Download Diabetes

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
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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
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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
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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.
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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
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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
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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
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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.
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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
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Dietary protein restriction
Lipid lowering therapy
Partial correction of anemia
Vitamin D administration
How are we doing?
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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
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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
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≥ 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
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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
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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
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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
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
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4360 Patients with type 2 diabetes
Rosiglitazone, metformin, glyburide
Double blind randomized
Treated 4 years
Outcome – time to medial failure
Results
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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
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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
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Euglycemic
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Rosiglitazone 11.6%
Placebo 26%
Rosiglitazone 50.5%
Placebo 30.3%
Cardiovascular
Heart Failure
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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
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Beta blockers like propanolol
ACES
ARBS
Renin inhibitors
NSAIDS
Potassium sparing diuretics
Lowering Potasium
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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
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Lifestyle Modification
ACE inhibitor therapy
ARB therapy
Control Blood sugar
Control Blood pressure
Vitamin D
Titrate proteinuria