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

• 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 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 Suppl 1 (May), 2004: pp S14-S15

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 medicationsused to treat

high blood pressure

ACES & ARBS are the two major

classes of medicationsused to treat

high blood pressure

Effect of ACE Inhibitorson Progression of CKD

Maschio. N Engl J Med. 1996;334:939.

Proteinuria is a powerful determinant of Proteinuria is a powerful determinant of renal deterioration.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

20%

-40%

37%

22%

7% 4%

-60

-40

-20

0

20

40

60

Changes in proteinuria

Incidence of ESRD

Incidence of mortality

Per

cen

t

PlaceboCaptopril

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 InvestigatorsEffects 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

• 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." ScienceDaily 5 June 2008. 10 March 2009 <http://www.sciencedaily.com /releases/2008/06/080605073804.htm>.

Sulfonylureas

Biguanides

Thiazolidinediones “Glitazones”

Meglitinides

DPP-4 Inhibitors

Incretin Memetics

Insulin

ADA Guidelines

TYPE NAME MECHANISM ROUTE, TIME

Sulfonylureas GlimepirideGlipizideGlyburide

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 – tidXR – po qd

Thiazolidinediones “Glitazones”

Rosiglitazone (Avandia)Pioglitazone (Actos)

PPAR gamma ligand – improves glucose utilization

Po qd

Meglitinides Repaglinide (Prandin)Nateglinide (Starlix)

Close K channel and open Ca channel in Beta cell – increasing insulin

Po 5 – 30 min AC

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 HgbA1c after 6

months• Action lasts additional 9 months with

thiazolidinedione• With sulfonureas HgbA1C 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• HgbA1C – 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

HgbA1C

• American Diabetic Association 7.0%• American Society of Clinical

Endocrinologist 6.5%• Many local endocrinologist 6.0%• CONTROVERSY: The lower the HgbA1C

the lower the risk of microvascular disease, but the higher the risk of hypoglycemia

PREPARATION ONSET PEAK DURATION

MAX DURATION

RAPIDACTING

Lispro (Humalog) 5 – 15 min

.5-1.5 hr 5 hr 4-6 hr

Aspart (Novolog)

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 24 hr

COMBINATIONS 70/30 NPH/Reg .5 to 1 hr Dual 10 -16 hr 14-18 hr

50/50 NPH/Reg

CONBINATIONANALOGUES

75/25 NPL/lispro 5 – 15 min

Dual 10 -16 hr 14-18 hr

70/30 NPL/aspart

Adapted from Hirsch IB, Edelman SV Practical Management of Type 1 Diabetes, PCI Book,, West Islip Ny (2005)

INSULININSULIN• 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

NORMALBDR

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, LachinJM, 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

– Rosiglitazone 11.6%– Placebo 26%

• Euglycemic – 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