Diabetic Nephropathy Lance Sloan MD Stephen Fadem MD

Diabetic Nephropathy Lance Sloan, MD Stephen Fadem, MD

Objectives • Educate physicians and nurses on practical management tips for diabetes control. • Identify goals for diabetes therapy in patients with CKD with emphasis on prevention and medication side effects

At the end of this online presentation you should • Understand the relationship between diabetes and kidney disease • Know the difference between type 1 and Type 2 diabetes • Be familiar with some of the clinical trials that have shaped our progress • List key management objectives for Diabetes as it relates to progressive CKD • Be familiar with therapy for diabetes

Incidence ESRD due to Diabetes in Network 14 is 206/million Each year in Texas 206/million patients start dialysis because of diabetic nephropathy. Texas has the highest incidence in the nation. Source: USRDS

Diabetes is the main cause of ESRD

Predicted and actual cost adjusted by diagnosis Dialysis management of diabetic ESRD patients, particularly with heart failure Source: USRDS

Two Types of Diabetes • Type 1 – onset in youth, destruction of beta cells and a requirement for insulin • Type 2 – onset as adult or young adult, related to insulin resistance. May be treated with lifestyle modification, oral medications, and later may require insulin

Type 1 Diabetes – Insulin dependent/Juvenile onset – 20 to 30% develop microalbuminuria after 15 years • Amin, R, Widmer, B, Dalton, N & Dunger, DB: Unchanged incidence of Microalbuminuria in Children with Type 1 Diabetes since 1986: A UK based inception cohort. Arch Dis Child: adc. 2008. 144337, 2009. – Of the ones who develop this less than half progress to diabetic nephropathy – Associated with microvascular disease – retina and kidney. The increased sugar is neurotoxic – hence neuropathy – 2. 2 percent will develop ESRD in 20 years and 7. 8 percent in 30 years • Finne P, Reunanen A, Stenman S, et al. Incidence of end stage renal disease in patients with type 1 diabetes. JAMA 2005; 294: 1782 -1787.

Type 1 Diabetes (Continued) – The microalbuminuria can regress – and it is not always related to the use of ACE or ARB therapy • Perkins, BA, Ficociello, LH, Silva, KH, Finkelstein, DM, Warram, JH & Krolewski, AS: Regression of Microalbuminuria in Type 1 Diabetes. N Engl J Med, 348: 2285 2293, 2003 – The risk of developing kidney failure after 20 to 25 years in patients who have no proteinuria is low – Labile swings in blood sugar because of autonomic insufficiency – Always requires insulin – If diabetic nephropathy develops, the patient will develop insulin resistance – metabolic syndrome due to kidney disease. Atherosclerosis and hypertension are not primary but secondary events

Type 2 Diabetes • Common in Hispanics, Native Americans and Pima Indians • Incidence of ESRD is lower, but the disease is more frequent – thus it is the most common cause of renal failure • United Kingdom Prospective Diabetes Study – UKPDS – large British study, (predominantly Caucasians) – Adler, AI, Stevens, RJ, Manley, SE, Bilous, RW, Cull, CA & Holman, RR: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int, 63: 225 32, 2003. – Incidence of microalbuminuria 25% but incidence of ESRD only 0. 8% – Microlbuminuria patients spent an average of 11 years before progressing to overt proteinuria – Only 2. 3% progress from macroalbuminuria to ESRD

Type 2 Diabetes (Continued) • Disease progresses slowly over many years and is associated with proteinuria. The urine should show more than just red cells. • In the elderly, it is impossible to clinically distinguish the hypertensive and atherosclerotic effects from the diabetic effects without a kidney biopsy. • Not associated with labile blood sugar swings • Insulin resistance

Incidence of Type 2 Diabetes • • Doubled in past 20 years Framingham Offspring Study Related to Lifestyle Change and Obesity BMI Increase confirmed by NHANES Dataset – Source: American Heart Association • Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007 – Total: 23. 6 million people • 7. 8 percent of the population—have diabetes. • Diagnosed: 17. 9 million people • Undiagnosed: 5. 7 million people – Source: NIDDK

Metabolic Syndrome • Characterized by insulin resistance – 50 to 75 million Americans – – – High blood pressure High blood sugars High levels of triglycerides Low levels of HDL Increased waist line • It is associated with – Diabetes, Hypertension, stroke, cardiovascular disease • Dominant Features – Obesity, lack of exercise

