. 2022 Oct 10;20:337. doi: 10.1186/s12916-022-02539-2

Table 4.

Recent clinical trials of GLP-1 RA agents with kidney outcomes

Study	Inclusion criteria	Participants	Kidney outcome	HR (95% CI) or other as specified
Studies with kidney outcomes as secondary outcome(s) only
LEADER [51] Aug 2010–Dec 2015 410 sites in 32 countries	Adults with T2D, age ≥50 yrs with established CVD, or age ≥60 yrs with CVD risk factors, HbA1c ≥7%, no GLP-1 RA or DPP-4i for 3 months prior to screening	N=4668 maximum 1.8mg liraglutide (as tolerated) once daily N=4672 placebo once daily BL: mean age 64 yrs, 64% male, 78% white, mean HbA1c 8.7%, mean duration T2D 13 yrs, mean eGFR (MDRD) 80, 26% had microalbuminuria, 11% had BL macroalbuminuria	A) Composite of new onset persistent macroalbuminuria, persistent doubling of serum creatine, kidney replacement therapy, death from kidney causes B) New onset persistent macroalbuminuria C) Persistent doubling of serum creatinine D) Kidney replacement therapy E) Death from kidney cause F) Decline in eGFR over 36 months G) Increase in UACR H) New onset microalbuminuria	A) 0.78 (0.67–0.92) B) 0.74 (0.60–0.91) C) 0.90 (0.67–1.20) D) 0.87 (0.61–1.25) E) 1.60 (0.52–4.90) F) Between group difference=1.02 (p=0.01) G) Between group difference=0.83 (p<0.001) H) 0.87 (0.83–0.93)
REWIND [52] July 2011–Aug 2018 371 sites in 24 countries	Adults with T2D, age ≥50 with previous CVD event or with CVD risk factors, HbA1c ≤9.5%	N=4949 1.5mg dulaglutide once weekly N=4952 placebo once weekly BL: mean age 66 yrs, 54% male, 76% white, mean duration T2D 11 yrs, mean HbA1c 7.4%, mean eGFR 77	A) Composite of development of macroalbuminuria (UACR>33.9 mg/mmol), sustained decline in eGFR ≥30%, or new chronic kidney replacement therapy B) Development of macroalbuminuria C) Sustained decline in eGFR ≥30% D) New chronic kidney replacement therapy	A) 0.85 (0.77–0.93) B) 0.77 (0.68–0.87) C) 0.89 (0.78–1.01) D) 0.75 (0.39–1.44)
Harmony Outcomes [53] July 2015–March 2018 610 sites in 28 countries	Adults with T2D and established CVD, age ≥40 yrs, HbA1c >7%, eGFR (MDRD) ≥30, not using GLP-1 RA at screening	N=4731 30–50 mg albiglutide as tolerated once weekly N=4732 placebo once weekly BL: mean age 64 yrs, 70% male, 70% white, mean duration T2D 14 yrs, mean HbA1c 8.7%, mean eGFR 79	Change in eGFR by treatment group	Mean eGFR difference=−1.11 (−1.84 to −0.39) at 8 months and -0.43 (−1.26 to 0.41) at 16 months. Figure 4 shows significant difference (no CI overlap) favoring albiglutide at 28 months but no numbers provided
SUSTAIN-6 [54] Feb 2013–March 2016 230 sites in 20 countries	Adults with T2D, age ≥50 yrs with established CVD, heart failure (NYHA class II or III), or chronic kidney failure OR age ≥60 yrs with one or more CVD risk factors, HbA1c ≥7%, no use of DPP-4i within 30 days prior to screening or GLP-1 RA within 90 days prior to randomization	N=1648 0.5mg or 1.0 mg semaglutide once weekly N=1649 placebo once weekly BL: mean age 65 yrs, 61% male, 83% white, 30% eGFR>90, mean HbA1c 8.7%, mean T2D duration 14 yrs	A) New or worsening nephropathy B) Persistent macroalbuminuria C) Persistent doubling of serum creatinine and creatinine clearance per MDRD <45 D) Need for continuous kidney replacement therapy	A) 0.64 (0.46–-0.88) B) 0.54 (0.37–0.77) C) 1.28 (0.64–2.58) D) 0.91 (0.40–2.07)
AMPLITUDE-O [55] April 2018–Dec 2020 344 sites in 28 countries	Adults with T2D, HbA1c >7%, age ≥18 yrs with history of CVD, OR males ≥50 yrs/females ≥55 yrs with eGFR (MDRD) 25.0 to 59.9 and ≥1 CV risk factor, no use of GLP-1 RA or DPP-4i within 3 months prior to screening	N=1359 initial dose 2mg efpeglenatide once weekly, titrated to 4mg or 6mg once daily to study end N=1358 6mg efpeglenatide once weekly N=1359 placebo once weekly BL: mean age 65 yrs, 67% male, 87% white, mean HbA1c 8.9%, mean eGFR 72, mean duration T2D 15 yrs, median UACR 28.3	A) Incident macroalbuminuria B) Between-group difference in UACR C) LS mean difference in eGFR D) Decrease in eGFR≥40% for ≥30 days, ESKD, or all-cause death E) Composite of MACE, death from non-CV cause, hospitalization for heart failure, or occurrence of (A)	A) 0.68 (0.57–0.79) B) 0.68 (0.58–0.80) C) Lower by 21% (14–28%) D) Higher by 0.9 (0.3–1.50) E) 0.77 (0.57–1.02) F) 0.71 (0.59–0.87)
