diabetic nephropathy: markers and prevention of …...(macroalb., doubling s-creat., esrd, renal...

Johannes MannDepartment of Nephrology & HypertensionFriedrich Alexander Universität Erlangen-NürnbergandKfH Kidney Center, München-SchwabingGERMANY

Diabetic nephropathy: Markers and prevention of complications

Antalya, October 2016

Estimated future prevalence of diabetic nephropathy in Europe*

Estim

ate

d r

ela

tive p

revale

nce r

ate

(p

er

million p

opula

tion)

0

20.000

40.000

60.000

80.000

100.000

120.000

140.000

160.000

180.000

200.000

2010 2015 2020 2025

0

2.000

4.000

6.000

8.000

10.000

12.000

14.000

2010 2015 2020 2025

Year Year

CKD stage 3

CKD stage 4

CKD stage 5

CKD, chronic kidney disease. *Austria, Belgium, Denmark, Finland, Greece, Iceland, Italy, Netherlands, Norway, Spain, Sweden, UKKainz A et al. Nephrol Dial Transplant 2015;30:iv1113 (Supplementary data); SYSKID Project

Low GFR

High urine albumin

Renal markers as an open door to future renal and CV outcomes

Death

Renalevents

CV events

CV, cardiovascular; GFR, glomerular filtration rate

*Renal outcomes defined as: death as a result of kidney disease, requirement for dialysis or transplantation, or doubling of serum creatinine to >200 μmol/l. eGFR in ml/min/1.73 m2

eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; UACR, urine albumin-to-creatinine ratioNinomiya T et al. J Am Soc Nephrol 2009;20:1813

Albuminuria and low GFR independently predict renal outcomes* in type 2 diabetes

eGFR ≥90

eGFR 60–89

eGFR <60

0

5

10

15

20

25

MacroMicro

Normo

Hazard

ratio

Baseline UACRBaseline eGFR

ADVANCE study: N=10,640;

average follow-up 4.3 years

Preventing nephropathy in type 2 diabetes

What did we do?

1. Glucose control

2. BP control

3. RAS inhibition

4. Multifactorial intervention

5. … And many failed attempts

6. Diet, physical activity, smoking: no RCT

BP, blood pressure; RAS, renin–angiotensin system; RCT, randomised controlled trial

Intensive vs conventional glucose-lowering strategies

StudyDiabetes duration (mean)

Antihyperglycaemicmedication

Follow-up(median)

HbA1c: baseline, between-arm

differenceMicrovascular CVD Mortality

UKPDS1

Newly diagnosed

SU/insulin or metformin vs

dietary restriction

10 years7.1% (all patients),

–0.9% ↓ ↔ ↔UKPDS

long-term follow-up2

10 years post

intervention

No difference in HbA1c between treatment arms

↓ ↓ ↓

ADVANCE3 8 years

Intensive glucose control including

gliclazide vs standard treatment

5 years7.5% (both arms),

–0.8% ↓ ↔ ↔

ACCORD4,5 10 yearsMultiple drugs in both arms

3.4 years8.1% (both arms),

–1.1% ↓ ↔ ↑

VADT6 11.5 yearsMultiple drugs in both arms

5.6 years9.4% (both arms),

–1.5% ↔ ↔ ↔1. UKPDS Group. Lancet 1998;232:837; 2. UKPDS Group. N Engl J Med 2008;359:1577; 3. ADVANCE Collaborative Group. N Engl J Med 2008;358:2560; 4. Gerstein HC et al. N Engl J Med 2008;358:2545; 5. Gerstein HC et al. Lancet 2014;384:1936; 6. Duckworth W et al. N Engl J Med 2009;360:29

BP and renal outcomes (mainly new microalbuminuria) in type 2 diabetes without nephropathy (ADVANCE study)

Median systolic BP (mmHg)

No. of person–years

106 116 125 135 144 154 168

1431 4266 8974 11,983 9138 4942 3470

Annual patient

event

rate

(%

)

Achieved systolic BP (mmHg)

100 110 120 130 140 150 160 1704

5

6

7

8

9

10p<0.0001 for trend

*New-onset microalbuminuria or nephropathy, doubling of serum creatinine to >200 μmol/l, or ESRD BP, blood pressure; ESRD, end-stage renal diseasede Galan B et al. J Am Soc Nephrol 2009;20:883

