Update on clinical diabetes in older veterans

Kristina Utzschneider, MDAssistant 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

NHANES 1999-2002 2011 20212031

20-29 40-49 60-69 ≥70

Age (years)50-5930-39

Prevalencediabetes(percent)

0

5

10

15

20

25

30

Mainous et al, Diabetologia 50:934, 2007

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 States32.7% have symptoms of diabetic peripheral neuropathy

27.4% have diabetic retinopathy

13.1% have comorbid neuropathy and retinopathyCandrilli 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 patientsU.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)

ScreenScreen

RandomizeRandomize

Standard lifestyle teachingStandard lifestyle teaching

Intensive Intensive LifestyleLifestyle(n = 1079)(n = 1079)

MetforminMetformin(n = 1073)(n = 1073)

PlaceboPlacebo(n = 1082)(n = 1082)

TroglitazoneTroglitazonen= 585n= 585Until 6/98Until 6/98

Diabetes Prevention Program Research Group, Diabetes Care 22:623-34, 1999

DPP: Average weight changeDPP: Average weight change

0 6 12 18 24 30 36 42 48Months in study

Lifestyle

Metformin

+

-8-7-6-5-4-3-2-101

Wei

ght c

hang

e (K

g)

Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002

Placebo

0 1 2 3 4

0

10

20

30

40

Placebo (n=1082)

Metformin (n=1073, p<0.001 vs. Plac)

Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent of subjects developing diabetesPercent of subjects developing diabetes

Years in study

Cum

ulat

ive

inci

denc

e (%

)

Lifestyle

Metformin

Placebo

Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002

Diabetes incidence rates by age

0

3

6

9

12

15

25-44(n=1000)

45-59(n=1586)

>60(n=648)

Cas

es/1

00 p

erso

n-yr

Lifestyle Metformin Placebo

Diabetes Prevention Program Research Group, NEJM 346:393-403, 2002

Can we prevent diabetes complications?

Glycemic Control in the UKPDS

Patients followed for 10 years

IntensiveConventional

All patients assigned to regimen

IntensiveConventional

9

Median

HbA1c (%)

Time from Randomization (y)

0

7

8

6

0 3 6 9 12 15

UKPDS Group. Lancet: 352:837-853; 1998

ADA Goal

Effect of Glycemic Control in the UKPDS

* Combined microvascular and macrovascular events

Endpoints

Intensive (rate/1000

pt yrs

Conventional (rate/1000

pt yrs)

% Decrease p value

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

UKPDS Group: Lancet 352:837–853; 1998

%Decrease in

Relative Risk **

Any diabetes-related endpoint

21%

**

Diabetes-related death

21% **

All cause

mortality

14%*

Stroke

12%

**

Peripheral vascular disease†

43%

**

Myocardial infarction

14%

**

Micro-vascular disease

37%

**

Cataract extraction

19%

†Lower extremity amputation or fatal peripheral vascular disease*p = 0.035; **p < 0.0001

Effect of 1% Decrease in A1c on Diabetes-relatedComplications - UKPDS Observational Analysis

UKPDS Group - UKPDS 35: Br Med J 321:405-412; 2000

DCCT – glycemic control

Diabetes Control and Complications Trial Research Group, NEJM 329:977-986, 1993.

Total 1441 patients with IDDM enrolledMean 6.5 years follow-up

0 1 2 3 4 5 6 7 8 9 10

Year of Study

Glycosylated hemoglobin (%)

5

6

7

8

9

10

11

Conventional

Intensive

DCCT – retinopathy

Diabetes Control and Complications Trial Research Group, NEJM 329:977-986, 1993.

Primary prevention Secondary prevention

DCCT: retinopathy progression by HbA1c and years of follow-up

0 1 2 3 4 5 6 7 8 9 Time during study (years)

Rate/100person-years

0

16

12

8

4

20

24

Diabetes Control and Complications Trial Research Group, Diabetes 44: 968-983, 1995.

