Memorandum
The tables below contain the status, key baseline characteristics, and most notable endpoint results of major diabetes and obesity CVOTs, organized by therapy class. These tables contain both reported and ongoing trials and will be updated as data become available. For more information, trial names link to Close Concerns’ reports on each readout, and we have also included the primary outcomes papers when available. If you’d like additional detail on any of these studies, just ask! We have tried to be as thorough as possible, but if you see anything inaccurate below, please let us know that as well.
- Latest updates as of April 12, 2023: The expansive growth in outcomes trials over the past decade has moved the field (and our landscape!) well beyond the cardiovascular realm. It is always fascinating to recall that CVOTs began to ensure that glycemic lowering agents were causing no harm, and in doing so, revealed the massive benefits that these therapies could have on other outcomes. As a result, in 2022, we expanded our competitive landscape to include kidney, heart failure, and obesity outcomes trials. We have now updated this landscape with four major readouts added to our landscape:
- DELIVER, investigating SGLT-2 dapagliflozin (Farxiga) in heart failure with preserved ejection fraction (HFpEF);
- EMPA-KIDNEY, investigating SGLT-2 empagliflozin (Jardiance) in CKD;
- SURMOUNT-1, investigating GIP/GLP-1 dual agonist tirzepatide in obesity or overweight; and
- STEP-TEENS, investigating semaglutide 2.4 mg (Wegovy) in adolescents with obesity
- On April 10, tirzepatide's SURMOUNT-2 completed, and full results will be presented at ADA 2023. Over the next week, we are looking forward to the completion for semaglutide’s STEP-HFpEF (April 19, 2023). Additionally, SURMOUNT-3 will complete May 2023, and SURMOUNT-4 will complete May 2023.
Major Cardiovascular Outcomes Trials
SGLT-2 Inhibitors
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
EMPA-REG OUTCOME for empagliflozin (Lilly/BI’s Jardiance) (outcomes paper) Completed – reported EASD 2015 |
7,020 >99% |
Age: 63 BMI: 31 A1C: 8.1% Diabetes Duration: >8 years (57% >10 years, 25% 5-10 years, 18% <5 years) |
3.1 years No other SGLT-2 inhibitors |
14% RRR (HR=0.86, 95% CI: 0.74-0.99, p=0.038 for superiority, p<0.001 for non-inferiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: 38% RRR (HR=0.62, 95% CI: 0.49-0.77) All-Cause: 32% RRR (HR=0.68, 95% CI: 0.57-0.82) |
Indication for reducing CV death approved by FDA December 2016 Heart Failure: 35% RRR (HR=0.65, 95% CI: 0.50-0.85) |
|
CANVAS for canagliflozin (J&J’s Invokana) (outcomes paper) Completed – reported ADA 2017 |
10,142 66% |
Age: 63 BMI: 32 A1c: 8.2% Diabetes Duration: 14 years |
2.4 years (5.7 years in CANVAS vs. 2.1 in CANVAS-R) No other SGLT-2 inhibitors |
14% RRR (HR=0.86, 95% CI: 0.75-0.97, p=0.0158 for superiority, p<0.0001 for non-inferiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke)
|
CV: NS (HR=0.87, 95% CI: 0.72-1.06) All-Cause: NS (HR=0.87, 95% CI: 0.74-1.01) |
~doubled risk for lower-limb amputations with canagliflozin (HR=1.97, 95% CI: 1.41-2.75, p<0.001); CV indication requested October 2017
Heart Failure: 33% RRR (HR=0.67, 95% CI: 0.52-0.87)
|
|
DECLARE-TIMI 58 for dapagliflizon (AZ’s Farxiga) Completed – reported AHA 2018 (outcomes paper) |
17,276 41% |
Age: 64 BMI: 32 A1c: 8.3% Diabetes Duration: 12 years |
