Transcript Update on clinical diabetes in older veterans Kristina Utzschneider, MD Assistant Professor of Medicine VA Puget Sound Health Care System and the University of Washington February.

Update on clinical
diabetes in older veterans
Kristina Utzschneider, MD
Assistant Professor of Medicine
VA Puget Sound Health Care System and the University of
Washington
February 25, 2008
Disclosure statement
I have nothing to disclose
An epidemic on the way
30
Prevalence
diabetes
(percent)
NHANES 1999-2002
2011
2021
2031
25
20
15
10
5
0
20-29
Mainous et al, Diabetologia 50:934, 2007
30-39
40-49
50-59
Age (years)
60-69
≥70
The burden of diabetes in the VA
health care system
Prevalence of diabetes in the VA system:
16% VA vs. 7.2% US general population
6.8 million veterans were enrolled to receive VA care in 2002
4.5 million enrolled veterans made 46.5 million outpatient visits
564,700 veterans were hospitalized in VA medical centers in 2002
Diabetes was the third most common VA diagnosis
Diabetes accounted for 25% pharmacy costs and >1.7 million
hospital bed days
Reiber et al, Diabetes Care 27: B3, 2004
Complications of diabetes
Increased mortality
Microvascular complications
Retinopathy
Nephropathy
Neuropathy
Macrovascular complications
Cardiovascular disease
Diabetic complications: burden of illness
Approximately 12 million adults age ≥40 years have
diabetes in the United States
32.7% have symptoms of diabetic peripheral neuropathy
27.4% have diabetic retinopathy
13.1% have comorbid neuropathy and retinopathy
Candrilli et al, Journal of Diabetes and its Complication 21:306-314, 2007
In 2005 485,012 people in the United States had end
stage renal disease (ESRD)
Over 30% ESRD due to diabetes:
Type 1: 27,714 patients
Type 2: 150,875 patients
U.S. Renal Data System, USRDS 2007 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, 2007.
Can we prevent diabetes?
Diabetes Prevention Program
(DPP)
Screen
Randomize
Standard lifestyle teaching
Intensive
Lifestyle
(n = 1079)
Metformin
(n = 1073)
Placebo
(n = 1082)
Diabetes Prevention Program Research Group, Diabetes Care 22:623-34, 1999
Troglitazone
n= 585
Until 6/98
Weight change (Kg)
DPP: Average weight change
+1
0
-1
-2
-3
-4
-5
-6
-7
-8
Placebo
Metformin
Lifestyle
0
6
12
18
24
30
36
Months in study
Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002
42
48
Cumulative incidence (%)
Percent of subjects developing diabetes
Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
40
Metformin (n=1073, p<0.001 vs. Plac)
Placebo
Placebo (n=1082)
30
Metformin
20
Lifestyle
10
0
0
1
2
Years in study
Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002
3
4
Cases/100 person-yr
Diabetes incidence rates by age
15
Lifestyle
Metformin
Placebo
12
9
6
3
0
25-44
(n=1000)
45-59
(n=1586)
Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002
>60
(n=648)
Can we prevent diabetes
complications?
Glycemic Control in the UKPDS
9
8
Patients followed for 10 years
Conventional
Intensive
Median
HbA1c (%)
All patients assigned to regimen
7
ADA Goal
6
0
0
3
6
9
12
15
Time from Randomization (y)
UKPDS Group. Lancet: 352:837-853; 1998
Conventional
Intensive
Effect of Glycemic Control in the UKPDS
Endpoints
Intensive Conventional
(rate/1000
(rate/1000
pt yrs)
pt yrs
%
p value
Decrease
Any diabetes related *
40.9
46
11
0.029
Microvascular
8.6
11.4
25
0.0099
Myocardial Infarction
14.7
17.4
16
0.052
Stroke
5.6
5.0
-
0.52
PVD
1.1
1.6
-
0.15
* Combined microvascular and macrovascular events
UKPDS Group: Lancet 352:837–853; 1998
Effect of 1% Decrease in A1c on Diabetes-related
Complications - UKPDS Observational Analysis
Any
diabetes- DiabetesAll
Peripheral Microrelated
related
cause Myocardial
vascular vascular Cataract
endpoint death mortality infarction Stroke disease† disease extraction
%
Decrease in
Relative Risk
21%
21%
**
**
14%
14%
**
**
12%
*
19%
**
37%
43%
**
†Lower
extremity amputation or fatal peripheral vascular disease
*p = 0.035; **p < 0.0001
UKPDS Group - UKPDS 35: Br Med J 321:405-412; 2000
**
DCCT – glycemic control
11
Conventional
10
9
Glycosylated
hemoglobin (%)
8
7
Intensive
6
5
0
1
2
3
4
5
6
7
8
Year of Study
Total 1441 patients with IDDM enrolled
Mean 6.5 years follow-up
Diabetes Control and Complications Trial Research Group, NEJM 329:977-986, 1993.