Captopril + other antihypertensives

Placebo + other antihypertensives

*

Follow-up (years)

0 1 2 3 4

0

10

20

30

40

50*Risk reduction 50%, p=0.006 vs placebo, n=405

ACEi, angiotensin-converting enzymeLewis EJ et al. N Engl J Med 1993;329:1456

ACE inhibitors in type 1 diabetes and renal outcomes

Death

or

need for

dia

lysis

or

transpla

nta

tion (

%)

No new treatments for diabetic kidney disease identified for over 15 years

1980 1990 2010 20152000

No new DKD-specific treatment in the past 16 years

High blood pressure

identified as DKD risk

factor

β-blockers1

Hydralazine2

Captopril3

T1D

IDNT4

Irbesartan T2D

RENAAL5

LosartanT2D

RAAS blockade

DKD, diabetic kidney disease; T1D, type 1 diabetes; T2D, type 2 diabetes; IDNT, Irbesartan Type 2 Diabetic Nephropathy Trial; RAAS, renin–angiotensin–aldosterone system; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan1. Mogensen CE et al. Br Med J (Clin Res Ed) 1982;285:685; 2. Parving HH et al. Lancet 1983;1:1175; 3. Lewis EJ et al. N Engl J Med 1993;329:1456; 4. Lewis EJ et al. N Engl J Med 2001;345:851; 5. Brenner BM et al. N Engl J Med 2001;345:861

We cannot say we did not try … treating diabetic nephropathy

Dual blockade of RAS: ONTARGET, ALTITUDE,

NEPHRON-D, ORIENT

Endothelin blockade: ASCEND, SONAR

Statins: CARDS

Vitamin D: PRIMO, VITAL

Vitamin B: DIVINE

Antioxidant/-inflammatory: BEACON, pirfenidone

Epoetin: TREAT

Glycosaminoglycan (soludexide): SUN-MACRO

TGF inhibitors: September 2016!

DEVOTE(Insulin degludec, insulin)n=7637; duration ~3 yrs

completion Q3 2016

FREEDOM (ITCA 650, GLP-1RA in DUROS)

n=4000; duration ~2 yrscompletion Q3 2018

TECOS(Sitagliptin, DPP-4i)

n=14,761; duration ~7–5 yrscompletion Q1 2015

CAROLINA(Linagliptin, DPP-4i vs SU)n=6000; duration ~8 yrs

completion Q1 2019

CANVAS(Canagliflozin, SGLT2i)

n=4330; duration 4+ yrscompletion Q1 2017

ELIXA(Lixisenatide, GLP-1RA)


REWIND(Dulaglutide, QW GLP-1RA)n=9622; duration ~6.5yrs

completion Q3 2018

SUSTAIN 6(Semaglutide, GLP-1RA)

n=3260; duration ~2.8 yrscompletion Q1 2016

Pre-approval Post-approvalPre+post-approval Other

LEADER(Liraglutide, GLP-1RA)

n=9340; duration 3.5–5 yrscompletion Q4 2015

DECLARE-TIMI-58(Dapagliflozin, SGLT2i)

n=17,276; duration ~6 yrscompletion Q2 2019

SAVOR TIMI-53(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrsQ2 2013 - RESULTS

CARMELINA(Linagliptin, DPP-4i)


EXAMINE(Alogliptin, DPP-4i) n=5380;

follow-up ~3.5 yrsQ2 2013 - RESULTS

NCT01703208(Omarigliptin, QW DPP-4i)n=4000; duration ~3 yrs

completion Q4 2017

EMPA-REG OUTCOME(Empagliflozin, SGLT2i)

n=7064; duration up to 5 yrscompletion Q2 2015

20192015 20202013 2014 2016 2017 2018

EXSCEL(Exenatide, QW GLP-1RA)

n=14,000; duration ~7.5 yrscompletion Q2 2018

CANVAS-R(Canagliflozin, SGLT2i)


VERTIS(Ertugliflozin, SGLT2i)


Terminated

ALECARDIO(Aleglitazar, PPAR-αγ )

n=7226; follow-up 2.0 yrsTermin. Q3 2013 RESULTS

CREDENCE (cardio-renal)(Canagliflozin, SGLT2i)


