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

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

3. 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),

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

5. Natural History of DM Nephropathy

6. Changing paradigm of albuminuria/decline gfr in DMII
MIPDS: 31% micromacro 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

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

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

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

10. 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; , 2001

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

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

15. Trends in diabetic complications
NEJM 370; , 2014
A National Health Interview Survey
B US Census Bureau

16. Trends in diabetic complications
NHIS DATA, #US adults with DM
(MILLIONS)

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

18. Metanalysis BP lowering outcomes in diabetes

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

20. 7020 pts, 3.1 yrs duration, all established cv disease, 1;1;1 10mg, 25mg, placebo
NEJM 375; , 2016

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

23. NEJM 375; , 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%

24. LEADER trial. NEJM 375; , 2016.

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

26. NEJM 375; , 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

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

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

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

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

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

32. 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