9
10
DCCT – retinopathy
Primary prevention
Secondary prevention
Diabetes Control and Complications Trial Research Group, NEJM 329:977-986, 1993.
DCCT: retinopathy progression by
HbA1c and years of follow-up
Mean HbA1c = 11%
24
10%
9%
20
Conventional treatment
16
Rate/100
person-years 12
8
8%
4
7%
0
0
1
2
3
4
5
6
7
Time during study (years)
Diabetes Control and Complications Trial Research Group, Diabetes 44: 968-983, 1995.
8
9
DCCT: Results summary
Improved glycemic control reduced the risk of
clinically meaningful:
Relative risk reduction
Retinopathy
Nephropathy
Neuropathy
Cardiovascular events
76%
54%
60%
78%
Diabetes Control and Complications Trial Research Group, NEJM 329:977-986, 1993.
Diabetes Control and Complications Trial Research Group, Am J Cardiol 70:894-900, 1995.
p≤0.002
p<0.04
p≤0.002
p=0.065
Glycosylated hemoglobin (%)
DCCT/EDIC
DCCT Intervention
11
Training EDIC observation
Conventional
10
9
8
7
Intensive
6
5
0
1
2
3
4
5
6
7
8
9
Study year
DCCT/EDIC Study Research Group: N Engl J Med 353:2643–2653; 2005
1
2
3
4
5
6
7
Prior intensive glycemic control decreases
subsequent CVD events in type 1 diabetes
0.12
Conventional Rx: 98 events in 52 patients
Intensive Rx: 46 events in 31 patients
0.10
Cumulative
incidence
of any
predefined
CV outcome
RRR = 42% (95% CI 9-63); p=0.02
0.08
0.06
0.04
0.02
0.00
0
2
4
6
8
10
12
Years
14
16
CV Outcomes:
Nonfatal MI, CVD death, subclinical MI, angina confirmed by ETT or angiography,
revascularization with angioplasty or CABG
DCCT/EDIC Study Research Group: N Engl J Med 353:2643–2653; 2005
18
20
Is lower better? the ACCORD Study
10,251 patients with type 2 diabetes and at high risk for CVD were
randomized to:
Intensive glucose control arm: A1c <6%
Standard glucose control arm: A1c 7-7.9%
Treatment algorithms included all types of oral and injectable
medications
Half were then further randomized to the lipid trial and the other
half to the blood pressure trial
THE TRIAL WAS STOPPED EARLY DUE TO EXCESS
MORTALITY IN THE INTENSIVE GLUCOSE CONTROL ARM
257 deaths intensive arm vs. 203 deaths in the control arm
The reason for the increase in mortality is not clear
Steno 2: Effect of a multifactorial intervention
on mortality in type 2 diabetes
160 subjects
stratified by urine albumin
then randomized
80 intensive therapy
12 died
7 CVD
1 withdrew
67 completed intervention
12 died
2 CVD
10 other
55 completed follow-up study
Gaede et al: N Engl J Med 358:580-591, 2008
80 conventional therapy
15 died
7 CVD
2 withdrew
63 completed intervention
25 died
12 CVD
13 other
38 completed follow-up study
Steno 2: Intensive treatment reduced
mortality and CV events
Gaede et al: N Engl J Med 358:580-591, 2008
Current standards of medical care
(ADA guidelines)
Glycemic control
A1c <7.0% (primary target)
Pre-prandial glucose 90-130 mg/dl
Peak post-prandial glucose <180 mg/dl
Lipids
LDL <100 mg/dl
HDL >40 mg/dl
Triglycerides <150 mg/dl
Blood pressure
<130/80mm Hg
Aspirin therapy
Smoking cessation
American Diabetes Association: Diabetes Care 30:S4-S41, 2007
Geriatric guidelines for diabetes
American Geriatrics Society (AGS)
A1c <7% in healthy adults
Target A1c <8% in older adults with life expectancy <5 years
BP goal <140/80 mm Hg
Screen for comorbid conditions:
depression
polypharmacy
urinary incontinence
falls
pain
cognitive impairment
Brown et al, J Am Geriat Soc 51:S265-S280, 2003
Treatment of type 2 diabetes:
ADA consensus algorithm
Nathan et al, Diabetes Care 31:173-175, 2008
Current treatment options
Oral agents:
Metformin
Sulfonylureas: 2nd generation: glipizide, glyburide 3rd generation: glimepiride
Meglitinides: repaglinide, nateglinide
Thiazolidinediones: pioglitazone, rosiglitazone
Alpha glucosidase inhibitors: acarbose
Dipeptidyl peptidase 4 (DPP-4) inhibitors: sitagliptin
Injected medications:
Insulin
long acting: NPH, ultralente, detemir, glargine
short acting: Regular, aspart, lispro, glulisine
GLP-1 analogues: exenatide
Amylin analogues: pramlintide
*Medications in white available at the VA (some are non-formulary)
Comparison diabetes medications
Expected
decrease A1c
1-2%
Advantages
Disadvantages
Low cost, many benefits
metformin
1-2%
Low cost, weight neutral
sulfonylureas
1-2%
Low cost
thiazolidinediones
0.5-1.4%
Pioglitazone: improved
lipid profile
insulin
1.5-3.5%
Low cost, no dose limit
Fails for most in first
year
GI side-effects, rare
lactic acidosis
Weight gain,
hypoglycemia
Fluid retention, CHF,
weight gain,
osteoporosis, ?
