Early Management of Diabetic Kidney Disease Mark E. Molitch, MD Saturday, March 5, 2016 8:45 a.m. – 9:30 a.m.

At present, 44% of the patients developing end stage renal disease (ESRD) in the U.S. have diabetes as its cause (1) and this number is climbing, primarily because the number of people with diabetes is increasing. However, the overall proportion of diabetic patients developing ESRD has decreased progressively and substantially since 1996 (2). This decrease is due to 3 things: (1) the markedly improved glycemic control of patients over this time; (2) better hypertension management; and (3) use of drugs that block the renin-angiotensin-aldosterone (RAAS) system. In the 1960’s, about one-third of patients developed ESRD by about 30 years duration of diabetes (3). Recently, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study showed that the cumulative incidences of ESRD were only 1% in the prior Intensive Group and 2% in the prior Conventional Group in subjects who had mean diabetes durations of 28 years (4). Control of these factors also improves cardiovascular disease (CVD) outcomes as well and patients with diabetic CKD have a much higher risk of CVD than those without CKD (5,6).

Glycemic control, with an A1c target of ~7%, is the only modality shown to prevent/delay the onset of nephropathy as well as retard progression of established chronic kidney disease (CKD) (7). However, as CKD progresses, alterations in become important and the risk of hypoglycemia increases (8). doses need to be reduced. When the eGFR is < 60 ml/min/1.73m2, glyburide, nateglinide, and should be stopped. At 45-50 ml/min/1.73m2, , miglitol, , and should be stopped and the doses reduced for , , , and . At 30 ml/min/1.73m2, metformin, and should be stopped and the doses reduced further for Sitagliptin and alogliptin. The , , , dulaglitide, and can be used at all stages of CKD (8).

Albuminuria and reduced eGFR independently and additively increase CVD risk, even at the earliest stage of microalbuminuria (5,6). Although glycemic control may improve mortality modestly (9), hypertension and lipid control have greater importance in reducing CVD, especially in those with type 2 DM (8,10). Hypertension develops in over 80% of diabetic patients with CKD. Hypertension control is very important as CKD progresses and the BP target should be < 140/90 mmHg (8,10). Although lower BP levels results in further CKD benefits and cerebrovascular disease, there are no further benefits in CVD and even the potential for harm (11). Often it takes multiple drugs to bring BP under control, especially as CKD advances (10). The initial antihypertensive drug should generally be an angiotensin converting enzyme (ACE) inhibitor or an aldosterone receptor blocker (ARB). Several studies have shown that these RAAS blockers may retard progression of CKD over and above their antihypertensive effects (8,10,11). Whether they should be started in the normotensive individual with only microalbuminuria is controversial, as many studies have now shown that as many individuals with microalbuminuria revert to normal albuminuria as progress to macroalbuminuria even without use of RAS blockers (12).

Lipid management is also important. The presence of microalbuminuria or a reduced GFR can be considered major CVD risk factors (probably greater than smoking) and would provide strong rationale for starting a statin. Although most of the large studies excluded patients with CKD, those that did showed that statins lower CVD outcomes as much as in patients without CKD, except for patients who have progressed to dialysis (8,10). Thus, a multi-pronged approach is necessary for the well-being of patients with diabetes, with and without CKD, as has been shown in the Steno Study (13).

References:

1. U.S. Renal Data System. USRDS 2014 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2014. 2. Burrows NR, Li Y, Geiss LS. Incidence of treatment for end-stage renal disease among individuals with diabetes in the U.S. continues to decline. Diabetes Care 2010;33;73-77. 3. Krolewski AS, Warram JH, Christleib AR, Busick EJ, Kahn CR. The changing natural history of nephropathy in type 1 diabetes. Am J Med 1985;78:785-794. 4. DCCT/EDIC Research Group (Writing Group: DeBoer IH Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Zinman B. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011;365:2366-2376. 5. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJL, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012;380:1662–1673. 6. Afkarian M, Sachs MC, Kestenbaum B et al. Kidney disease and increased mortality risk in . J Am Soc Nephrol 2013;24:302-308. 7. DeBoer IH for the DCCT/EDIC Research Group. Kidney disease and related findings in the DCCT/EDIC Study. Diabetes Care 2014;37:24-30. 8. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, deBoer IH, Goldstein-Fuchs J, Hirsch IB, Kalantar-Zadeh K, Narva AS, Navaneethan SD, Neumiller JJ, Patel UD, Ratner RE, Whaley-Connell AT, Molitch ME. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37:2864-2883. 9. DCCT/EDIC Research Group. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313(1):45-53. 10. Molitch ME, Adler AI, Flyvbjerg A, Nelson RG, So W-Y, Wanner C, Kasiske BL, Wheeler DC, de Zeeuw D, Mogensen CE. Diabetic Kidney Disease‒ A clinical update from Kidney Disease: Improving Global Outcomes. Kidney International. 2015;87(1):20-30. 11. Mancia G, Grassi G, Zanchetti A. Antihypertensive treatment and blood pressure in diabetic and nondiabetic patients. The lower, the better? Diabetes Care 2011;34(Suppl 2):S304-S307. 12. DeBoer IH, Rue TC, Cleary PA, Lachine JM, Molitch ME, Steffes MW, Sun W, Zinman B, Brunzell JD for the DCCT/EDIC Study Research Group. Long-term renal outcomes of patients with type 1 13. diabetes and microalbuminuria: an analysis of the DCCT/EDIC cohort. Arch Intern Med 2011;171:412-420 14. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-91