Diet Plays a Major Role • The Sugar Fix – High fructose corn syrup • Decreases the ATP in cells – this decreases cell respiration and causes hypoxia in cells • Releases cytokines that impair nitrous oxide synthesis • Releases uric acid which increases blood pressure • Causes leptin resistance (Leptin turns off the appetite) continue to be hungry • Supersized – HFCS is in many soft drinks and other products • Americans eat more sugar, now have an epidemic of obesity, the metabolic syndrome, heart disease and diabetes

Management Objectives • Lifestyle – An aspirin a day – Smoking and Exercise – Weight/cholesterol • • Blood Pressure ACE and ARB Vitamin D Diabetes Control

Lifestyle - An aspirin a day - Smoking and Exercise - Weight/cholesterol • Can be a rewarding way to keep diabetes under control. • Requires a lifelong strategy • Diet: Avoid fructose, excess salt, trans fats and excess carbohydrates • Two alcoholic beverages at most/day • 25% incident diabetics are smokers – Potentiates kidney disease – Increases inflammation • Gentle aerobic exercise • Aspirin a day to reduce cardiovascular risk

ACE and ARB Blood Pressure Control

Blood pressure goal in CKD < 130/80 • Any person with abnormal kidneys is at risk for heart disease • Most patients will require two or more medications to control their blood pressure • Lowering the systolic blood pressure to <130 mm Hg is usually associated with a reduction in diastolic blood pressure to <80 mm Hg Adapted from American Journal of Kidney Diseases, Vol 43, No 5, Suppl 1 (May), 2004: pp S 14 -S 15

Many blood pressures medications may be needed to control severe blood pressure

Blood pressure is poorly controlled in patients with kidney disease

ACES & ARBS are the two major classes of medications used to treat high blood pressure

Effect of ACE Inhibitors on Progression of CKD Maschio. N Engl J Med. 1996; 334: 939.

Proteinuria is a powerful determinant of renal deterioration. Source: The New England Journal of Medicine -- November 12, 1998 -- Vol. 339, No. 20 Mechanisms of Disease: Pathophysiology of Progressive Nephropathies Giuseppe Remuzzi, Tullio Bertani

Collaborative Study Group – Reduction of proteinuria in Type 1 DM with ACE Placebo Captopril 60 37% 40 22% 20% Percent 20 7% 4% 0 -20 -40 -60 -40% Changes in proteinuria Incidence of ESRD Incidence of mortality Lewis EJ, et al. N Engl J Med. 1993; 329: 1456 -1462.

ARBS in Diabetes – The RENAAL Trial – (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) • Brenner. BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20; 345(12): 861 9. – – – Randomized, double blind, multicenter, placebo controlled Losartan Vs Placebo and conventional BP medications 1513 patients Outcome: Composite of doubling creatinine, ESRD, Death Followup 3. 4 years RESULT: Reduced doubling of creatinine by 25% and ESRD by 28%

ARBS in Diabetes IRMA • IRMA (Irbesartan Microalbuminuria) study – Parving HH, Lehnert H, Bröchner Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20; 345(12): 870 8 • • • multicenter, randomized, double blind, placebo controlled trial, randomized 590 patients with type 2 diabetic nephropathy (albuminuria) Randomized to irbesartan, 150 mg, 300 mg (Avapro) or placebo Blood pressure medications allowed Endpoint was overt nephropathy – a urine albumin at least 30% greater than baseline – – 10/194 (300 mg group) – reached endpoint 19/195 (150 mg group) – reached endpoint 30/201 (Placebo group) – reached endpoint Blood pressure unchanged

ARBS in Diabetes IDNT • IDNT (Irbesartan Diabetic Nephropathy Trial) – Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851 860. • • • Randomized, double blind, placebo controlled 1715 patients to irbesartan, amlodipine or placebo 2. 6 years BP therapy allowed (with exception on study drugs) Result: – Lowered risk of developing ESRD by 23%

What slows progression? • Proven interventions – Control blood sugar in diabetics – Strict blood pressure control – Certain meds: ACES (Angiotensin converting enzyme inhibition) and ARBS (angiotensin 2 receptor blockade) • Studied, but inconclusive – – Dietary protein restriction Lipid lowering therapy Partial correction of anemia Vitamin D administration

How are we doing? Elderly diabetic patients Medical insurance claims 65 years and older 30, 750 patients studied (58. 7% also had high blood pressure and/or protein in the urine) • Of these only 50. 7% (CI 50. 0 51. 4) received an ACE or ARB • • Am J Kidney Dis. 2005 Dec; 46(6): 1080 -7.