Source: ClinicalTrials.gov. 2016. ‘Completion date’ is the estimated completion date for the primary outcomes measureCVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; PPAR, peroxisome proliferator‐activated receptors; QW, once weekly; SGLT2, sodium–glucose cotransporter-2 inhibitor;

SU, sulphonylureaMcMurray JJV et al. Lancet Diabetes Endocrinol 2014; pii: S2213-8587(14)70031-2

The new guidelines have led to roughly 150,000 patients being followed in CVOTs

We cannot say we did not try: CVOT = ROT

Individual glucose-lowering drug vs placebo (since 2008 FDA guidance)

ELIXA2

EXAMINE3

SAVOR4

TECOS5

EMPA-REG OUTCOME6

LEADER7 and SUSTAIN 6

Cardiovascular risk in type 2 diabetes:

Summary of randomized trials

Cardiovascular events Mortality

Intensive vs less intensive glycemic control1

ACCORD

ADVANCE

UKPDS

VADT

1. Bergenstal RM et al. Am J Med 2010;123:374.e18; 2. Pfeffer MA et al. N Engl J Med 2015;373:2247-57; 3. White WB et al. N Engl J Med 2013;369:1327-35; 4. Scirica BM et al. N Engl J Med 2013;369:1317-26;5.Green JB et al. N Engl J Med 2015;373:232-42; 6. Zinman B et al. N Engl J Med 2015;373:2117-28; 7. Marso SP et al. N Engl J Med 2016; epub ahead of print.

12

We cannot say we did not try … treating diabetic nephropathy

LEADER: Liraglutide

SUSTAIN6: Semaglutide

EMPA-REG: Empagliflozin

LEADER: Study design

CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin;

MEN-2, multiple endocrine neoplasia type 2; MTC, medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.

Key exclusion criteria

• T1DM

• Use of GLP-1RAs, DPP-4i, pramlintide, or rapid-acting

insulin

• Familial or personal history of MEN-2 or MTC

• eGFR <30 ml/min/1.73 m2

Key inclusion criteria

• T2DM, HbA1c ≥7.0%

• Antidiabetic drug naïve; OADs and/or basal/premix insulin

• Age ≥50 years and established CV disease or chronic renal

failure

or

• Age ≥60 years and risk factors for CV disease

Liraglutide 0.6–1.8 mg OD + standard of care

Placebo + standard of care

Duration 3.5–5 years

Randomization (1:1)

Double-blindEnd of treatment

Placebo run-in

Safety follow-up

Safety follow-up

30 days2 weeks

Screening

Ussher JR, Drucker DJ. Circ Res 2014;114:1788–803.

Primary outcome

Marso, .. Mann et

al, NEJM

2016;375:311-

322

All cause

death

reduced, HR

0.85, p=0.02

Time to first nephropathy event (macroalb., doubling s-creat., ESRD, renal death)

1717

Subjects at risk

Liraglutide 4668 4602 4480 4304 4132 984 9

Placebo 4672 4609 4408 4196 4013 945 13

Full analysis set. Kaplan-Meier plot of EAC-confirmed nephropathy event. Cox regression analysis accounting for treatment. Analysis

includes events between randomisation date and follow-up date. Subjects without an event are censored at time of last contact (phone or

visit). CI: confidence interval; EAC: event adjudication committee;

HR: hazard ratio

0 10 20 30 40 50 60

0

2

4

6

8

10

T im e s in ce ra n d o m is a tio n (m o n th s)

Su

bje

cts

wit

h e

ve

nt (

%)

Time since randomisation (months)

HR=0.78

95% CI (0.67 ; 0.92)

P=0.03

Liraglutide Placebo

Su

bje

cts

wit

h e

ve

nt

(%)

Su

bje

cts

wit

h a

n e

ve

nt

(%)

Time to new onset of persistent macroalbuminuria

181818

Subjects at risk

Liraglutide 4668 4606 4499 4353 4199 1006 9

Placebo 4672 4615 4433 4252 4094 964 13

Full analysis set. Kaplan-Meier plot of EAC-confirmed new onset of persistent urine albumin ≥300 mg/g creatinine; events which occur

before randomisation date are not used for defining first event; subjects without an event are censored at time of last contact (phone or

visit)