Early Management of Diabetic Kidney Disease Mark E. Molitch, M.D. Disclosures • Financial 63rd Annual Advanced Postgraduate Course • Research support from Novartis, Novo American Diabetes Association Nordisk, Bayer • Consulting with Pfizer, Novartis, Novo San Francisco, CA Nordisk, Lilly, Merck, Janssen

March 5, 2016

Mark E. Molitch, M.D. Division of Endocrinology, Metabolism & Molecular Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois

Incident counts & adjusted rates, Incidence of Diabetic End-Stage Renal Disease per by primary diagnosis 100,000 People with Diabetes, U.S., 1980 – 2008 We are making a difference!

Incident ESRD patients; rates adjusted for age, gender, & race.

USRDS - 2008 National Diabetes Surveillance System, U.S. Renal Data System, National Health Interview Survey

Risk Categories for Kidney and Mortality Outcomes

Levey AS et al. Ann Intern Med. 2011;154(1):65-67 Primary & Secondary GFR Nephropathy Outcomes in DCCT/EDIC

Number of Events Relative Risk Reduction

Microalbuminuria eGFR Intensive Conventional Risk P-value > 40 mg/24 h Microalbuminuria Category Therapy Therapy Reduction > 40 mg/24 h (%, 95% CI) eGFR < 60* 24 46 50 (18, 69) 0.006 Albuminuria > 300 mg/24 h Albuminuria eGFR < 45 24 39 40 (1, 64) 0.045 > 300 mg/24 h eGFR < 30 13 23 44 (-9, 72) 0.088 ESRD 8 16 51 (-14, 79) 0.098 eGFR <60 or 53 80 37 (10, 55) 0.011 Primary Prevention Secondary Intervention death * Sustained eGFR < 60 mL/min/1.73m2 (primary outcome of this study) DCCT Research Group Risk reduction is relative difference in risk of impaired GFR (in percent) NEJM 1993;342:381 comparing intensive to conventional diabetes therapy

DeBoer et al., NEJM 2011;365:2366

Annual Transition Rates In Patients with 10-Year Excess Mortality in Type 2 Diabetes by Type 2 Diabetes in the UKDPS Kidney Disease Status in NHANES III (n=15,046) 1.4% No Nephropathy 2.0% 3.0% Microalbuminuria 2.8% Death 4.6% Albuminuria

2.3% 19.2% Elevated Creatinine or Renal Replacement Rx

2 Adler et al., Kidney Intl 2003;63:225 Impaired GFR = <60 ml/min/1.73m Afkarian M et al., JASN 2013;24:302

Albuminuria and Decreased GFR have Additive Risks for Cardiovascular Glycemic Management in the Disease in Diabetes: Potential Links Patient with Progressing CKD • Common Genetic Predisposition • Endothelial Dysfunction • Associated Hypertension • Insulin Resistance • Atherogenic Dyslipidemia • • Volume overload Use in CKD • Glyburide , and CKD – Glyburide clearance not affected but renal clearance of metabolites is reduced with CKD • Nateglinide does not accumulate – Risk of hypoglycemia high with CKD and should not be used with CKD but metabolite M1 is with eGFR < 60 metabolically active and its clearance • Glimepiride is greatly delayed with CKD – Glimepiride clearance not affected but renal clearance of metabolites is reduced with CKD – Nateglinide should not be used for 2 – Risk of hypoglycemia increased and should be used with eGFR < 60 ml/min/1.73m caution with eGFR < 60 and avoided with eGFR < 30 • Repaglinide does not accumulate • Glipizide and no dose change is needed in – Less than 10% renally cleared – Use with caution with eGFR < 30 CKD