ACCOMPLISH TRIAL • • • Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial Has been stopped early – accomplished its goal benazepril plus amlodipine better than benazepril plus hydrochlorothiazide Study group – Hypertensives at risk secondary to previous events or diabetes 11, 464 patients – – – • • ≥ 55 years old BP ≥ 160 60. 4% with diabetes Obese Cardiovascular, renal disease or target damage 70% treated with two or more agents Only 37. 5% had blood pressure les than 140/90 Endpoints – cardiovascular morbidity MI, (stroke, unstable angina, bypass) or death ACE/amlodipine Risk reduced by 20% compared with ACE/diuretic – SOURCE: Presented by KA Jamerson, American College of Cardiology, March 31, 2008

Vitamin D

Vitamin D • Type 1 Diabetes in children might be prevented with vitamin D supplements and 5 – 10 minutes of noon sunlight • Epidemiology study • UCSD – SOURCE: University of California San Diego. "Sun Exposure And Vitamin D Levels May Play Strong Role In Risk Of Type 1 Diabetes In Children. " Science. Daily 5 June 2008. 10 March 2009 <http: //www. sciencedaily. com /releases/2008/06/080605073804. htm>.

Vitamin D Makes the News

Diabetes Control q. Sulfonylureas q. Biguanides q. Thiazolidinediones “Glitazones” q. Meglitinides q. DPP-4 Inhibitors q. Incretin Memetics q. Insulin

ADA Guidelines

Medications for Diabetes TYPE NAME MECHANISM ROUTE, TIME Sulfonylureas Glimepiride Glipizide Glyburide Increases insulin production through K channels of beta cells Po qd or bid Biguanides Metformin (Glucophage) Reduce hepatic glucose output and increase its muscle uptake Po bid – tid XR – po qd Thiazolidinedio nes “Glitazones” Rosiglitazone (Avandia) Pioglitazone (Actos) PPAR gamma ligand – improves glucose utilization Po qd Meglitinides Repaglinide (Prandin) Nateglinide (Starlix) Close K channel and open Po 5 – 30 min AC Ca channel in Beta cell – increasing insulin DPP 4 Inhibitors Sitagliptin (Januvia) Blocks, DPP 4 which catalyzes enzyme breaking down insulin 100 mg po qd Incretin Memetics Exenatide (Byetta) Stimulates beta cells and slows digestion 10 mcg sc 60 min AC AM and PM meal

SULFONYUREAS • First category of oral agents for diabetes – now in third generation • Mainly for type 2 diabetes – work on existing beta cells • Increase secretion of insulin by binding to potassium channels and opening calcium channels • Can cause hypoglycemia and weight gain

BIGUANIDES • Metformin used in obese type 2 diabetics • Maximum reduction in Hgb. A 1 c after 6 months • Action lasts additional 9 months with thiazolidinedione • With sulfonureas Hgb. A 1 C tends to increase • Reduced cardiovascular risks – Pharmacotherapy. 2007 Aug; 27(8): 1102 10. Loss of glycemic control in patients with type 2 diabetes mellitus who werereceiving initial metformin, sulfonylurea, or thiazolidinedione monotherapy. Riedel AA, Heien H, Wogen J, Plauschinat CA.

ROSIGLITAZONE • Controversy regarding risk of causing MI – Odds ratio 1. 43 • • ADOPT – increased fractures Associated with macular edema Stimulates the PPARγ receptor Not to be used in heart failure – Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007; 356(24): 2457 2471.

INCRETIN MIMETICS • Exenatide (Byetta) • From the saliva of the gila monster • Incretin – mimetic – Enhances beta cell insulin – Blocks glucagon – Delays gastric emptying • Injection sub cutaneously 30 to 60 minutes before first and last meal – adjunctive therapy • Side effects – Gastrointestinal symptoms • FDA warning – pancreatitis – may be fatal

WHEN TO START INSULIN • Start with oral agents (metformin) and proceed to insulin if goal is not achieved • May be able to manage for up to 6 years • Hgb. A 1 C – use a target • In kidney patients and those who may be operating heavy machinery – because of the risk of hypoglycemia – may want to have a higher goal • Mono duo triple therapy – disease has advanced

Hgb. A 1 C • American Diabetic Association 7. 0% • American Society of Clinical Endocrinologist 6. 5% • Many local endocrinologist 6. 0% • CONTROVERSY: The lower the Hgb. A 1 C the lower the risk of microvascular disease, but the higher the risk of hypoglycemia