4.2 years No other SGLT-2 inhibitors, pioglitazone, or rosiglitazone |
17% RRR (HR=0.83, 95% CI: 0.73-0.95, p=0.005 for superiority) co-primary endpoint of hospitalization for heart failure and CV death
NS (HR=0.93, 95% CI: 0.84-1.03, p<0.001 for non-inferiority, p=0.17 for superiority) co-primary endpoint of 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.98, 95% CI: 0.82-1.17)
All-Cause: NS (HR=0.93, 95% CI: 0.82-1.04) |
Hospitalization for Heart Failure: 17% RRR (HR=0.83, 95% CI: 0.73-0.95, p=0.005 for superiority) |
|
VERTIS CV for ertugliflozin (Merck/Pfizer’s Steglatro) Completed – reported ADA 2020 (outcomes paper) |
8,246 99.9% |
Age: 64 BMI: 31- 32 A1c: 8.2% Diabetes Duration: 13 years |
3.5 years Yes – 76% on metformin, 47% on insulin, 41% on SUs, 11% on DPP-4s, 3% on GLP-1s |
NS (HR=0.97; 95% CI: 0.85-1.11) 3-point MACE (CV death, nonfatal MI, nonfatal stroke) |
CV death: NS (HR=0.92; 95% CI: 0.77-1.11; p=0.39) |
Significant effect on HHF nonetheless – 30% RRR (HR=0.70; 95% CI: 0.54-0.90; p=0.006) |
|
SCORED for sotagliflozin (Sanofi/Lexicon’s Zynquista) Completed March 2021 (outcomes paper)
Trial closed early due to COVID and funding issues |
10,584 88% |
Patients with T2D and CKD Age: 69 years BMI: 31.8 A1c: 8.3% |
16 months Yes – 88% on RAAS inhibitor, 55% on metformin, 27% on SUs, 20% on DPP-4s, 63% on insulin, 6% on GLP-1 |
26% RRR (HR=0.74; 95% CI: 0.63-0.88), p=0.0004, NNT=54) (total CV death, HHF, and urgent HF visit) |
CV death: NS (HR=0.90; 95% CI: 0.73-1.12)
All-cause mortality: NS (HR=0.99; 95% CI: 0.83-1.18) |
HHF included in primary endpoint; only enrolling those w/ eGFR 25-60 mL/min/1.73 m2 |
GLP-1 Agonists
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
LEADER for liraglutide (Novo Nordisk’s Victoza) (outcomes paper) Completed – reported ADA 2016 |
9,340 81% |
Age: 64 BMI: 33 A1c: 8.7% Diabetes Duration: 13 years |
3.8 years No other GLP-1 agonists or DPP-4 inhibitors |
13% RRR (HR=0.87, 95% CI: 0.78-0.97, p=0.01 for superiority, p<0.001 for non-inferiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: 22% RRR (HR=0.78, 95% CI: 0.66-0.93) All-Cause: 15% RRR (HR=0.85, 95% CI: 0.74-0.97)
|
Indication for reducing MACE approved by FDA August 2017 Heart Failure: NS (HR=0.87, 95% CI; 0.73-1.05) |
|
REWIND for dulaglutide (Lilly’s Trulicity) (outcomes paper) Completed – reported ADA 2019 |
9,901 31% |
Age: 66 BMI: 32 A1c: 7.3% Diabetes Duration: 10 years |
5.4 years No other GLP-1 agonists or DPP-4 inhibitors |
12% RRR (HR=0.88, 95% CI: 0.79-0.99, p=0.026 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.91, 95% CI: 0.78-1.06) All-Cause: NS (HR=0.90, 95% CI: 0.80-1.01) |
No difference between primary and secondary prevention cohorts (HR=0.87, 95% CI: 0.74-1.02 for both) |
|
EXSCEL for exenatide once-weekly (AZ’s Bydureon) (outcomes paper) Completed – reported EASD 2017 |
14,752 73% |
Age: 63 BMI: 32 A1c: 8.0% Diabetes Duration: 12 years |
3.2 years No other GLP-1 agonists |
NS (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.88, 95% CI: 0.76-1.02) All-Cause: exploratory (HR=0.86, 95% CI: 0.77-0.97) |
Heart Failure: NS (HR=0.94, 95% CI: 0.78-1.13) |
|
SUSTAIN-6 for semaglutide (Novo Nordiks’s Ozempic) (outcomes paper) Completed – reported EASD 2016 |
3,297 83% |
Age: 65 BMI: 33 A1c: 8.7% Diabetes Duration: 14 years |
2.1 years No other GLP-1 agonists or DPP-4 inhibitors |
