¿Qué aportan los Inhibidores SGLT2? Impacto sobre el riñón. Nefroprotección Dr Jose Luis Górriz Servicio de Nefrologia. Hospital Clínico Universitario. INCLIVA Universidad de Valencia. 24 de Octubre de 2019 @jlgorriz II Forum Multidisciplinar de Riesgo Multidisciplinar en Diabetes
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¿Qué aportan los Inhibidores SGLT2?Impacto sobre el riñón. Nefroprotección
Dr Jose Luis Górriz
Servicio de Nefrologia. Hospital Clínico Universitario. INCLIVA
Universidad de Valencia.
24 de Octubre de 2019
@jlgorriz
II Forum Multidisciplinar de Riesgo Multidisciplinar en Diabetes
Gorriz JL. Prim Care Diabetes. 2019 Aug 7
Kidney outcomes in SGLT-2 inhibitor trials(doubling of serum creatinine, ESKD, or death from renal causes)
Wanner C. New Engl J Med 2016, June 14Neal B. New Engl J Med 2017, 377(7):644-657
Perkovic V. Poster FR-PO 1058. ASN New Orleans. Novbre 2017Ratz I. Diabetes Obes Metab. 2018;20:1102–1110
Mann JFE. N Engl J Med 2017;377:839-48.
40
45
50
55
60
65
70
75
80
Week
Placebo
Empagliflozin
Ad
just
ed
mea
n (
95
% C
I) e
GFR
(mL/
min
/1.7
3m
2)
12 28 52 94 10880 12266 136 150 164 178 1920 4
Patients with normoalbuminuria
Patients with microalbuminuria
Patients with macroalbuminuria
Post-hoc analysis. MMRM using all data obtained until study end in patients treated with ≥1 dose of study drug. Normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; macroalbuminuria: UACR >300 mg/g.
EMPA-REG OUTCOME: Cambios en FGe según grado de albuminuria (empagliflozina vs placebo)
Mosenzon O. Lancet Diabetes Endocrinol. 2019;7(8):606-617Ratz I. Presented at: ADA 79th Scientific Sessions; June 7-11, 2019; San Francisco, CA. 244-OR.
Dapaglflozin increased the likelihood of patients improving in albuminuria category, regardless of baseline UACR
iSGLT2: Datos enpacientes con FGe
reducido
[.14.]
Cardiovascular outcomes in patients with prevalent kidney disease* (EMPA REG OUTCOME)
Time to CV death Time to all cause mortality
Time to hospitalizationfor heart failure
Time to all cause hospitalization
Wanner C. Circulation. 2018 Jan 9;137(2):119-129*Defined as eGFR (MDRD) <60 mL/min/1.73m2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline.
New onset or worsening nephropathy in patients with prevalent kidney disease*
HR 0.58
(95% CI 0.47, 0.71)
p<0.001
Cum
ula
tive
pro
ba
bili
ty o
f e
ve
nt (%
)
*Defined as eGFR (MDRD) <60 mL/min/1.73m2 and/or macroalbuminuria (urine albumin-to-creatinine ratio >300 mg/g) at baseline.
Kaplan-Meier estimates in patients with prevalent kidney disease treated with ≥1 dose of study drug. Hazard ratios are based on Cox regression analyses. Post-hoc analyses.eGFR, estimated glomerular filtration rate. MDRD, Modification of Diet in Renal Disease.
Wanner C. New Engl J Med 2016, June 14
CREDENCEStudy Design and Population
Meg J. Jardine, MBBS, PhD, FRACP
Perkovic V. New Eng J Med April 14, 2019
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation
Lower Baseline Renal Function in CREDENCE Participants
20% 26%
9%
60%
8% 11% 7%
88%-100
-80
-60
-40
-20
0
20
40
60
80
100
eGFR <60
UACR >300
1. Neal B, et al. N Engl J Med. 2017;377(7):644-657.2. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.3. Raz I, et al. Diabetes Obes Metab. 2018;20(5):1102-1110.
CREDENCECANVAS
Program1
EMPA-REG OUTCOME2 DECLARE3
60
80
100
20
40
Prespecified Hierarchical Testing
Primary
1. ESKD, doubling of serum creatinine, or renal or CV death
Secondary
2. CV death or hospitalization for heart failure
3. CV death, MI, or stroke
4. Hospitalization for heart failure
5. ESKD, doubling of serum creatinine, or renal death
6. CV death
7. All-cause mortality
8. CV death, MI, stroke, hospitalization for heart failure, or hospitalization for unstable angina
Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472.