ELIXA [56] June 2010–Feb 2015 829 sites in 49 countries [57]	Adults with T2D, HbA1c 5.5% to 11.0%, age≥30 yrs, with acute coronary syndrome (STEMI, non-STEMI, or unstable angina) <180 days before screening, HbA1c 5.5 to 11%, and eGFR (MDRD) ≥30, taking GLP-1 RA or DPP-4i during study	N=3034 10μg lixisenatide increased up to 20μg once daily N=3034 placebo once daily BL: mean age 60 yrs, 69% male, 75% white, mean duration T2D 9 yrs, mean HbA1c 7.7%, mean eGFR 76	Percent change in UACR from BL to study week 108 (BL UACR and study week 108 data available for n=2830 placebo, n=2803 lixisenatide)	+34% placebo, +24% lixisenatide, p<0.01, adjusted for BL UACR, treatment, region, BL use of ACEi and ARB; +32% placebo, +26 lixisenatide, p=0.07, adjusted for BL and 3-month HbA1c
EXSCEL [58] June 2010–April 2017 688 sites in 35 countries [59]	Adults with T2D, HbA1c 6.5% to 10.0%, age≥18 yrs, eGFR (MDRD) ≥30, range of CV risk factors, taking 0 to 3 oral glycemic control drugs or insulin with or without use of 1–2 oral glycemic drugs, never used GLP-1 RA	Propensity score matched N=572 placebo; N=572 exenatide once weekly +SGLT2i; N=575 exenatide once weekly; N=575 exenatide once weekly + SGLT2i BL: mean age 63 yrs, 62% male, 76% white, mean duration T2D 12 yrs, mean HbA1c 8%	Outcome comparisons between 1: placebo only with exenatide + SGLT2i, and 2: exenatide only with exenatide + SGLT2i: A) Change over time in eGFR (per MDRD) B) Composite of persistent 40% reduction in eGFR, kidney dialysis, or kidney transplant C) Composite of “B” plus new macroalbuminuria	A) (1) 1.94 (0.94–2.94); (2) 2.38 (1.40–3.35) B) (1) 0.32 (0.06–1.59); (2) 0.21 (0.05–0.97) C) (1) 0.43 (0.15–1.22); (2) 0.35 (0.13–0.98)
AWARD 7 [60] July 2012–Dec 2016 99 sites in 9 countries	Adults with T2D and stage 3 or 4 CKD, age≥18 yrs, HbA1c 7.5% to 10.5%, taking insulin alone or with oral glucose control drug, taking maximum tolerated dose of ACEi or ARB, not taking GLP-1 RA or DPP-4i	N=192 1.5mg dulaglutide once weekly; N=190 0.75mg dulaglutide once weekly; N=194 insulin glargine once daily BL: mean age 65 yrs, 69% white, 52% male, mean HbA1c 8.6%, mean duration T2D 18 yrs, mean eGFR (CKD-EPI) by creatinine 36 (35 by cystatin C), median UACR = 214 for dulaglutide 1.5mg, = 234 for dulaglutide 0.75mg, = 196 for insulin glargine	Outcome comparisons between (1) insulin glargine vs dulaglutide 1.5mg, and (2) insulin glargine vs dulaglutide 0.75mg A) Change in eGFR per CKD-EPI creatinine B) Change in eGFR per CKD-EPI cystatin C C) UACR change from BL D) Change in eGFR per MDRD E) Kidney events of increase in serum creatinine >30% from BL, ESKD	A) Week 26 LS mean change (1): −0.1 (p<0.05), (2): −0.4 (p<0.05) Week 52 Change (1): −1.1 (ns), (2): −1.5 (ns) B) Week 26 LS mean change (1): 0.8 (p<0.05), (2): 1.1 (p<0.0001); Week 52 Change (1): −0.7 (p<0.05), (2): −0.7 (p<0.05) C) Week 26 Among those with BL macro-albuminuria, UACR decreased for dulaglutide 1.5mg vs insulin by 43.1% (p=0.008) at week 26 and decreased by 29% (p=0.02) at week 52; for dulaglutide 0.75mg, a decrease of 25.3% (no p-value provided) at week 26 and decrease of 12.3 (no p-value provided) at week 52; for those without BL macroalbuminuria, decrease of 0.4% at week 26 (ns) and decrease of 3.4 % (ns) at week 52 for dulaglutide 1.5mg; for dulaglutide 0.75mg, decrease of 18% (ns) at week 26 and decrease of 15.3% (ns) at week 52 D) Week 26 LS mean change (1): no change (p<0.05), (2): −0.2 (p<0.05); Week 52 change (1): −0.4 (p<0.05), (2) −1.3 (ns) E) Number of events Dulaglutide 1.5mg = 79 (41%); Dulaglutide 0.75mg = 73 (38%); Insulin = 91 (47%)