26% RRR (HR=0.74, 95% CI: 0.58-0.95, p=0.02 for superiority, p<0.001 for non-inferiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.98, 95% CI: 0.65-1.48) All-Cause: NS (HR=1.05, 95% CI: 0.74-1.50)
|
76% increased risk for retinopathy w/ semaglutide (HR=1.76, 95% CI: 1.11-2.78); Premarket CVOT not designed for superiority; does not support CV indication Heart Failure: NS (HR=1.11, 95% CI: 0.77-1.61) |
|
ELIXA for lixisenatide (Sanofi’s Adlyxin) (outcomes paper) Completed – reported ADA 2015 |
6,068 100% |
Age: 60 BMI: 30 A1c: 7.7% Diabetes Duration: 9 years |
2.1 years No other GLP-1 agonists or DPP-4 inhibitors |
NS (HR=1.02, 95% CI: 0.89-1.17, p=0.81) 4-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina)
|
CV: NS (HR=0.98, 95% CI: 0.78-1.22) All-Cause: NS (HR=0.94, 95% CI: 0.78-1.13) |
Heart Failure: NS (HR=0.96, 95% CI: 0.75-1.23)
|
|
HARMONY for albiglutide (GSK’s Tanzeum) Completed – reported EASD 2018 |
9,463 100%
|
Age: 64 BMI: 32 A1c: 8.7% Diabetes Duration: 14 years |
1.6 years No other GLP-1 agonists |
22% RRR (HR=0.78, 95% CI: 0.68-0.90, p=0.0006 for superiority, p<0.0001 for non-inferiority) |
CV: NS (HR=0.93, 95% CI: 0.73-1.19) All-Cause: NS (HR=0.95, 95% CI: 0.79-1.16) |
GSK has withdrawn commercial support for Tanzeum; current commercial status unclear |
|
PIONEER 6 for oral semaglutide (Novo Nordisk) (outcomes paper) Topline results announced |
3,183 85% |
Age: 66 BMI: 32 A1c: 8.2% Diabetes duration: 15 years |
1.3 years No other GLP-1 agonists or DPP-4 inhibitors |
NS (HR=0.79, 95% CI: 0.57-1.11, p<0.001 for non-inferiority, p=0.17 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: 51% RRR (HR=0.49, 95% CI: 0.27-0.92, p=0.03) All-Cause: 49% RRR (HR=0.51, 95% CI: 0.31-0.84, p=0.008) |
|
|
AMPLITUDE-O for efpeglenatide (ex-Sanofi) (outcomes paper) completed. Read out at ADA 2021 |
4,076 90% |
Age: 64.5 BMI: 33 A1c: 8.9% Diabetes duration: 15.4 years |
1.8 years Pre-randomization therapy continued, no DPP-4s or GLP-1s |
27% RRR (HR= 0.73; 95% CI: 0.58-0.92; p<0.0001 for non-inferiority; p=0.0069 for superiority) (first non-fatal MI, stroke, or death from CVD or undetermined cause) |
Not reported |
32% RRR in kidney composite outcome (HR=0.68; 95% CI: 0.57-0.79; p<0.0001) (decrease in eGFR of ≥40% for ≥30 days, ESKD or death from any cause) |
|
FREEDOM-CVOT for ITCA 650, implantable exenatide device (Intarcia) (outcomes paper) – Read out at ATTD Forum 2021
|
4,156 76% |
Age: 63 BMI: 32 A1c: 8.0% Diabetes duration: 10.3 years |
1.3 years No DPP-4, GLP-1, SGLT-2, or rapid-acting insulin |
NS (HR=0.1.21, 95% CI: 0.9-1.63, p=0.004 for non-inferiority) 4-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina) |
CV: NS (HR=0.1.22, 95% CI: 0.70-2.12) All-Cause: NS (HR=1.20, 95% CI: 0.79-1.81) |
Nearly statistically significant reduction in MACE (HR=0.91, 95% CI: 0.83–1.00, p=0.06) Intarcia will have advisory committee meeting for ITCA 650 in summer of 2023 |
|
SOUL for Novo Nordisk's oral semaglutide Ongoing – expected completion July 2024 |
~9,642
|
- |
- |
- |
- |
- |
|
SELECT – for semaglutide Ongoing –expected completion September 2023 **does NOT include PWD, only people with obesity or overweight** |
~17,500
|
- |
- |
- |
- |
- |
DPP-4 Inhibitors
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
EXAMINE for alogliptin (Takeda’s Nesina) (outcomes paper) Completed – reported ESC 2013 |
5,380 100% |
Age: 61 BMI: 29 A1c: 8.0% Diabetes Duration: 7 years |