Balant et al., Diabetologia 1973;9:331 Holstein et al., Eur J Clin Pharmacol 2003;59:91 Nagai et al., Diab Res Clin Pract 2003;59:191 Rosencranz et al., Diabetologia 1996;39:1617 Ferreira et al., Diabetes Care 2012 doi:10.2337/dc12-1365/-/DC1 Inoue et al., Clin Nephrol 200360:90

Metformin Dosing What to Do? Thiazolidinediones and CKD eGFR (ml/min/1.73m2 Metformin Dosing • and >60 No limitation of dosing – Clearance not affected by kidney function > 45 – <60 Caution with dosing Monitor eGFR every 3 – 6 mos • No dose reduction needed in CKD > 30 - <45 Maximum dose 1000 mg/day – Potential problems with fluid retention Monitor eGFR every 3 – 4 mos – Bone disease - ? Additive to renal osteodystrophy < 30 Stop metformin – Slight increased risk of bladder cancer (??) • Stop metformin in inpatients if: – Unstable – Hypotensive – Hypoxic – Septic – Acute worsening of renal function Budde et al., Br J Clin Pharmacol 2003;55:368 Colmers et al., CMAJ 2012;184:E675 Lipska et al., Diabetes Care 2011;34:1431 Panchapakesan et al., Nephrology 2009;14:298 Betteridge, Diabetic Medicine 2011;28:759 KDIGO Controversies, In preparation

Alpha-Glucosidase Inhibitors Acarbose and Miglitol Incretins • GLP-1 receptor agonists • Acarbose - Minimal absorption with < 2% of drug and active metabolites – Exenatide – discontinue for eGFR < 30 appearing in urine – Liraglutide – no dose adjustments - Package insert states that in patients with eGFR < 25 ml/min/1.73m2, the peak concentration is increased 6x and the – – no dose adjustments AUC is increased 5X but no long-term trials in patients with – Albiglutide – no dose adjustments serum creatinine > 2 mg/dL - Should not be used if serum creatinine > 2 mg/dL • DPP4 Inhibitors

• Miglitol Sitagliptin Saxagliptin Alogliptin - 50-70% absorption with >95% excreted in urine GFR > 50 100 mg/d 5 mg/d 25 mg/d 5 mg/d - Package insert states that in patients with eGFR < 25 ml/min/1.73m2, the peak concentration is increased 2x and no GFR 30 – 50 50 mg/d 2.5 mg/d 12.5 mg/d 5 mg/d long-term trials in patients with serum creatinine > 2 mg/dL GFR < 30 25 mg/d 2.5 mg/d 6.25 mg/d 5 mg/d - Should not be used if serum creatinine > 2 mg/dL Primary outcome: SGLT2 Inhibitors 3-point MACE

• Increase urinary glucose excretion, thereby HR 0.86 (95.02% CI 0.74, 0.99) lowering blood glucose p=0.0382* • Less effective with eGFR < 60 ml/min/1.73m2 • Possibly more adverse effects (volume loss, hyperkalemia) with eGFR < 45 ml/min/1.73m2 – For eGFR < 60 ml/min/1.73m2, Canagliflozin should be kept at 100 mg/day and higher dose (300 mg) avoided – Canagliflozin and Empagliflozin currently not approved for use with eGFR <45 ml/min/1.73m2 – Dapagliflozin not approved for use with eGFR < 60 3 ml/min/1.73m Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498) 20

Empa-Reg: Kidney Outcomes Empa-Reg: Kidney Outcomes

• Entire study: Empagliflozin 4687 subjects Placebo 2333 subjects – Outcome of Doubling of Creatinine, ESRD, or Renal Death: HR 0.54, p,0.0002 – Outcome of new-onset or worsening of nephropathy: HR 0.61, p<0.001 A Empagliflozin Placebo HR No. subjects with eGFR <60 1212 607 (ml/min/1.73m2) Primary Outcome (MACE 3) 171 (15%) 99 (16% 0.88 All Cause Mortality 115 (9%) 72 (12%) 0.80 Cardiovascular Death 75 (6%) 48 (8%) 0.78 MACE 3: Cardiovascular death, MI, Stroke