INSULIN

INSULIN PREPARATION RAPID ACTING Lispro (Humalog) Aspart (Novolog) ONSET PEAK DURATION MAX DURATION 5 – 15 min . 5 1. 5 hr 4 6 hr Glulisine (Apidra) SHORT Regular . 5 – 1 hr 2 – 3 hr 5 – 8 hr 6 – 10 hr INTERMEDIATE NPH (isophane) 2 – 4 hr 4 10 hr 10 16 hr 14 18 hr Lente (zinc) 2 – 4 hr 4 12 hr 12 18 hr 16 20 hr LONG Ultralente 6 – 10 hr 10 16 hr 18 24 hr 20 14 hr LONG ANALOGUE Glargine (Lantus) 2 – 4 hr No Peak 20 24 hr COMBINATIONS 70/30 NPH/Reg . 5 to 1 hr Dual 10 16 hr 14 18 hr 5 – 15 min Dual 10 16 hr 14 18 hr 50/50 NPH/Reg CONBINATION ANALOGUES 75/25 NPL/lispro 70/30 NPL/aspart Adapted from Hirsch IB, Edelman SV Practical Management of Type 1 Diabetes, PCI Book, , West Islip Ny (2005)

INSULIN • Glucose homeostasis declines – – Loss of post prandial glycemic control – Decline in control around breakfast – Nocturnal Hyperglycemia • Consider prandial insulin before starting basal insulin • Basal insulin typically started in type 2

Diabetes and the eye • Type 1 – Almost always have retinopathy and neuropathy by the time they develop nephropathy, but many patients with retinopathy do not have nephropathy – Detected clinically by the doctor or opthalmologist • Type 2 – Retinopathy will likely be accompanied by nephropathy – If no retinopathy is present, they may have something other than diabetic nephropathy

Background Diabetic Retinopathy NORMAL BDR

ADOPT A Diabetes Outcome Progression Trial • • • 4360 Patients with type 2 diabetes Rosiglitazone, metformin, glyburide Double blind randomized Treated 4 years Outcome – time to medial failure Results – – • Monotherapy at five years – when compared with metformin 32% risk reduction with rosiglitazone 63% risk reduction with glyburide Better blood sugar control with glitazone N Engl J Med. 2006 Dec 7; 355(23): 2427 -43. Epub 2006 Dec 4. . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin. JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group.

DREAM • • • Lancet. 2006 Sep 23; 368(9541): 1096 105. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Multicenter – RCT – Rosiglitazone v placebo – follow up median of 3 years Primary Outcome – Composite – incident diabetes or death Type Intent to treat GOAL: prevent type 2 diabetes in high risk patients 5269 adults ≥ 30 years old with abnormal glucose tolerance, no prior CV diease Composite reached – – • Euglycemic – – – • Rosiglitazone 11. 6% Placebo 26% Rosiglitazone 50. 5% Placebo 30. 3% Cardiovascular Heart Failure – – Rosiglitazone 0. 5% Placebo 0. 1%

Common Medications to avoid in CKD • NSIADS – Ibuprofen (Motrin) – Indomethacin (Indocin) – Naproxen (Aleve, Anaprox, Naprosyn) – (Celecoxib) Celebrex – (Rofecoxib) Vioxx • METFORMIN – Glucophage, Diaformin

DRUGS THAT RAISE POTASSIUM • • • Beta blockers like propanolol ACES ARBS Renin inhibitors NSAIDS Potassium sparing diuretics

Lowering Potasium • • • Glucose and insulin Albuterol Kayexalate Loop diuretics Thiazide diuretics

Hardening of the Arteries • Vascular Calcification – Potentiated by metabolic syndrome and kidney disease – Accumulation of phosphorus with decreased bone turnover in CKD associated with the metabolic syndrome potentiates changes in cells inside blood vessel walls – These vessels accumulate phosphorus and calcium – leading to vascular calcification – Common in diabetes and in CKD

Diabetes Complications • Vascular Disease – Peripheral vascular disease – Amputations • Autonomic insufficiency – Gastroparesis – Postural hypotension – Bladder dysfunction • Neuropathy – Charcot Joints – Burning Neuropathy

Impact of diabetes on dialysis blood pressure management • Autonomic insufficiency – BP drops and very labile • Medial Calcification – Wide Pulse Pressure • Hypertensive cardiomyopathy – Preload – Cardiac function – Afterload

Summary of prevention • • Lifestyle Modification ACE inhibitor therapy ARB therapy Control Blood sugar Control Blood pressure Vitamin D Titrate proteinuria

The End