Increased risk MI?,
expensive
Weight gain,
injections,
monitoring
lifestyle
Nathan et al, Diabetes Care 31:173-175, 2008
Medical treatment in the elderly;
things to keep in mind
Sulfonylureas
more frequent severe hypoglycemia in the elderly
renal impairment can increase half-life of glyburide
Metformin
increased risk lactic acidosis if renal impairment – especially if >80 years old
(check estimated GFR), CHF, hepatic impairment
TZDs
increased risk of fractures (elderly already at high risk)
co-morbid illness: CHF/CAD
Insulin
risk hypoglycemia
visual acuity
Rosiglitazone: rates of MI and CVD Death
Study
All small trials
DREAM
ADOPT
Overall
All small trials
DREAM
ADOPT
Overall
Odds Ratio
(95% CI)
p value
1.45 (0.88-2.39)
1.65 (0.74-3.68)
1.33 (0.80-2.21)
1.43 (1.03-1.98)
0.15
0.22
0.27
0.03
Death from CVD Causes
25/6557 (0.38)
7/3700 (0.19) 2.40 (1.17-4.91)
12/2365 (0.51)
10/2634 (0.38) 1.20 (0.52-2.78)
1/1456 (0.14)
5/2854 (0.18) 0.80 (0.17-3.86)
1.64 (0.98-2.74)
0.02
0.67
0.78
0.06
Rosiglitazone
Control
# of events / Total # (%)
Myocardial Infarction
44/10280 (0.43) 22/6105 (0.36)
15/2635 (0.57)
9/2634 (0.34)
27/1456 (1.85)
41/2895 (1.44)
Nissen SE and Wolski K: N Engl J Med 356:2457-2471; 2007
Limitations of meta-analyses
• Validity is dependent upon the quality of the
systematic review and the quality of trials
included in the review
• Different estimates of treatment effect (data and
outcomes)
• Meta-analysis is not the most rigorous way to
reach definite conclusions about adverse events
• Meta-analyses are designed to generate
hypotheses and do not provide definitive answers
RECORD: adjudicated primary events
16
Primary Outcome
Hospitalization and
Death from CVD
12
Cumulative
Incidence
(%)
Rosiglitazone
(217 events)
Control
(202 events)
8
4
HR=1.08 (95% CI 0.89-1.31)
p=0.43
0
0
12
24
36
48
60
Time from Randomization (months)
Numbers at risk
Rosiglitazone
Placebo
2227
2220
Home P et al: N Engl J Med 357:28-38; 2007
2087
2080
1980
1958
1878
1856
1694
1692
445
444
Pioglitazone: Rates of CVD Events
Pioglitazone
Control
Death/MI/stroke
Death
MI
Death/MI
Stroke
Serious heart failure
(n=8,554)
n (%)
375 (4.38)
209 (2.44)
131 (1.53)
309 (3.61)
104 (1.22)
200 (2.34)
Death/serious heart failure
Death/MI/stroke/serious
heart failure
Lincoff AM et al: JAMA 298:1180-1188; 2007
(n=7,836)
n (%)
450 (5.74)
224 (2.86)
159 (2.03)
357 (4.56)
131 (1.67)
139 (1.77)
Hazard Ratio
(95% CI)
p
value
0.82 (0.72-0.94)
0.92 (0.76-1.11)
0.81 (0.64-1.02)
0.85 (0.73-0.99)
0.80 (0.62-1.04)
1.41 (1.14-1.76)
0.005
0.38
0.08
0.04
0.09
0.002
361 (4.22)
321 (4.10)
1.11 (0.96-1.29)
0.17
508 (5.94)
523 (6.67)
0.96 (0.85-1.09)
0.54
Increased fractures with rosiglitazone in women
Cumulative Incidence of First Fracture (%)
Men
Women
20
20
15
15
Rosiglitazone
Metformin
Glyburide
10
10
5
5
0
0
0
1
2
Rosiglitazone
Metformin
Glyburide
3
4
Time (years)
Kahn et al, Diabetes Care, published online Feb 5, 2008
5
0
1
2
3
Time (years)
4
5
Fractures with pioglitazone
• Pioglitazone (n >8100) and comparator (n >7400), with
a maximum duration of follow up of 3.5 years
• <12,000 patient years of exposure in each group
• No increased risk of fractures in men
• More fractures in women taking pioglitazone (1.9 / 100
patient years) than comparator (1.1 / 100 patient years)
• The majority of fractures in women taking pioglitazone
were in the distal upper limb (forearm, hand and wrist) or
distal lower limb (foot, ankle, fibula and tibia)
Takeda Healthcare Provider Letter - March 2007
Who should use insulin?