7%

8%

9%10%

Conventional treatment

Mean HbA1c = 11%

DCCT: Results summary

Improved glycemic control reduced the risk of clinically meaningful:

Relative risk reduction

Retinopathy 76% p≤0.002

Nephropathy 54% p<0.04

Neuropathy 60% p≤0.002

Cardiovascular events 78% p=0.065

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.

DCCT/EDIC

DCCT Intervention Training

Study year

5

6

7

8

9

11

10

Gly

cosy

late

d he

mog

lobi

n (%

)

Conventional

Intensive

1 2 3 4 50 7 26 8 9

EDIC observation

3 4 5 6 71

DCCT/EDIC Study Research Group: N Engl J Med 353:2643–2653; 2005

Prior intensive glycemic control decreases subsequent CVD events in type 1 diabetes

DCCT/EDIC Study Research Group: N Engl J Med 353:2643–2653; 2005

RRR = 42% (95% CI 9-63); p=0.02Cumulativeincidence

of any predefinedCV outcome

0 2 4 6 8 10 12 14 16 18 20

0.10

0.08

0.06

0.04

0.02

0.00

0.12

CV Outcomes:Nonfatal MI, CVD death, subclinical MI, angina confirmed by ETT or angiography, revascularization with angioplasty or CABG

Conventional Rx: 98 events in 52 patientsIntensive Rx: 46 events in 31 patients

Years

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 armThe reason for the increase in mortality is not clear

Steno 2: Effect of a multifactorial intervention

on mortality in type 2 diabetes

Gaede et al: N Engl J Med 358:580-591, 2008

160 subjects stratified by urine albumin

then randomized

80 intensive therapy 80 conventional therapy

67 completed intervention 63 completed intervention

12 died 7 CVD1 withdrew

15 died 7 CVD2 withdrew

12 died 2 CVD 10 other

25 died 12 CVD 13 other

55 completed follow-up study 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 controlA1c <7.0% (primary target)

Pre-prandial glucose 90-130 mg/dl

Peak post-prandial glucose <180 mg/dl

LipidsLDL <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

Nathan et al, Diabetes Care 31:173-175, 2008

Treatment of type 2 diabetes: ADA consensus algorithm

Current treatment optionsOral agents:

MetforminSulfonylureas: 2nd generation: glipizide, glyburide 3rd generation: glimepirideMeglitinides: repaglinide, nateglinideThiazolidinediones: pioglitazone, rosiglitazoneAlpha glucosidase inhibitors: acarboseDipeptidyl peptidase 4 (DPP-4) inhibitors: sitagliptin

Injected medications:Insulin

long acting: NPH, ultralente, detemir, glargineshort acting: Regular, aspart, lispro, glulisine

GLP-1 analogues: exenatideAmylin analogues: pramlintide

*Medications in white available at the VA (some are non-formulary)

Expected decrease A1c

Advantages Disadvantages

lifestyle 1-2% Low cost, many benefits Fails for most in first year

metformin 1-2% Low cost, weight neutral GI side-effects, rare lactic acidosis

sulfonylureas 1-2% Low cost Weight gain, hypoglycemia

thiazolidinediones 0.5-1.4% Pioglitazone: improved lipid profile

Fluid retention, CHF, weight gain,

osteoporosis, ? Increased risk MI?,

expensive

insulin 1.5-3.5% Low cost, no dose limit Weight gain, injections, monitoring

Nathan et al, Diabetes Care 31:173-175, 2008

Comparison diabetes medications

Medical treatment in the elderly;

things to keep in mindSulfonylureas more frequent severe hypoglycemia in the elderlyrenal impairment can increase half-life of glyburide

Metforminincreased risk lactic acidosis if renal impairment – especially if >80 years old (check estimated GFR), CHF, hepatic impairment

TZDsincreased 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 Rosiglitazone Control Odds Ratio (95% CI) p value