1.5 years No other DPP-4 inhibitors or GLP-1 agonists |
NS (HR=0.96, 95% CI: 0.84-1.16) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.85, 95% CI: 0.66-1.10) All-Cause: NS (HR=0.88, 95% CI: 0.71-1.09)
|
Heart Failure: NS (HR=1.07, 95% CI: 0.79-1.46)
|
|
SAVOR-TIMI for saxagliptin (AZ’s Onglyza) (outcomes paper) Completed – reported ESC 2013 |
16,492 79% |
Age: 65 BMI: 31 A1c: 8.0% Diabetes Duration: 10 years |
2.1 years No other DPP-4 inhibitors or GLP-1 agonists |
NS (HR=1.00, 95% CI: 0.89-1.12, p<0.001 for non-inferiority, p=0.99 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=1.03, 95% CI: 0.87-1.22) All-Cause: NS (HR=1.11, 95% CI: 0.97-1.27)
|
Significant signal for increased risk of heart failure with saxagliptin Heart Failure: 27% risk increase (HR=1.27, 95% CI: 1.07-1.51) |
|
TECOS for sitagliptin (Merck’s Januvia) (outcomes paper) Completed – reported ADA 2015 |
14,671 100% |
Age: 66 BMI: 30 A1c:7.2% Diabetes Duration: 12 years |
3.0 years No other DPP-4 inhibitors or GLP-1 agonists, rosiglitazone prohibited at enrollment & discouraged during trial |
NS (HR=0.98, 95% CI: 0.89-1.08, p<0.001 for non-inferiority) 4-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization or unstable angina) |
CV: NS (HR=1.03, 95% CI: 0.89-1.19) All-Cause: NS (HR=1.01, 95% CI: 0.90-1.14)
|
Heart Failure: NS (HR=1.00, 95% CI: 0.83-1.20)
|
|
CARMELINA for linagliptin (Lilly’s Tradjenta) (outcomes paper) Completed – reported EASD 2018 |
7,003 57% (100% CVD or CKD) |
Age: 66 BMI: 31 A1c: 7.9% Diabetes Duration: - |
- No DPP-4 inhibitors, GLP-1 agonists, or SGLT-2 inhibitors |
NS (HR=1.02, 95% CI: 0.89-1.17, p=0.0002 for non-inferiority, p=0.7398 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.96, 95% CI: 0.81-1.14) All-Cause: NS (HR=0.98, 95% CI: 0.84-1.13) |
Albuminuria progression: HR=0.86, 95% CI: 0.78-0.95, p=0.0034 Heart failure: NS (HR=0.90, 95% CI: 0.74-1.08) |
|
CAROLINA for linagliptin vs. glimepiride (outcomes paper) |
6,072 35% |
Age: 64 BMI: 30 A1c: 7.2% Diabetes Duration: 6 years |
- No history or baseline use of DPP-4 inhibitors, GLP-1 agonists, insulin (>2 weeks), TZDs |
NS (HR=0.98, 95% CI: 0.84-1.14) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=1.00, 95% CI: 0.81-1.24) All-Cause: NS (HR=0.91, 95% CI: 0.78-1.06) |
Significantly lower risk on all hypoglycemia endpoints with linagliptin |
Insulin
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
DEVOTE for insulin degludec (Novo Nordisk’s Tresiba) (outcomes paper) Completed – reported ADA 2017 |
7,637 85% |
Age: 65 BMI: 34 A1c: 8.4% Diabetes Duration: 16 years |
2 years Any |
NS (HR=0.91, 95% CI: 0.78-1.06, p<0.001 for non-inferiority, p=0.21 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=0.96, 95% CI: 0.76-1.21) All-Cause: NS (HR=0.91, 95% CI: 0.76-1.11)
|
Severe hypoglycemia reduced by 40% with insulin degludec (HR=0.60, 95% CI: 0.48-0.76); nocturnal severe hypoglycemia reduced by 53% (HR=0.47, 95% CI: 0.31-0.73) |
|
ORIGIN for insulin glargine (Sanofi’s Lantus) – presented ADA 2012 (outcomes paper) |
12,537 59% |
Age: 64 BMI: 30 A1c: 6.4% Diabetes Duration: 5 years |
6.2 years Any therapy besides Lantus |
NS (HR=1.02, 95% CI: 0.94-1.11, p=0.63 for superiority) 3-point MACE (CV death, non-fatal MI, non-fatal stroke) |
CV: NS (HR=1.00, 95% CI: 0.89-1.13) All-Cause: NS (HR=0.98, 95% CI: 0.90-1.08) |
- |
PSCK9 Inhibitors
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