Wanner et al. Presented at Am Soc Nephrology Meeting, San Diego, Nov. 2015 Wanner et al. Presented at Am Soc Nephrology Meetings, San Diego, Nov. 2015

Glycemic Management in CKD: Summary • eGFR < 60 ml/min/1.73m2: – Reduce dose of canagliflozin, stop dapagliflozin Blood Pressure – Avoid glyburide • eGFR < 45 ml/min/1.73m2: – Reduce doses of Insulin – Reduce doses of metformin, sitagliptin, saxagliptin, alogliptin – Restrict to glipizide – Stop acarbose, miglitol, nateglinide, canagliflozin, & empagliflozin • eGFR < 30 ml/min/1.73m2: – Stop metformin and exenatide – Reduce doses of sitagliptin, saxagliptin, alogliptin further Relative Risk of Reaching a Renal End Point (doubling of Relative Risk of Reaching serum creatinine or SCr > 6.0 or RRT) by Level of Achieved a Renal End Point SBP in the Irbesartan Diabetic Nephropathy Trial (IDNT) (doubling of serum creatinine or SCr > 6.0 or RRT) and All Cause Mortality by Level of Achieved SBP in the Irbesartan Diabetic Nephropathy Trial (IDNT)

Pohl et al., JASN 2005;16:3027 Pohl et al., JASN 2005;16:3027

Relative Risk of Reaching a Renal End Point ACCORD BP Study: (doubling of serum Primary and Secondary Outcomes creatinine or SCr > 6.0 or • Patients with T2D and hypertension (N = 4733) RRT) and All Cause • Random assignment Mortality by Level of – Intensive therapy: target SBP < 120 mm Hg Achieved SBP in the – Standard therapy: target SBP < 140 mm Hg Irbesartan Diabetic • 1° outcome: nonfatal MI, nonfatal stroke, death from CV causes Nephropathy Trial (IDNT) • Mean follow-up = 4.7 y Outcome Intensive Standard HR P-value SBP after 1 year (mmHg) 119.3 133.5 NR NR 1° outcome (annual rate) 1.87 2.09 0.88 .20 Death from any cause 1.28 1.19 1.07 .55 (annual rate) Stroke (annual rate) 0.32 0.53 0.59 .01 AEs (rate) 3.3 1.3 NR <.001

Pohl et al., JASN 2005;16:3027 ACCORD Study Group. N Engl J Med2 010;362:1575-85 INVEST: Cumulative Event Rate for Primary Outcome INVEST Study – Secondary Analysis in (first occurrence of all-cause mortality, nonfatal MI or stroke) Subjects with Type 2 Diabetes

• 6400 subjects with type 2 DM and CAD over age 50

• Treated with Verapamil or Trandolapril followed by an >140 ACE inhibitor, a diuretic or both to achieve BP < 130/85 <130 130-140 • Current analysis compared: − “Tight” control - SBP < 130 (n=2175) − “Usual” control – SBP 130-140 (n=2255) − “Uncontrolled” – SBP > 140 (n=1970) • Primary Outcome: first occurrence of all-cause mortality, nonfatal MI or nonfatal stroke

Cooper-DeHoff, R. M. et al. JAMA 2010;304:61-68 Cooper-DeHoff, R. M. et al. JAMA 2010;304:61-68.

INVEST: Adjusted Risk of All-Cause Mortality ONTARGET: Relationships Between Outcome Risks and In-Trial BP 30 3 Interval 95% Confidence HR, Primary study outcome

25 2.5

20 2

15 1.5

10 1

Adjusted 4.5-y Risk 4.5-y Adjusted (%) Events of 5 0.5

0 0 112 121 126 130 133 136 140 144 149 161 In-treatment SBP, deciles (mmHg) • 25,620 subjects, 38% with diabetes • Primary Outcome: Composite of CV death, MI, stroke, or hosp for CHF • J-shaped curve (nadir ≈ 130 mm Hg) for primary outcome minus stroke • Continual risk increase (no J-shaped curve) for stroke • Suggests increased risk of events in patients with extensive vascular disease when BP is decreased below a critical level Cooper-DeHoff, R. M. et al. JAMA 2010;304:61-68. Sleight P, et al. J Hypertens. 2009;27:1360.

ADA Standards of Care BP Guidelines • Blood Pressure Targets ‒ Systolic < 140 ‒ Diastolic < 90 ‒ <130/80 mmHg may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden • Treatment ‒ Confirmed BP > 140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely subsequent titration of pharmacological therapy to achieve blood pressure goals.