CI: confidence interval; EAC: event adjudication committee; HR: hazard ratio

0 10 20 30 40 50 60

0

2

4

6

T im e s in ce ra n d o m is a tio n (m o n th s)

Su

bje

cts

wit

h e

ve

nt (

%)

Time since randomisation (months)

Liraglutide Placebo

HR=0.74

95% CI (0.60 ; 0.91)

P=0.02

Su

bje

cts

wit

h e

ve

nt

(%)

Time to first microvascular endpoints

Hazard ratio (95% CI)

Favours PlaceboFavours Liraglutide

Full analysis set. EAC-confirmed microvascular events including events with onset between date of randomisation and date of follow-up. Cox

proportional hazard model adjusted for treatment. Development of diabetes-related blindness was not analysed as an individual component as

only one event was observed. *New onset of persistent macroalbuminuria: urine albumin ≥300 mg/g creatinine. †Persistent doubling of serum

creatinine level and eGFR ≤45 mL/min/1.73m2 per MDRD

%: proportion of subjects; CI: confidence interval; EAC: event adjudication committee; N: number of subjects

Hazard ratio(95% CI)

Liraglutide Placebo

N % N %

Number of subjects 4668 100 4672 100

Microvascular endpoint 0.84 (0.73 ; 0.97) 355 7.6 416 8.9

Nephropathy 0.78 (0.67 ; 0.92) 268 5.7 337 7.2

New onset of persistent macroalbuminuria* 0.74 (0.60 ; 0.91) 161 3.4 215 4.6

Persistent doubling of serum creatinine† 0.88 (0.66 ; 1.18) 87 1.9 97 2.1

Need for continuous renal replacement therapy 0.87 (0.61 ; 1.24) 56 1.2 64 1.4

Death due to renal disease 1.59 (0.52 ; 4.87) 8 0.2 5 0.1

Retinopathy 1.15 (0.87 ; 1.52) 106 2.3 92 2.0

Vitreous haemorrhage 1.45 (0.84 ; 2.50) 32 0.7 22 0.5

Treatment with photocoagulation or intravitreal agent 1.16 (0.87 ; 1.55) 100 2.1 86 1.8

0,1 1,0 10,0

TIME TO FIRST OCCURRENCE OF CV DEATH OR NON-FATAL MI OR NON-FATAL STROKESUSTAIN6: Primary outcome

Figure 1A. Kaplan Meier plot for first event adjudication committee-confirmed CV death, non-fatal MI and non-fatal stroke using ‘in-trial’ data from subjects in the full analysis set.

*Not prespecified. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.

Marso et al. NEJM [in press]

0

5

10

15

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Subje

cts

with a

n e

vent

(%)

Time since randomisation (weeks)

Number of subjects at risk

Semaglutide 1648 1619 1601 1584 1568 1543 1524 1513

Placebo 1649 1616 1586 1567 1534 1508 1479 1466

HR, 0.74 (95% CI, 0.58; 0.95)

Events: 108 semaglutide; 146 placebo

P<0.001 for non-inferiority

P=0.02 for superiority

Semaglutide, 6.6%

Placebo, 8.9%

109

SUSTAIN6: New or worsening nephropathy with semaglutide once per week

Supplementary Figure 5B. Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using ‘in-trial’ data from subjects in the full analysis set. HR is from a proportional hazard model. CI, confidence interval; EAC, (external) event adjudication committee; HR, hazard ratio.Marso et al. NEJM [in press]

Semaglutide, 3.8%

0

2

4

6

8

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Patients

with a

n e

vent

(%)

Weeks since randomisation

HR, 0.64 (95% CI, 0.46; 0.88)Events: 62 Semaglutide; 100 PlaceboP=0.005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

109

Placebo, 6.1%

• Key inclusion criteria

– Adults with type 2 diabetes and established cardiovascular disease

• At baseline, 75.6% of patients had coronary artery disease, 23.3% had a

history of stroke, 20.8% had peripheral artery disease,10.1% had heart

failure*

– BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)

• Study medication was given in addition to standard of care

22

*Based on narrow standardized MedDRA query (SMQ) “cardiac failure”. eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.Zinman B et al. N Engl J Med 2015;373:2117-28.