Type 1 diabetes
-Basal and prandial insulin
Type 2 diabetes patients not well controlled
on oral agents or those who cannot tolerate
or have contraindications to oral agents
-Add basal insulin (hs NPH or glargine) to achieve
fasting glucose < 130 mg/dl
-Add prandial insulin if A1c does not reach goal
Insulin analogues
Action times for insulin
Insulin
Starts
Peaks
Ends
aspart/lispro
10-20 min
1.5-2.5 hr
4-5 hr
Low most
likely at
2-5 hr
regular
30-45 min
2-4 hr
5-7 hr
3-7 hr
NPH
1-3 hr
4-9 hr
14-20 hr
4-16 hr
lente
2-4 hr
8-14 hr
16-24 hr
6-16 hr
ultralente
2-4 hr
8-14 hr
18-24 hr
8-18 hr
glargine
1-2 hr
6 hr
18-26 hr
5-10 hr
detemir
1-3 hr
8-10 hr
18-24 hr
8-16 hr
Treatment of type 2 diabetes:
ADA consensus algorithm
1. Initiate lifestyle intervention and metformin at time of
diagnosis
2. Optimize glycemic control – within or as close to nondiabetic range as possible
3. Monitor A1c at regular intervals and add medications
and transition to new regimen if not meeting goals
4. Early addition of insulin in patients not meeting target
A1c goals
Nathan et al, Diabetes Care 31:173-175, 2008
Adding basal insulin: glargine vs. NPH
-110 type 2 DM patients, A1c >8% on oral meds
-90% were on a sulfonylurea plus metformin
-Randomized to receive:
bedtime glargine + metformin (G+MET)
bedtime NPH + metformin (NPH+MET)
-Starting dose:
10 units if metformin alone
20 units if had been on SU + metformin
-Subjects self-titrated insulin:
increase 2 units if FPG>100 mg/dl x 3d
increase 4 units if FPG>180 mg/dl x 3d
-Followed for 36 weeks
Yki-Jarvinen et al, Diabetologia 49:442-451, 2006
Symptomatic hypoglycemia:
glargine vs. NPH
Run-in period
Symptomatic hypoglycemia
(episodes/patient-year)
12
12
8
8
4
4
0
0
Glargine
12
Symptomatic hypoglycemia
(episodes/patient-year)
0-12 weeks
NPH
13-24 weeks
Glargine
12
8
8
4
4
0
0
Glargine
Yki-Jarvinen et al, Diabetologia 49:442-451, 2006
NPH
*
NPH
25-36 weeks
Glargine
NPH
Comparison diabetes medications:
newer therapies
Expected
decrease A1c
0.5-0.8%
Advantages
Disadvantages
Weight neutral
0.5-1.0%
Weight loss
DPP-4 inhibitors
(Sitagliptin)
Meglitinides
0.5-0.8%
Weight neutral
1-1.5%
Short duration
Amylin analogues
(pramlintide)
0.5-1.0%
Weight loss
Expensive, frequent GI
side-effects, 3x/day
dosing
Expensive, injections,
frequent GI side-effects,
little experience
Expensive, little
experience
Expensive, 3x/day dosing,
hypoglycemia
Expensive, injections,
3x/day dosing, frequent
GI side effects, little
experience
α-glucosidase
inhibitors (acarbose,
miglitol)
GLP-1 agonists
(exenatide)
Nathan et al, Diabetes Care 31:173-175, 2008
Measurement of the incretin effect:
OGTT and matched IV infusion
200
Glucose (mg/dl)
Oral
IV
150
200
150
100
100
50
50
0
-30 0
60
120
180
Time (min)
Nauck MA et al: J Clin Endocrinol Metab 63:492-498; 1986
Insulin (pmol/l)
0
-30 0
60
120
Time (min)
180
GLP-1 release and its effects
Meal
ingestion
Brain
