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 endstage 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 populationhave 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 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%

Percent

40

22%

20%

7%

20

4%

0
-20
-40

-60

-40%

Changes in

Incidence of

Incidence of

proteinuria

ESRD

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 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, Brchner-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

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 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 PPAR 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
RAPID
ACTING

Lispro (Humalog)
Aspart (Novolog)

ONSET

PEAK

DURATION

MAX DURATION

5 15
min

.5-1.5 hr

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

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, 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

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