Randomized and treated

(n=7020)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)

Placebo

(n=2333)

Screening(n=11531)

EMPA-REG OUTCOME®

Urine albumin to

creatinine ratio

eGFR (MDRD)

Renal factors

eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

23

Doubling of serum creatinine*, initiation of renal replacement therapy, or death due to renal disease

24

*Accompanied by eGFR (MDRD) ≤45 mL/min/1.73m2.Post-hoc analyses. Kaplan-Meier estimate. Hazard ratio based on Cox regression analyses.

Summary

•After many failed attempts we now have at

least 3 antidiabetic drugs that improve renal

outcomes:

•Empagliflozin, Liraglutid and Semaglutide

HR 0.86

(95.02% CI 0.74, 0.99)

p=0.0382*

Primary outcome: 3-point MACE

Cumulative incidence function. *Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498).Zinman B et al. N Engl J Med 2015;373:2117-28.

26

14% reduction

Placebo

Empagliflozin

Incident or worsening nephropathy(Macroalbuminuria, doubling of serum creatinine, renal replacement

therapy, renal death)

Kaplan-Meier estimate. Hazard ratio based on Cox regression analyses.

27

ESRD, end-stage renal disease; SBP, systolic blood pressure; Scr, serum creatinine Sarafidis PA et al. Kidney Int 2014;85:536

Achieved BP and renal outcomes in type 2 diabetes with overt nephropathy, stage G3A2 (IDNT study)

>149

<134

SBP (mmHg)

141−149134−140

Glucose control and ESRD in type 2 diabetes ADVANCE-ON study

HR 0.54 95% CI: 0.34, 0.85

p=0.007

2

Patients

with e

nd-s

tage

renal dis

ease* (

%)

1

0

4 6 10Follow-up (years)

2 80

Standard control

Intensive control

No. at risk

Intensive 5571 5402 5186 4124 3764 2811

Standard 5569 5400 5173 4041 3681 2683

53 events 29 events

*Defined as requirement for renal-replacement therapy. ESRD, end-stage renal disease

HR, hazard ratio. Zoungas S et al. N Engl J Med 2014;371:1392

ARBs in type 2 diabetes and renal outcomes

ARB, angiotensin receptor blocker; BL, baseline; SCr, serum creatinineLewis EJ et al. N Engl J Med 2001;345:851

Placebo

Irbesartan

Follow-up (months)

Patients

with d

oubllin

g o

f BL S

Cr

(%)

0 6 12 18 24 36 54

10

20

30

60

030 42 48

40

50

70 *Risk reduction 23%, p=0.009 vs placebo(and vs amlodipine)

Early reduction in albuminuria with ARB predicts long-term risk of ESRD

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

HR r

ela

tive t

o 0

%

in a

lbum

inuria r

eduction

Albuminuria reduction, %

<-40

<40

≥-40 ≥-10 ≥10 ≥40 ≥60

<-10 <10 <60

ARB, angiotensin receptor blocker;ESRD, end-stage renal disease; HR, hazard ratioDe Zeeuw D et al. Kidney Int 2004;64:2309

DEVOTE(Insulin degludec, insulin)n=7637; duration ~3 yrs

completion Q3 2016

FREEDOM (ITCA 650, GLP-1RA in DUROS)


TECOS(Sitagliptin, DPP-4i)

n=14,761; duration ~7–5 yrscompletion Q1 2015

CAROLINA(Linagliptin, DPP-4i vs SU)n=6000; duration ~8 yrs

completion Q1 2019

CANVAS(Canagliflozin, SGLT2i)

n=4330; duration 4+ yrscompletion Q1 2017

ELIXA(Lixisenatide, GLP-1RA)


REWIND(Dulaglutide, QW GLP-1RA)n=9622; duration ~6.5yrs

completion Q3 2018

SUSTAIN 6(Semaglutide, GLP-1RA)


Pre-approval Post-approvalPre+post-approval Other

LEADER(Liraglutide, GLP-1RA)

n=9340; duration 3.5–5 yrscompletion Q4 2015

DECLARE-TIMI-58(Dapagliflozin, SGLT2i)

n=17,276; duration ~6 yrscompletion Q2 2019

SAVOR TIMI-53(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrsQ2 2013 - RESULTS