FOURIER for evolocumab (Amgen’s Repatha) – presented ACC 2017 (outcomes paper) |
27,564 100% |
Age: 63 Weight: 85 kg (187 lbs) |
2.2 years High or moderate intensity statin therapy required |
15% RRR (HR=0.85, 95% CI: 0.79-0.92) 5-point MACE (CV death, non-fatal MI, non-fatal stroke, coronary revascularization, hospitalization for unstable angina) |
CV: NS (HR=1.05, 95% CI: 0.88-1.25) All-Cause: NS (HR=1.04, 95% CI: 0.91-1.19) |
- |
|
ODYSSEY Outcomes for alirocumab (Sanofi/Regeneron’s Praluent) – presented at ACC 2018 (outcomes paper) |
18,924 100% |
Age: 58 Weight: - |
2.8 years High-intensity atorvastatin/rosuvastatin therapy required |
15% RR (HR=0.85, 95%CI: 0.78-0.93) 5-point MACE (CV death, non-fatal MI, non-fatal stroke, coronary revascularization, hospitalization for unstable angina) |
CV: NS (HR=0.88, 95% CI: 0.74-1.05) All-Cause: 15% RRR (observational) (HR=0.85, 95% CI: 0.73-0.98)
|
-
|
Multi-Agonists
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
SURPASS-CVOT for tirzepatide Ongoing –estimated completion October 2024 |
~12,500 |
- |
- |
- |
- |
- |
Other
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Baseline Characteristics |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
FIGARO-DKD for finerenone (Bayer’s Kerendia) (outcomes paper) Read out at ESC 2021 |
7,437 45% |
Age: 64 years A1c: 7.7% eGFR:68 mL/min/1.73m2 Diabetes Duration:14.5 years |
3.4 years On guideline directed medical therapy (8% on SGLT-2, 7% on GLP-1) |
13% RRR (HR=0.87, 95% CI: 0.76-0.98; P=0.03) (CV death, non-fatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) |
CV death: NS (HR=0.90; 0.74-1.09) All-Cause Mortality: NS (HR=0.89; 95% CI: 0.77-1.04) |
Notably, non-significant finding on first secondary composite renal outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) (in contrast to FIDELIO-DKD) |
Heart Failure Outcomes Trials
SGLT-2 Inhibitors
|
Trial and Status |
Enrollment |
Baseline Characteristics |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
DAPA-HF for dapagliflozin (AZ’s Farxiga) (outcomes paper) Read out at ESC 2019 |
4,744 |
Age: 66 years BMI: 28 eGFR: 65 mL/min/1.73m2 45% had diabetes |
18.2 months Yes |
26% RRR (HR=0.74; 95% CI: 0.65-0.85; p=0.00001; NNT=21) 3-point MACE (CV death/HF hospitalization/urgent HF visit) |
CV death: 18% RRR (HR=0.82; 95% CI: 0.69-0.98; p=0.029) All-cause mortality: 17% RRR (HR=0.83; 95% CI: 0.71=0.97) |
Treatment effect was consistent across both patient populations of people with diabetes and people without diabetes |
|
EMPEROR-Reduced for empagliflozin (Lilly/BI’s Jardiance) (outcomes paper) Read out at ESC 2019 |
3,730 |
Age: 67 years BMI: 28 eGFR: 62 mL/min/1.73m2 50% had diabetes
|
16 months Yes |
25% RRR (HR=0.75; 95% CI: 0.65-0.86; p<0.0001) (death from cardiovascular causes/hospitalization for heart failure)
|
CV death: NS (HR=0.92; 95% CI: 0.75-1.12) All-cause mortality: NS (HR=0.92; 95% CI: 0.77-1.10) |
30% RRR on the key secondary endpoint of total HHFs (HR: 0.70; 95% CI: 0.58-0.85; p=0.0003) No difference between patients with and without diabetes |
|
SOLOIST-WHF for sotagliflozin (Sanofi/ Lexicon’s Zynquista) Read out at ADA 2021 (outcomes paper) Trial closed early due to COVID and funding issues |
1,222
|
Age: 70 BMI: 30-31 A1c: 7.1%
|
9 months Yes – 91% on any RAAS inhibitor, 52% on metformin, 18% on SUs, 16% on DPP-4s, 35% on insulin |
