (exenatide) 0.91 (0.83, 1.00) 0.06
Harmony Outcomes9 (albiglutide) 0.78 (0.68, 0.90) 0.0006
REWIND†10 (dulaglutide) 0.88 (0.79, 0.99) 0.026
DPP-4 inhibitor SAVOR-TIMI 5311 (saxagliptin) 1.00 (0.89, 1.12) 0.99
EXAMINE12 (alogliptin) 0.96 (≤1.16)‡ 0.315
TECOS13 (sitagliptin) 0.99 (0.89, 1.10) 0.84
CARMELINA14 (linagliptin) 1.02 (0.89, 1.17) <0.001§
Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
ELIXA and TECOS data are for 4P-MACE, all other data are for 3P-MACE
*FDA-mandated upper 95% CI of the HR for CV safety is a margin of 1.3 for post-approval trials and 1.8 for pre-approval trials. SUSTAIN-6 and PIONEER 6 were pre-approval trials;
†3P-MACE included death from unknown causes; ‡Upper bound of the one-sided 95% CI, α=0.01; §p-value for non-inferiority, all others are for superiority
See slide notes for full list of references
1.3
FDA-mandated upper
95% CI for CV safety*
1.8
Favours study drug Favours placebo
7. HHF SGLT2i 呈現一致的趨勢
Drug class Trial (study drug) HR (95% CI) p-value
SGLT2 inhibitor EMPA-REG OUTCOME1 (empagliflozin) 0.65 (0.50, 0.85) 0.002*
CANVAS Program2 (canagliflozin) 0.67 (0.52, 0.87) NR†
DECLARE-TIMI 583 (dapagliflozin) 0.73 (0.61, 0.88) NR†
GLP-1 RA ELIXA4 (lixisenatide) 0.96 (0.75, 1.23) 0.75
LEADER5 (liraglutide) 0.87 (0.73, 1.05) 0.14
SUSTAIN-66 (inj. semaglutide) 1.11 (0.77, 1.61) 0.57
PIONEER 67 (oral semaglutide) 0.86 (0.48, 1.55) NR†
EXSCEL8 (exenatide) 0.94 (0.78, 1.13) NR†
Harmony Outcomes‡9 (albiglutide) 0.85 (0.70, 1.04) 0.113
REWIND§10 (dulaglutide) 0.93 (0.77, 1.12) 0.46
DPP-4 inhibitor SAVOR-TIMI 5311 (saxagliptin) 1.27 (1.07, 1.51) 0.007*
EXAMINE12 (alogliptin) 1.19 (0.90, 1.58) 0.22¶
TECOS**13 (sitagliptin) 1.00 (0.83, 1.20) 0.98
CARMELINA14 (linagliptin) 0.90 (0.74, 1.08) 0.26
Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
Dapagliflozin is FDA-approved to reduce the risk of HHF in adults with T2D and established CV disease or multiple CV risk factors
*Nominal p-value; †p-value not reported in publication; ‡CV death or HHF was a composite secondary endpoint; HHF data alone were not reported in the primary publication; §HF outcome
was hospital admission for HF or urgent visit; ¶Post hoc analysis value; **Adjusted for history of HF at baseline
See slide notes for abbreviations and full list of references
0.25 0.5 1 2
Favours study drug Favours placebo
8. Composite kidney outcomes SGLT2i 與 GLP1 表現不錯
Patients Events Weights (%) HR (95% CI) HR (95% CI)
SGLT2 inhibitor*†1
EMPA-REG OUTCOME (empagliflozin) 6185 913 24.9 0.61 (0.53, 0.70)
CANVAS Program (canagliflozin) 10,142 847 25.0 0.57 (0.50, 0.66)
DECLARE-TIMI 58 (dapagliflozin) 17,160 1675 50.1 0.66 (0.60, 0.73)
GLP-1 RA1*‡
ELIXA (lixisenatide) 5286 375 20.0 0.84 (0.68, 1.02)
LEADER (liraglutide) 9340 605 32.2 0.78 (0.67, 0.92)
SUSTAIN-6 (inj. semaglutide) 3297 162 7.7 0.64 (0.46, 0.88)
EXSCEL (exenatide) 14,752 773 40.1 0.88 (0.76, 1.01)
REWIND (dulaglutide)2 9901 1338 – 0.76 (0.68, 0.84)
DPP-4 inhibitor
CARMELINA (linagliptin)3 6979 633 – 1.04 (0.89, 1.22)
Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
p-value for subgroup differences between SGLT2 inhibitors and GLP-1 RAs was 0.01
*New-onset macroalbuminuria, sustained doubling of serum creatinine or a 40% decline in eGFR, end-stage kidney disease or death due to kidney
causes; †Q statistic=2.99; p=0.22, I2=33.2%; ‡Q statistic =3.60; p=0.31, I2=16.6% (excluding REWIND)
1. Zelniker TA et al. Circulation 2019;139:2022; 2. Gerstein HC et al. Lancet 2019;394:131; 3. Rosenstock J et al. JAMA 2019;321:69
Favours study drug Favours placebo
0.25 0.5 1 2
14. | 14
PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
Glucose-
lowering
Medication in
Type 2
Diabetes:
Overall
Approach
Pharmacologic
Approaches to
Glycemic
Management:
Standards of Medical
Care in Diabetes -
2020. Diabetes Care
2020;43(Suppl. 1):S98-
S110
39. CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. CKD is classified
based on Cause, GFR category (G1–G5), and Albuminuria category (A1–A3), abbreviated as CGA.
40. Figure 2 | Kidney–heart risk factor management.
SGLT2i and RAS blockade are recommended for most patients
41. Figure 4 | Monitoring of serum creatinine and potassium during ACEi or ARB treatment—dose adjustment and monitoring of side effects.
ACEI/ARB
42. Figure 18 | Treatment algorithm for selecting antihyperglycemic drugs for patients with T2D and CKD
Metformin
43. Figure 24 | Algorithm for initiation of SGLT2 inhibitor therapy for patients with T2D, CKD, and eGFR 30 ml/min per 1.73 m2, who are
already being treated with antihyperglycemic medications.
SGLT2i