CARMELINA(Linagliptin, DPP-4i)


EXAMINE(Alogliptin, DPP-4i) n=5380;

follow-up ~3.5 yrsQ2 2013 - RESULTS

NCT01703208(Omarigliptin, QW DPP-4i)n=4000; duration ~3 yrs

completion Q4 2017

EMPA-REG OUTCOME(Empagliflozin, SGLT2i)

n=7064; duration up to 5 yrscompletion Q2 2015

20192015 20202013 2014 2016 2017 2018

EXSCEL(Exenatide, QW GLP-1RA)

n=14,000; duration ~7.5 yrscompletion Q2 2018

CANVAS-R(Canagliflozin, SGLT2i)


VERTIS(Ertugliflozin, SGLT2i)


Terminated

ALECARDIO(Aleglitazar, PPAR-αγ )

n=7226; follow-up 2.0 yrsTermin. Q3 2013 RESULTS

CREDENCE (cardio-renal)(Canagliflozin, SGLT2i)


Source: ClinicalTrials.gov. 2016. ‘Completion date’ is the estimated completion date for the primary outcomes measureCVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; PPAR, peroxisome proliferator‐activated receptors; QW, once weekly; SGLT2, sodium–glucose cotransporter-2 inhibitor;

SU, sulphonylureaMcMurray JJV et al. Lancet Diabetes Endocrinol 2014; pii: S2213-8587(14)70031-2

CVOTs within diabetes

The new guidelines have led to roughly 150,000 patients being followed in CVOTs

*CV outcomes defined as: CV death, non-fatal myocardial infarction or non-fatal strokeeGFR in ml/min/1.73 m2. CV, cardiovascular; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; UACR, urine albumin-to-creatinine ratioNinomiya T et al. J Am Soc Nephrol 2009;20:1813

Albuminuria and low GFR independently predict CV outcomes* in type 2 diabetes

eGFR ≥90

eGFR 60–89

eGFR <60

0

1

2

3

4

MacroMicro

NormoH

azard

ratio

ADVANCE study: N=10,640;

average follow-up 4.3 years

Baseline UACRBaseline eGFR

SUSTAIN6: Microvascular outcomes

Supplementary Table 9. †The primary composite outcome in the time-to-event analysis consisted of the first occurrence of either death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. ‡The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, revascularisation (coronary and peripheral), hospitalisation for unstable angina or heart

failure. CI, confidence interval; HR, hazard ratio; PYR, patient years of risk time (time from randomisation until first event or censoring).

Marso et al. NEJM [in press]

Semaglutide PlaceboHR

(95% CI)P valueNo. (%) Incidence rate

per 100 PYRNo. (%) Incidence rate

per 100 PYR

Retinopathy complications 50 (3.0) 1.49 29 (1.8) 0.86 1.76 1.11; 2.78 0.02

Need for retinal photocoagulation 38 (2.3) 1.13 20 (1.2) 0.59 1.91 1.11; 3.28 0.02

Vitreous haemorrhage 16 (1.0) 0.47 7 (0.4) 0.21 2.29 0.94; 5.57 0.07

Need for treatment with

intravitreal agent16 (1.0) 0.47 13 (0.8) 0.38 1.25 0.59; 2.56 0.58

Onset of diabetes-related

blindness5 (0.3) 0.15 1 (0.1) 0.03 5.01 0.59; 42.88 0.14

New or worsening nephropathy 62 (3.8) 1.86 100 (6.1) 3.06 0.64 0.46; 0.88 0.005

Persistent macroalbuminuria 44 (2.7) 1.31 81 (4.9) 2.47 0.54 0.37; 0.77 0.001

Persistent doubling of serum

creatinine level and creatinine

clearance per MDRD

<45 ml/min/1.73m2

18 (1.1) 0.53 14 (0.8) 0.41 1.28 0.64; 2.58 0.48

Need for continuous

renal-replacement therapy11 (0.7) 0.32 12 (0.7) 0.35 0.91 0.40; 2.07 0.83

diabetic nephropathy: markers and prevention of …...(macroalb., doubling s-creat., esrd, renal...

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