Study

Inclusion criteria

Participants

Kidney outcome

HR (95% CI) or other as specified

Studies with kidney outcomes as secondary outcome(s) only

LEADER [51]

Aug 2010–Dec 2015

410 sites in 32 countries

Adults with T2D, age ≥50 yrs with established CVD, or age ≥60 yrs with CVD risk factors, HbA1c ≥7%, no GLP-1 RA or DPP-4i for 3 months prior to screening

N=4668 maximum 1.8mg liraglutide (as tolerated) once daily

N=4672 placebo once daily

BL: mean age 64 yrs, 64% male, 78% white, mean HbA1c 8.7%, mean duration T2D 13 yrs, mean eGFR (MDRD) 80, 26% had microalbuminuria, 11% had BL macroalbuminuria

A) Composite of new onset persistent macroalbuminuria, persistent doubling of serum creatine, kidney replacement therapy, death from kidney causes

B) New onset persistent macroalbuminuria

C) Persistent doubling of serum creatinine

D) Kidney replacement therapy

E) Death from kidney cause

F) Decline in eGFR over 36 months

G) Increase in UACR

H) New onset microalbuminuria

A) 0.78 (0.67–0.92)

B) 0.74 (0.60–0.91)

C) 0.90 (0.67–1.20)

D) 0.87 (0.61–1.25)

E) 1.60 (0.52–4.90)

F) Between group difference=1.02 (p=0.01)

G) Between group difference=0.83 (p<0.001)

H) 0.87 (0.83–0.93)

REWIND [52]

July 2011–Aug 2018

371 sites in 24 countries

Adults with T2D, age ≥50 with previous CVD event or with CVD risk factors, HbA1c ≤9.5%

N=4949 1.5mg dulaglutide once weekly

N=4952 placebo once weekly

BL: mean age 66 yrs, 54% male, 76% white, mean duration T2D 11 yrs, mean HbA1c 7.4%, mean eGFR 77

A) Composite of development of macroalbuminuria (UACR>33.9 mg/mmol), sustained decline in eGFR ≥30%, or new chronic kidney replacement therapy

B) Development of macroalbuminuria

C) Sustained decline in eGFR ≥30%

D) New chronic kidney replacement therapy

A) 0.85 (0.77–0.93)

B) 0.77 (0.68–0.87)

C) 0.89 (0.78–1.01)

D) 0.75 (0.39–1.44)

Harmony Outcomes [53]

July 2015–March 2018

610 sites in 28 countries

Adults with T2D and established CVD, age ≥40 yrs, HbA1c >7%, eGFR (MDRD) ≥30, not using GLP-1 RA at screening

N=4731 30–50 mg albiglutide as tolerated once weekly

N=4732 placebo once weekly

BL: mean age 64 yrs, 70% male, 70% white,

mean duration T2D 14 yrs, mean HbA1c 8.7%, mean eGFR 79

Change in eGFR by treatment group

Mean eGFR difference=−1.11

(−1.84 to −0.39) at 8 months and -0.43

(−1.26 to 0.41) at 16 months.