33% RRR (HR=0.67; 95% CI: 0.52-0.85; p=0. 0009, NNT=4) (total CV death, hospitalization for HF, and urgent HF visit) |
Not reported |
People treated with sotagliflozin were alive and out of hospital for 2.9 additional years per 100 patient years compared to placebo (p=0.027). |
|
EMPEROR-Preserved for empagliflozin (Lilly/BI’s Jardiance) (outcomes paper) Read out at ESC 2021 |
5,988 |
Age: 72 years BMI: 30 eGFR: 60.6 mL/min/1.73m2 49% had diabetes |
26.2 months Yes |
21% RRR (HR=0.79; 0.69-0.90; p<0.001)
(CV death/HHF) |
CV death: NS (HR=0.91; 95% CI: 0.76-1.09) All-cause mortality: NS (HR=1.00; 95% CI: 0.87-1.15) |
27% RRR on total heart failure hospitalizations (HR=0.73; 95% CI: 0.61-0.88; p<0.001) |
|
DELIVER for dapagliflozin (AZ’s Farxiga) (outcomes paper) Read out at ESC 2022
|
6,263 |
Age: 72 years eGFR: 61 mL/min/1.73m245% had diabetes |
27.6 months Yes |
18% RRR (HR=0.82; 0.73-0.92; p=0.0008)(CV death/worsening HF) |
CV death: NS (HR=0.88; 95% CI: 0.74-1.05) All-cause mortality: NS (HR=0.94; 95% CI: 0.83-1.07) |
21% RRR on worsening HF (HR=0.79; 95% CI: 0.69-0.91; p=0.001) |
GLP-1 Receptor Agonists
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
STEP HFpEF for semaglutide Ongoing – expected completion April 2023 |
516 |
-- |
-- |
-- |
-- |
-- |
Multi Agonists
|
Trial and Status |
Enrollment, Percent w/ Baseline CV Disease |
Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline |
Study Design: Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
SUMMIT for tirzepatide Ongoing – expected completion June 2024 |
~700 |
-- |
-- |
-- |
-- |
-- |
Kidney Outcomes Trials
SGLT-2 Inhibitors
|
Trial and Status |
Enrollment |
Baseline Characteristics |
Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
CREDENCE for canagliflozin (J&J’s Invokana) (stopped early for overwhelming efficacy) Read out at WCN 2019 (outcomes paper) |
4,401 |
Age: 63 BMI: 31 kg/m2 A1c: 8.3% eGFR: 56 mL/min/1.73m2 Diabetes duration: 15.8 years |
2.6 years Conducted on top of current CKD standard-of-care |
30% RRR (HR=0.70; 95% CI: 0.59=082; p=0.00001) (end-stage kidney disease, doubling of the serum creatinine level, or renal or CV death) |
CV death: NS (HR=0.78; 95% CI: 0.61-1.00; p=0.05)
All-cause mortality: NS (HR=0.74; 95% CI: 0.63-0.86) |
31% RRR in CV death or HHF (HR=0.69; 95% CI: 0.67 to 0.95; p=0.01) 34% RRR in end-stage kidney disease, doubling of serum creatinine, or renal death (HR=0.66; 95% CI: 0.53-0.81; p<0.001) |
|
DAPA-CKD for dapagliflozin (AZ’s Farxiga) (stopped early for overwhelming efficacy) Read out at ESC 2020 (outcomes paper) |
4,304 |
Age: 62 BMI: 29.5 kg/m2 eGFR: 43 mL/min/1.73m2 67% with diabetes |
2.4 years Conducted on top of current CKD standard-of-care |
39% RRR (HR=0.61; 95% CI: 0.51-0.72; p<0.001) (sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes) |
CV death: NS (HR=0.81, 95% CI: 0.58-1.12) All-cause mortality: 31% RRR (HR=0.69; 95% CI: 0.53-0.88; p=0.004) |
Primary endpoint was consistent for patients with and without diabetes interaction p-value: 0.24 |
|
EMPA-KIDNEY for empagliflozin (stopped early for overwhelming efficacy) Presented at ASN 2022 (outcomes paper) |
6,609 |
Age: 64 BMI: 30 kg/m2 eGFR: 37 mL/min/1.73m2 46% with diabetes |
2.0 years Conducted on top of current CKD standard-of-care |
28% RRR (HR: 0.72; 95% CI: 0.64-0.82; p<0.0001) (CV death or kidney progression, defined as ESKD, sustained ≥40% eGFR decline, sustained decrease in eGFR to <10 mL/min/1.73 m2, or death from renal causes) |