Cardiorenal outcomes in patients with proteinuric DKD in EMPA-REG OUTCOME®
versus CREDENCE
Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
*Excludes fatal stroke. Data for patients who did not have an event were censored on the last day they were known to be free of the outcome. ‘CREDENCE-like’ definition: eGFR ≥30 to <90
ml/min/1.73 m2 and UACR >300 mg/g. CREDENCE-like subgroup is reflected without corresponding all others subgroup from EMPA-REG OUTCOME but the data were consistent between
the analyzed subgroups and the overall population. ESKD defined as initiation of RRT or sustained eGFR <15 ml/min/1.73 m2. eGFR according to CKD-EPI. CV, cardiovascular; DKD,
60% reduction in the rate of eGFR decline with canagliflozin
On treatment
–1.85/year
Empagliflozin slowed the annual decline in eGFR in patient subgroups at higher risk for CKD progression assessed by mean eGFR slopes(Overall population)
*Adjusted mean eGFR over prespecified study periodsWanner C. J Am Soc Nephrol. 2018;29(11):2755-2769
In prevalent CKD, empagliflozin also slowed the annual decline in eGFR in patient subgroups at higher risk for CKD progression assessed by mean eGFR slopes
Wanner C. J Am Soc Nephrol. 2018;29(11):2755-2769
eGFR slopes depending on urinary albumin-to-creatinine ratio
Wanner C. J Am Soc Nephrol. 2018;29(11):2755-2769
EMPA-REG OUTCOME1: Renal Benefit of SGLT2-i
1. Wanner C. N Engl J Med. 2016;375:323–34; 2. Neal B. N Engl J Med. 2017;377:644–57
Week
Enf cardiovascular
+0.23 ml/min per year per 1.73 m2 (95%CI: +0.05 to 0.4)
EMPA-REG OUTCOME: incident for worsening nephropathy by baseline age
Monteiro P. Age Ageing. 2019 Oct 3. pii: afz096
T2DM is becoming a non-proteinuric state
Afkarian M. JAMA. 2016;316(6):602-610
RR of albuminuria (adjusted for eGFR): 0.73 vs 1988-1994
And a substantial % of DKD is now non-proteinuric
Halimi JM. Diabetes Metab. 2012 Oct;38(4):291-7
NHANES prevalence of non-proteinuric DKD : 50 %
Efecto de los iSGLT2 endiabéticos no proteinúricos
[.34.]
Trial design, key inclusion/exclusion criteria, and subgroup
definitions
Key inclusion criteria
• Adults (≥18 years of age) with T2DM
• HbA1c ≥7% and ≤10%*
• Established CV disease (prior MI, CAD, stroke, UA or occlusive PAD)
• BMI ≤45 kg/m2
Key exclusion criteria
• eGFR <30 ml/min/1.73 m2 (MDRD)
• Acute coronary syndrome, stroke or transient
ischemic attack within 2 months prior to informed
consent
35
Placebo (n=2333)
Pooled
Randomized
and treated
(n=7020)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Screening
(N=11,531)
*Stable background therapy for ≥12 weeks before randomization: for insulin, dose was to remain unchanged by >10% from the dose received 12 weeks
before randomization; for drug-naïve: HbA1c ≥7% and ≤9%. BMI, body mass index; CAD, coronary artery disease; CV, cardiovascular; DKD, diabetic
kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; MDRD, Modification of Diet in Renal Disease; MI, myocardial
1. Wanner C et al. N Engl J Med 2016;375:323; 2. Wanner C et al. EASD 2019; Barcelona, Spain; 16–20 September 2019.
Empagliflozin reduced the risk of cardio-renal outcomes,
regardless of DKD phenotype
Nominal p-value <0.0001
Interaction p-
value 0.4265
40
†ESKD defined as initiation of RRT or sustained eGFR <15 ml/min/1.73 m². ‡ESKD defined as initiation of RRT or sustained eGFR <10 ml/min/1.73 m². Albuminuric DKD defined as UACR >300 mg/g with any eGFR [CKD-
EPI]; non-albuminuric DKD group defined as eGFR <60 ml/min/1.73 m2 and UACR ≤300 mg/g; all others group defined as eGFR ≥60 ml/min/1.73 m2 or UACR ≤300 mg/g. DKD, diabetic kidney disease; eGFR, estimated
glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; n/a, not applicable; NC, not calculated; RRT, renal replacement therapy; UACR; urinary albumin-to-creatinine ratio.
Source: Wanner C et al. EASD 2019; Barcelona, Spain; 16–20 September 2019.