• Satiety
Islets of Langerhans
• Increases insulin secretion
• May increase ß-cell mass
• Inhibits glucagon secretion
GLP-1
release from L
cells
Stomach
• Delays gastric emptying
GLP-1 release and inactivation
Mixed Meal
Intestinal
GLP-1
Release
GLP-1 (7-36)
Active
DPP4
Rapid Inactivation
(>80% of pool)
GLP-1(9-36)
Inactive
t1/2 = 1-2 min
Exenetide: glucose control
and body weight
0.0
Placebo- Open-label Extensions
controlled (10 µg exenatide bid)
trials
0
Intent-to-treat (n=551)
82-week completer (n=314)
1
-0.5
-0.8±0.1%
∆ A1c
(%)
∆ Body
Weight
(kg)
Placebo- Open-label Extensions
controlled (10 µg exenatide bid)
trials
2
-3.5±0.2 kg
3
-1.0
4
-1.1±0.1%
-1.5
-4.4±0.3 kg
5
0
20
40
60
80
Treatment (weeks)
Blonde L et al: Diabetes Obes Metab 8:436-447; 2006
0
20
40
60
80
Treatment (weeks)
Incidence of significant adverse events
with exenatide and insulin glargine
Adverse Event
Nausea
Vomiting
Diarrhea
Upper abdominal pain
Constipation
Dyspepsia
Anorexia
Decreased appetite
Exenatide
Insulin Glargine
(n=282), n (%) (n=267), n (%)
161 (57.1)
23 (8.6)
49 (17.4)
10 (3.7)
24 (8.5)
8 (3.0)
12 (4.3)
2 (0.7)
10 (3.5)
1 (0.4)
10 (3.5)
1 (0.4)
10 (3.5)
0 (0)
9 (3.2)
1 (0.4)
Heine RJ et al: Ann Intern Med 143:559-569; 2005
p
Value
<0.001
<0.001
0.006
0.012
0.011
0.011
0.002
0.021
Inhibition of DDP-4 increases active GLP-1 levels
Mixed Meal
Intestinal
GLP-1
Release
GLP-1 (7-36)
Active
DPP4
Rapid Inactivation
(>80% of pool)
GLP-1(9-36)
Inactive
t1/2 = 1-2 min
DPP-4 Inhibition Increases GLP-1 Levels and
Improves Glucose Tolerance in Type 2 Diabetes
275
14
Placebo (19)
Vildagliptin (18)
Glucose 225
(mg/dl)
GLP-1
(pmol/l)
175
10
6
125
2
300
120
Insulin 200
(pmol/l) 100
Glucagon 100
(pmol/l) 80
0
-30
0
30
60 90 120
Time (min)
Ahrén B et al: J Clin Endocrinol Metab 89:2078-2084; 2004
60
-30
0
30
60 90 120
Time (min)
Sitagliptin lowers HbA1c
0
-0.30
-0.64
-1.13
-0.4
PlaceboSubtracted
HbA1c
(%)
-0.8
-1.2
100 mg qD
Week 12
-1.6
<7
7 - 8.5
≥8.5
Baseline HbA1c (%)
Herman G et al: Diabetes 54 (Suppl 1):A134; 2005
Diabetes care: How is the VA doing?
100
1995
1997
1998
1999
2000
2001
2002
2003
2004
2005
80
%
60
40
20
0
HbA1c measured
Foot exam
visuala
Foot exam
sensorya
SOURCE: VHA External Peer Review Program
NOTE: results for VHA primary care outpatients with DM
aData for 2004 and 2005 not provided
Kupersmith et al, Health Affairs 26:w156-168w, 2007
Eye exam
A1c: How is the VA doing?
Kupersmith et al, Health Affairs 26:w156-168w, 2007
Copyright ©2007 by Project HOPE, all rights reserved.
Summary
Diabetes is a major health problem in the VA system
Good glycemic control decreases the risk of diabetes
complications
Lifestyle changes remain a cornerstone of diabetes
prevention and treatment
Multiple medications with different mechanisms of action
now exist for the treatment of diabetes
Diabetes treatment should be tailored to the patient,
especially in the geriatric population