Figure 4 shows significant difference (no CI overlap) favoring albiglutide at 28 months but no numbers provided

SUSTAIN-6 [54]

Feb 2013–March 2016

230 sites in 20 countries

Adults with T2D, age ≥50 yrs with established CVD, heart failure (NYHA class II or III), or chronic kidney failure OR age ≥60 yrs with one or more CVD risk factors, HbA1c ≥7%, no use of DPP-4i within 30 days prior to screening or GLP-1 RA within 90 days prior to randomization

N=1648 0.5mg or 1.0 mg semaglutide once weekly

N=1649 placebo once weekly

BL: mean age 65 yrs, 61% male, 83% white, 30% eGFR>90, mean HbA1c 8.7%, mean T2D duration 14 yrs

A) New or worsening nephropathy

B) Persistent macroalbuminuria

C) Persistent doubling of serum creatinine and creatinine clearance per MDRD <45

D) Need for continuous kidney replacement therapy

A) 0.64 (0.46–-0.88)

B) 0.54 (0.37–0.77)

C) 1.28 (0.64–2.58)

D) 0.91 (0.40–2.07)

AMPLITUDE-O [55]

April 2018–Dec 2020

344 sites in 28 countries

Adults with T2D, HbA1c >7%, age ≥18 yrs with history of CVD, OR males ≥50 yrs/females ≥55 yrs with eGFR (MDRD) 25.0 to 59.9 and ≥1 CV risk factor, no use of GLP-1 RA or DPP-4i within 3 months prior to screening

N=1359 initial dose 2mg efpeglenatide once weekly, titrated to 4mg or 6mg once daily to study end

N=1358 6mg efpeglenatide once weekly

N=1359 placebo once weekly

BL: mean age 65 yrs, 67% male, 87% white, mean HbA1c 8.9%, mean eGFR 72, mean duration T2D 15 yrs, median UACR 28.3

A) Incident macroalbuminuria

B) Between-group difference in UACR

C) LS mean difference in eGFR

D) Decrease in eGFR≥40% for ≥30 days, ESKD, or all-cause death

E) Composite of MACE, death from non-CV cause, hospitalization for heart failure, or occurrence of (A)

A) 0.68 (0.57–0.79)

B) 0.68 (0.58–0.80)

C) Lower by 21% (14–28%)

D) Higher by 0.9 (0.3–1.50)

E) 0.77 (0.57–1.02)

F) 0.71 (0.59–0.87)

ELIXA [56]

June 2010–Feb 2015

829 sites in 49 countries [57]

Adults with T2D, HbA1c 5.5% to 11.0%, age≥30 yrs, with acute coronary syndrome (STEMI, non-STEMI, or unstable angina) <180 days before screening, HbA1c 5.5 to 11%, and eGFR (MDRD) ≥30, taking GLP-1 RA or DPP-4i during study

N=3034 10μg lixisenatide increased up to 20μg once daily

N=3034 placebo once daily

BL: mean age 60 yrs, 69% male, 75% white, mean duration T2D 9 yrs, mean HbA1c 7.7%, mean eGFR 76

Percent change in UACR from BL to study week 108 (BL UACR and study week 108 data available for n=2830 placebo, n=2803 lixisenatide)

+34% placebo, +24% lixisenatide, p<0.01, adjusted for BL UACR, treatment, region, BL use of ACEi and ARB;

+32% placebo, +26 lixisenatide, p=0.07, adjusted for BL and 3-month HbA1c

EXSCEL [58]

June 2010–April 2017

688 sites in 35 countries [59]

Adults with T2D, HbA1c 6.5% to 10.0%, age≥18 yrs, eGFR (MDRD) ≥30, range of CV risk factors, taking 0 to 3 oral glycemic control drugs or insulin with or without use of 1–2 oral glycemic drugs, never used GLP-1 RA

Propensity score matched N=572 placebo; N=572 exenatide once weekly +SGLT2i; N=575 exenatide once weekly; N=575 exenatide once weekly + SGLT2i

BL: mean age 63 yrs, 62% male, 76% white, mean duration T2D 12 yrs, mean HbA1c 8%

Outcome comparisons between 1: placebo only with exenatide + SGLT2i, and 2: exenatide only with exenatide + SGLT2i:

A) Change over time in eGFR (per MDRD)

B) Composite of persistent 40% reduction in eGFR, kidney dialysis, or kidney transplant

C) Composite of “B” plus new macroalbuminuria

A) (1) 1.94 (0.94–2.94); (2) 2.38 (1.40–3.35)

B) (1) 0.32 (0.06–1.59); (2) 0.21 (0.05–0.97)

C) (1) 0.43 (0.15–1.22); (2) 0.35 (0.13–0.98)

AWARD 7 [60]

July 2012–Dec 2016

99 sites in 9 countries

Adults with T2D and stage 3 or 4 CKD, age≥18 yrs, HbA1c 7.5% to 10.5%, taking insulin alone or with oral glucose control drug, taking maximum tolerated dose of ACEi or ARB, not taking GLP-1 RA or DPP-4i

N=192 1.5mg dulaglutide once weekly;

N=190 0.75mg dulaglutide once weekly;

N=194 insulin glargine once daily

BL: mean age 65 yrs, 69% white, 52% male, mean HbA1c 8.6%, mean duration T2D 18 yrs, mean eGFR (CKD-EPI) by creatinine 36 (35 by cystatin C), median UACR = 214 for dulaglutide 1.5mg, = 234 for dulaglutide 0.75mg, = 196 for insulin glargine

Outcome comparisons between (1) insulin glargine vs dulaglutide 1.5mg, and (2) insulin glargine vs dulaglutide 0.75mg

A) Change in eGFR per CKD-EPI creatinine

B) Change in eGFR per CKD-EPI cystatin C

C) UACR change from BL

D) Change in eGFR per MDRD

E) Kidney events of increase in serum creatinine >30% from BL, ESKD

A) Week 26 LS mean change (1): −0.1 (p<0.05), (2): −0.4 (p<0.05) Week 52 Change (1): −1.1 (ns), (2): −1.5 (ns)

B) Week 26 LS mean change (1): 0.8 (p<0.05), (2): 1.1 (p<0.0001); Week 52 Change (1): −0.7 (p<0.05), (2): −0.7 (p<0.05)

C) Week 26 Among those with BL macro-albuminuria, UACR decreased for dulaglutide 1.5mg vs insulin by 43.1% (p=0.008) at week 26 and decreased by 29% (p=0.02) at week 52; for dulaglutide 0.75mg, a decrease of 25.3% (no p-value provided) at week 26 and decrease of 12.3 (no p-value provided) at week 52; for those without BL macroalbuminuria, decrease of 0.4% at week 26 (ns) and decrease of 3.4 % (ns) at week 52 for dulaglutide 1.5mg; for dulaglutide 0.75mg, decrease of 18% (ns) at week 26 and decrease of 15.3% (ns) at week 52

D) Week 26 LS mean change (1): no change (p<0.05), (2): −0.2 (p<0.05); Week 52 change (1): −0.4 (p<0.05), (2) −1.3 (ns)

E) Number of events Dulaglutide 1.5mg = 79 (41%); Dulaglutide 0.75mg = 73 (38%); Insulin = 91 (47%)

Abbreviations: GLP-1 RA glucagon-like peptide-1 receptor agonist, HR hazard ratio, CI confidence interval, LEADER Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results, T2D type 2 diabetes, CVD cardiovascular disease, HbA1c glycated hemoglobin, DPP-4i dipeptidyl peptidase-4 inhibitor, BL baseline, yrs years, eGFR estimated glomerular filtration rate, in mL/min/1.73 m² body surface area, MDRD Modification of Diet in Renal Disease, UACR urine albumin to creatinine ratio, in mg albumin to g creatinine, Harmony Outcomes Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes, REWIND Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes, SUSTAIN-6 Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes, NYHA New York Heart Association, AMPLITUDE-O Effect of Efpeglenatide on Cardiovascular Outcomes, CV cardiovascular, MACE major adverse cardiovascular events, ELIXA Evaluation of Lixisenatide in Acute Coronary Syndrome, STEMI ST-elevation myocardial infarction, ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, EXSCEL Exenatide Study of Cardiovascular Event Lowering, SGLT2i sodium glucose transport protein 2 inhibitor, AWARD 7 Assessment of Weekly Administration of LY2189265 (dulaglutide) in Diabetes, CKD-EPI chronic kidney disease epidemiology collaboration, ESKD end-stage kidney disease, LS least squares, ns non-significant, BL baseline