CV death: NS (HR: 0.84; 95% CI: 0.60-1.19) All-cause mortality: NS (HR: 0.87; 95% CI: 0.70-1.08; p=0.21) |
14% RRR on all-cause hospitalization (HR: 0.86, 95% CI: 0.78-0.95; p=0.003) – first SGLT-2 kidney outcome trial to demonstrate significance on this outcome
|
GLP-1 Receptor Agonists
|
Trial and Status |
Enrollment |
Baseline Characteristics |
Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
FLOW for semaglutide Expected completion August 2024 |
~3,508 |
-- |
-- |
-- |
-- |
-- |
Other
|
Trial and Status |
Enrollment |
Baseline Characteristics |
Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Mortality Results: CV Death, All-Cause Mortality |
Other Notable Findings |
|
FIDELIO-DKD for finerenone (Bayer’s Kerendia) Presented at ASN 2020 (outcomes paper) |
~5,734 |
Age: 66 eGFR: 44 mL/min/1.73m2 Diabetes duration: 16.6 years |
2.6 years Yes – on guideline directed medical therapy (34% on ACE, 57% on diuretic, 74% on statin) |
18% RRR (HR=0.82; 95% CI=0.73-0.93; p=0.0014; NNT=29) (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) |
CV death – not reported All-cause mortality: NS (HR=0.90; 95% CI: 0.75-1.07; p=0.2348) |
14% RRR for secondary CV endpoint (CV death, non-fatal MI, non-fatal stroke, or heart failure hospitalization) (HR=0.86, p=0.0339) |
|
CONFIDENCE for finerenone + empagliflozin (estimated completion June 2024) |
~807 |
-- |
-- |
-- |
-- |
-- |
Obesity Outcomes Trials
|
Trial and Status |
Comparator/Design |
Enrollment |
Mean Age (years), BMI (kg/m2), A1c |
Median Follow Up, Concomitant Medications Allowed? |
Primary Endpoint Result (components) |
Other Notable Findings |
|
STEP 1 for semaglutide -outcomes paper |
Semaglutide 2.4 mg vs. placebo in people with obesity or overweight with complications, without diabetes |
1,961 |
Age: 46 BMI: 38 kg/m2 A1c: 5.7% |
68 weeks; No other anti-obesity medication within 90 days before enrollment |
-14.9% body weight from baseline, -12.4% different than placebo (percentage change in body weight at week 68) 84.6% achieved a 5% of more reduction body weight |
Change in body weight from baseline was -15.3 kg at week 68-13.54 cm waist circumference with semaglutide compared to -4.13 with placebo |
|
STEP 2 for semaglutide – outcomes paper |
People with type 2 diabetes and obesity or overweight with complications; vs. placebo |
1,210 |
Age:55 BMI: 36 kg/m2 A1c: 8.1% |
68 weeks; No other anti-obesity medication within 90 days before enrollment, no new investigational diabetes medications 90 days before screening |
-9.6% change from baseline with semaglutide to 68 weeks in body weight vs -3.4% with placebo 69% of patients achieved weight reductions of at least 5% compared to 29% on placebo |
N/A |
|
STEP 3 for semaglutide – outcomes paper |
People with obesity or overweight with complications without diabetes, as an adjunct to intensive behavioral therapy; vs. placebo |
611 |
Age: 46 BMI: 38 kg/m2 A1c: 5.7%
|
68 weeks; No other anti-obesity medication within 90 days before enrollment |
-16% change in body weight from baseline with semaglutide vs -5.7% with placebo 87% of participants achieved weight reductions of at least 5% compared to 48% of placebo |
-8.3 cm waist circumference difference semaglutide vs placebo |
|
STEP 4 for semaglutide – presented at ENDO 2021 (outcomes paper) |
People with obesity or overweight with complications; continued semaglutide treatment vs. withdrawal |
