Diabetic nephropathy 2018 Dr. Lawrence J. Smith Chief, Renal Division Southern Illinois University SOM

Pathology of DM nephropathy Natural History Epidemiology Cardiovascular Endpoints Novel Diabetes Type 2 Intervention Trials Recommendations

Pathology -GBM thickening onset 2-3 years post DM -Mesangial expansion onset 5-7 years, correlates with progressive gfr loss Pathology Alicic, R. Z., Rooney, M. T., & Tuttle, K. R. (2017). Diabetic Kidney Disease Challenges, Progress, and Possibilities. Clinical Journal of the American Society of Nephrology, 12(12), 2032-2045.

Advanced DM Glomerulopathy KimmeLstiel-Wilson nodular sclerosis gbm thickening, progressive mesangial expansion, intercapillay sclerosis

Natural History of DM Nephropathy

Changing paradigm of albuminuria/decline gfr in DMII MIPDS: 31% micromacro 7.8 years f/u 31% micronormo 38% remained micro UKDPS 15 years f/u 2% per year progress normomicro 2% per year progress micromacro 30% develop egfr<60 or doubling creat 60% of pts with declining gfr have NO preceding albuminuria The magnitude of Ualb excretion should be viewed as a continuum of CV risk

Lewis,E. NEJM1993; 329:1456-1462. Type 1 DM 22 year duration, htn, proteinuria. Captopril 25 mg tid vs. placebo.

Mean decline gfr 11vs.17%/yr. P=0.03.

ARB Treatment Type 2 DM Nephropathy 1513 pts, Uprot/creat>300mg Creat 1.3-3.0(1.9), age 60, htn RENAAL Trial. Brenner, BM NEJM 345: 861-869, 2001.

Age 59, BP 159/87 Creat 1.67, Ualb 1.9 gm per 24 hrs. Irbesrtan 300mg, amlodipine 10 mg, placebo. Adjusted relative risks Doubling creat 0.71arb vs. placebo P=0.009 End stage renal disease 0.83 arb vs. placebo P=0.19 Irbesartan Treatment Type 2 DM Nephropathy(IDNT) Lewis, E NEJM 345; 851-860, 2001

JAMA 305; 2532-2543, 2011 Definition of DKD -Ualb >30mg/gm creat and/or -gfr<60ml/min/1.73m2 CKD_EPI equation

Diabetic Kidney Disease NHANES III 1988-96 Prevalence and Mortality (10 year f/u 2006) JASN 24: 302-308, 2013

Trends in diabetic complications NEJM 370; 1514-23, 2014 A National Health Interview Survey B US Census Bureau

Trends in diabetic complications NHIS DATA, #US adults with DM (MILLIONS) 1990 2000 2010 6.53 11.80 20.67

Meta-analysis BP lowering outcomes in diabetes JAMA 313(6)603-615, 2015 Relative risk reduction per 10mm Hg SBP reduction

Metanalysis BP lowering outcomes in diabetes

GFR as a Predictor of CV Mortality NEJM 373; 1720-1732, 2015 Swedish National National Diabetes Register 01/1998-12/2011 Glycemic control Proteinuria - microalbuminuria 30-300 Renal function (egfr) MDRD equation (mg/g creat)

7020 pts, 3.1 yrs duration, all established cv disease, 1;1;1 10mg, 25mg, placebo NEJM 375;323-334, 2016

SGLT-2 inhibitor (sodium-glucose cotransporter-2) sbp 4-5mm/dbp1-2 mm hg difference

NEJM 375; 311-322, 2016 LEADER Trial 9340 pts, 3.8 yrs f/u. A1c 8.7 Age 64, duration dm 12.8 yrs Liraglutide(GLP-1 agonist) 1.78mg/day SQ vs. placebo Gfr <60 24 %, Ualb>30mg 11%

LEADER trial. NEJM 375; 311-322, 2016.

Primary composite outcomes Cv death, nonfatal MI, nonfatal stroke.

NEJM 375;1834-1844, 2016 Sustain-6 Trial (GLP-1 agonist) Semaglutide 0.5 mg, 1.0 mg/ Weekly(SQ) vs. placebo 1:1:1:1:1 3297 pts, 2.1 yrs duration BP difference sbp 5/ dbp 3

Benefit measured as development of new macroalbuminuria 44 vs. 81(HR 0 No benefit seen for doubling creat, esrd.

Mortality associated with use of sglt-2 inhibitors, glp-1 agonists and dpp-4 inhibitors for type 2 dM (JAMA 2018; 319(15): 1580-1591)

Mortality associated with use of sglt-2 inhibitors, glp-1 agonists and dpp-4 inhibitors for type 2 diabetes

Mortality associated with use of sglt-2 inhibitors, glp-1 agonists and dpp-4 inhibitors for type 2 diabetes

Heart failure associated with use of sglt-2 inhibitors, glp-1 agonists and dpp-4 inhibitors for type 2 diabetes

Conclusions: Diabetic Nephropathy Htn treatment with ACEI(type 1) and ARB(type 2) primary therapy (avoid combination rx as increased risks for aki, hyperkalemia) 2) Burden of cv disease/mortality exceeds the burden of CKD with albuminuria and reduced gfr recognized as strong indicators of cv disease/death. Novel therapies SGLT-2 inhibitors and GLP-1 agonists have demonstrated cardiovascular protection in large randomized, controlled trials. (CVOT) Dedicated DKD trials with novel therapies are underway. -CREDENCE(canagliflozin) terminated 7/2018 “efficacy” end points reached -CARMELINA(linagliptin) completed 01/2018 -REWIND(dulaglutide) CVOT plus secondary renal outcome-5 year duration