Empagliflozin Placebo Hazard ratio
(95% CI)
Hazard ratio
(95% CI)
Interaction
p-valuen event/N % n event/N %
Incident or worsening nephropathy*
All patients 525/4124 12.7 388/2061 18.8 0.61 (0.53, 0.70)
All others 36/3253 1.1 33/1609 2.1 0.53 (0.33, 0.85)
0,125 0,25 0,5 1 2
Empagliflozin reduced the risk of adverse kidney outcomes,
regardless of DKD phenotype
Cox regression analyses in patients treated with ≥1 dose of study drug. Interaction p-value is for test of homogeneity of treatment group difference
between subgroups with no adjustment for multiple tests. Data for patients who did not have an event were censored on the last day they were known
to be free of the outcome. *Defined as progression to macroalbuminuria (UACR >300 mg/g); a doubling of serum creatinine, accompanied by an
eGFR of ≤45 ml/min/1.73 m2 (MDRD formula); initiation of RRT; or renal death (patients with albuminuric DKD were excluded from this analysis).Favours empagliflozin Favours placebo
Indicaciones de i-SGLT2 según filtrado glomerular
Clinical Practice Guideline on management of diabetes and CKD. Nephrol Dial Transplant (2015) 30: ii1–ii142Martinez-Castelao A, Gorriz JL, Sola E, Morillas C et al. Nefrologia 2012;32(4):419-26Modificado de RedGDPS. Enfermedad renal crónica y Diabetes Mellitus Autor: Dr. Antonio Rodríguez-PoncelasFichas técnicas de Dapagliflozina, Empagliflozina y Canagliflozina
FGe/Fármacos >60 45-59 30-44 15-29 < 15
Inhibidores SGLT2
Dapagliflozina No ajusteNo iniciar
Mantener. No ajuste(10 mg/dia)
No No No
Empagliflozina No ajusteNo iniciar. Mantener
Si FG< 60 en tto, 10 mg/diaNo No No
Canagliflozina No ajusteNo iniciar. Mantener.
Si FG< 60 en tto, 100 mg/diaNo No No
Recomendaciones actuales
Marzal D. SEC Monogr. 2018;6(2):35‐38
Diabetologia. 2018 Oct 5. [Epub ahead of print]ASCVD: atherosclerotic CV diseaseCKD: chronic kidney disease Davies MJ. Diabetes Care 2019;42(Suppl. 1):S90–S102
Presented at the 56th European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Congress; June 13, 2019; Budapest, Hungary.
ADA Standards of Care Updated With Renal Guidance Based on CREDENCE
• “The CREDENCE trial was the first sodium-glucose cotransporter 2 (SGLT2) inhibitor trial to assess renal-specific primary outcomes and ended early due to efficacy. Incorporating these findings into the Standards of Care now gives providers the latest evidence-based recommendations to treat people with type 2 diabetes and diabetes-related chronic kidney disease…”
– William T. Cefalu, MD, Chief Scientific, Medical and Mission Officer of the ADA1
• Based on the Grade A evidence from the CREDENCE trial, the ADA living guidelines (updated on June 3, 2019)2 propose the following:
– “For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT2 inhibitor in patients with an eGFR ≥30 mL/min/1.73 m2 and particularly in those with >300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both.”
1. American Diabetes Association. http://www.diabetes.org/newsroom/press-releases/2019/updates-standards-medical-care-diabetes.html. Accessed June 5, 2019.2. American Diabetes Association. Standards of Medical Care in Diabetes–2019. http://care.diabetesjournals.org/content/42/Supplement_1. Last updated June 3, 2019. Accessed June 5, 2019.
Futuro de la enfermedad renal
diabética
Renal Clinical outcome trials in DKD on going
Trial Drug (class) n Main inclusión criteria
Trial status Renal outcome
Fidelio-DKD Finerenone 4800 Type 2 DM eGFR 25-75, macroalbuminruia. K<4.8
Ongoing.April 2020
Composite: >40% eGFR reduction, dScr, ESKD, renal death
DAPA-CKD Dapagliflozin 4000 eGFR 25-75, proteinuria Ongoing.Ends: Nov 2020
Composite: >50% eGFR reduction, dScr, ESKD, cardiovascular death, renal death
EMPA-KIDNEY
Empagliflozin 5000 eGFR 20-45 or 40-90 with albuminuria
OngoingEmds: June 2022
Composite: kidney disease progression (ESKD, eGFR <10, renal death, or ≥40% reduction in eGFR) or cardiovascular death)
*DKD: diabetic kidney diseaseModificado de: Muskiet M. Lancet Diabetes Endocrinol. 2018 Dec 19
Otros: aR GLP-1 (FLOW) , selonseertib, Imarikiren, …