803 |
Age: 46 BMI: 38 kg/m2 A1c: 5.7% |
68 weeks; No other anti-obesity medication within 90 days before enrollment |
7.9% reduction in body weight from randomization (week 20) to week 68 with semaglutide compared to +6.9% with placebo |
-9.7 cm waist circumference difference semaglutide vs placebo |
|
STEP 5 for semaglutide – presented at ObesityWeek® 2021 (outcomes paper) |
People with overweight and obesity over 104 weeks; vs. placebo |
304 |
Age: 47 BMI: 39 kg/m2 A1c: 5.7% |
68 weeks; No other anti-obesity medication within 90 days before enrollment |
15.2% reduction in body weight with semaglutide at week 104 compared to 2.6% reduction with placebo 77% of participants lost more that 5% of their body weight compared to 34% with placebo |
-9 cm waist circumference reduction with placebo |
|
STEP 8 for semaglutide – presented at ObesityWeek® 2021 (outcomes paper) |
People with overweight or obesity; vs. liraglutide |
338 |
Age: 49 BMI: 38 kg/m2 A1c: 5.5% |
68 weeks; No other anti-obesity medication within 90 days before enrollment |
15.8% weight loss from baseline of 231 lbs. vs. 6.4% on liraglutide vs. 1.9% on placebo 87% of participants on semaglutide achieved ≥5% body weight loss, compared to 58% on liraglutide and 30% on placebo |
0.2% reduction in A1c with semaglutide compared to 0.1% increase on placebo |
|
STEP-TEENS for semaglutide – presented at ObesityWeek® 2022 (outcomes paper) |
Adolescents (12-17 years old) with obesity; vs. placebo |
201 |
Age: 15 BMI: 37 kg/m2 A1c: 5.4% |
68 weeks; No other anti-obesity medication or glucose-lowering agents within 90 days before enrollment |
16.1% reduction in BMI vs. 0.6% with placebo 73% of participants on semaglutide achieved ≥5% weight loss vs. 18% on placebo |
0.4% A1c reduction with semaglutide vs. 0.1% reduction with placebo 37% of participants on semaglutide achieved ≥20% body weight loss vs. 3% on placebo |
|
SURMOUNT-1 for tirzepatide – presented at ADA 2022 (outcomes paper) |
Weight loss in obesity or overweight without diabetes; vs. placebo |
2,539 |
Age: 45 BMI: 38 kg/m2 A1c: 5.6% |
72 weeks; No other anti-obesity medication within 90 days before enrollment |
16%, 21%, and 23% weight loss with 5 mg, 10 mg, and 15 mg doses vs. 2% with placebo 89%, 96%, and 96% of participants with 5 mg, 10 mg, and 10 mg doses achieved ≥5% weight loss vs. 28% of those on placebo |
41% of participants had prediabetes at baseline, and ≥95% of those with prediabetes reverted to normoglycemia |
|
SURMOUNT-2 for tirzepatide (Completed April 10, 2023; Full results at ADA 2023) |
Weight loss in type 2 diabetes with obesity or overweight; vs. placebo |
900 |
-- |
-- |
-- |
-- |
|
SURMOUNT-3 for tirzepatide (estimated completion May 2023) |
Weight loss in obesity or overweight without diabetes; after lifestyle program; vs. placebo |
800 |
-- |
-- |
-- |
-- |
|
SURMOUNT-4 for tirzepatide (estimated completion May 2023) |
Weight maintenance in obesity or overweight without diabetes; continuing tirzepatide vs. withdrawal |
750 |
-- |
-- |
-- |
-- |
|
OASIS 1 for semaglutide 50 mg tablets (estimated completion May 2023) |
Semaglutide tablets in obesity or obesity; vs. placebo |
660 |
-- |
-- |
-- |
-- |
|
SURMOUNT-MMO for tirzepatide (estimated completion October 2027) |
Morbidity/mortality reduction in obesity and overweight without diabetes |
~15,000 |
--- |
-- |
-- |
-- |