Diabetes Care 2016;39(Suppl 1):S60-S71 4D Study: Primary Composite End Point (Cardiac Death, Nonfatal MI & Stroke) Atorvastatin in Diabetic Dialysis Patients 60 Relative Risk Reduction 8 % Placebo 50 (95 % CI: 0.77-1.10, P=0.37)

40 Atorvastatin 30

20 Placebo Atorvastatin

Cumulative incidence(%) 10

0 0 12345 5.5 years Years from Randomization Placebo 636 532 383 252 136 51 29 Atorvastatin 619 515 378 252 136 58 19 Median follow-up time of 4 years Wanner et al., NEJM 2005;353:238

Aurora Study SHARP: Major Atherosclerotic Events by renal status at randomization

Eze/simv Placebo Risk ratio & 95% CI (n=4650) (n=4620)

Non‐dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246(16.5%) Any patient 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4 Eze/simv Placebo better better 2776 Patients with ESRD (19.2% with DM) assigned to Rosuvastatin 10 mg 23% with Diabetes vs. Placebo, Primary Endpoint: CVD death, nonfatal MI or nonfatal stroke

43% reduction in LDL Fellstrom B et al. N Engl J Med 2009;360:1395-1407

Steno-2: Multifactorial Intervention and CVD Summary of Lipids and CKD in Type 2 DM • Patients with diabetes and CKD are at very INTENSIVE THERAPY high risk of CVD  Dietary intervention • CVD events can be significantly reduced with statins in patients with diabetes • Total fat <30% calories • CVD events can be significantly reduced with • Saturated fat <10% calories statins in patients with CKD prior to dialysis  Exercise: 30 min 3-5x/w • CVD events cannot be reduced with statins  Smoking cessation in patients with diabetes undergoing dialysis  All prescribed ACE-I/ARB – Reasons remain unclear - ? CVD too far progressed?  Glycemic control: Metformin/SU/insulin • CVD events can be reduced with statins in  Hypertension: ACE-I /ARB/diuretics/CCA/BB patients following renal transplantation  Lipid: Statins/fibrates • Risks of rhabdomyolysis with statins are low - <0.1% Gaede P et al. N Engl J Med. 2003;348:383-93. stroke, amputation, or surgery for peripheral arterial disease. arterial peripheral for or surgery amputation, stroke, nonfatal PCI, MI, CABG, nonfatal CVcauses, from of death endpoint Composite Steno-2: Multifactorial Interventionand Steno-2: • • • •

the Patient is Referred to the Nephrologist? is Referredtothe the Patient Primary composite Transplantation (if kidney only) and Peritoneal Dialysis: Hemo- diabetes of of othercomplications management Continued management Continued glucose What is the Role of the Diabetologist Once What istheRoleofDiabetologist – – – – – – – endpoint (%) Dyslipidemia disease Macrovascular Retinopathy Worsened glucosecontrol to managetheglucose! how knows Nobody Neuropathy, periphe andhypoglycemia hyper- The nephrologistnothavedoes 30 60 10 20 40 50 0 • • • • Cyclosporine Sirolimus Tacrolimus Glucocorticoids 0 True Co-management Is Needed True Co-management 2 96 12 CVD inTypeDM 2 HR = 0.47 (95 % CI, 0.24 - 0.73; 0.73; - 0.24 CI, %(95 0.47 = HR 24 Thank You Conventional Follow-up (mo) Follow-up ral and autonomic ral and Therapy 36 P=.008) with immunosuppressive agents immunosuppressive with 48 Gaede Pet al. our expertise in managing Intensive Therapy 60 72 N Engl J Med 84 . 2003;348:383-93. • • • • • • • • • • • When toRefer to theNephrologist nephrologist with diabetes Continue toco-manage progresses to nephrologistasdisease Refer Treat 2 dyslipidemia andBPaggressivelyManage of ACEinhibitors andARBsand use CVD with BP glycemic, and lipidcontrol Delay progression of nephropathy and control Prevent nephropathy with glycemic are progressing Lack of comfort in dealing with as theyproblems ml/min/1.73m 30 approaching GFR Rapidly falling GFR Blood difficult to pressure 3 control despite drugs nephropathy If concern about diagnosis of diabetic – – – – – – – – – Hyperkalemia Fluid Retention Blood Pressure Anemia Secondary Hyperparathyroidism Active sediment Disproportionate proteinuria No albuminuria No retinopathy o hyperparathyroidism and anemia Summary 2