# of events / Total # (%)

Myocardial Infarction

All small trials 44/10280 (0.43) 22/6105 (0.36) 1.45 (0.88-2.39) 0.15

DREAM 15/2635 (0.57) 9/2634 (0.34) 1.65 (0.74-3.68) 0.22

ADOPT 27/1456 (1.85) 41/2895 (1.44) 1.33 (0.80-2.21) 0.27

Overall 1.43 (1.03-1.98) 0.03

Death from CVD Causes

All small trials 25/6557 (0.38) 7/3700 (0.19) 2.40 (1.17-4.91) 0.02

DREAM 12/2365 (0.51) 10/2634 (0.38) 1.20 (0.52-2.78) 0.67

ADOPT 1/1456 (0.14) 5/2854 (0.18) 0.80 (0.17-3.86) 0.78

Overall 1.64 (0.98-2.74) 0.06

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

0 12 24 36 48 600

4

8

12

16

Numbers at riskRosiglitazonePlacebo

22272220

20872080

19801958

18781856

16941692

445444

Rosiglitazone(217 events)

HR=1.08 (95% CI 0.89-1.31)p=0.43

CumulativeIncidence

(%)

Time from Randomization (months)

Control(202 events)

Primary OutcomeHospitalization andDeath from CVD

Home P et al: N Engl J Med 357:28-38; 2007

Pioglitazone: Rates of CVD Events

Lincoff AM et al: JAMA 298:1180-1188; 2007

Pioglitazone(n=8,554)

n (%)

Control(n=7,836)

n (%)

Hazard Ratio(95% CI)

p value

Death/MI/stroke 375 (4.38) 450 (5.74) 0.82 (0.72-0.94) 0.005

Death 209 (2.44) 224 (2.86) 0.92 (0.76-1.11) 0.38

MI 131 (1.53) 159 (2.03) 0.81 (0.64-1.02) 0.08

Death/MI 309 (3.61) 357 (4.56) 0.85 (0.73-0.99) 0.04

Stroke 104 (1.22) 131 (1.67) 0.80 (0.62-1.04) 0.09

Serious heart failure 200 (2.34) 139 (1.77) 1.41 (1.14-1.76) 0.002

Death/serious heart failure 361 (4.22) 321 (4.10) 1.11 (0.96-1.29) 0.17

Death/MI/stroke/serious heart failure 508 (5.94) 523 (6.67) 0.96 (0.85-1.09) 0.54

Increased fractures with rosiglitazone in women

Time (years)

Cumulative Incidence of First Fracture (%)

0 1 2 3 4 50

5

10

15

20

Rosiglitazone

GlyburideMetformin

0 1 2 3 4 50

5

10

15

20

Rosiglitazone

GlyburideMetformin

Time (years)

Men Women

Kahn et al, Diabetes Care, published online Feb 5, 2008

Fractures with pioglitazone

Takeda Healthcare Provider Letter - March 2007

• 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)

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 Low most likely at

aspart/lispro 10-20 min 1.5-2.5 hr 4-5 hr 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 algorithm1. Initiate lifestyle intervention and metformin at time of

diagnosis

2. Optimize glycemic control – within or as close to non-diabetic 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 alone20 units if had been on SU + metformin

-Subjects self-titrated insulin:increase 2 units if FPG>100 mg/dl x 3dincrease 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

Yki-Jarvinen et al, Diabetologia 49:442-451, 2006

Symptomatic hypoglycemia (episodes/patient-year)

Run-in period 0-12 weeks

13-24 weeks 25-36 weeks

0

4

8

12

0

4

8

12

0

4

8

12

0

4

8

12

Glargine NPH

Glargine NPH

Glargine NPH

Glargine NPH

*

Symptomatic hypoglycemia (episodes/patient-year)

Expected decrease A1c

Advantages Disadvantages

α-glucosidase inhibitors (acarbose, miglitol)

0.5-0.8% Weight neutral Expensive, frequent GI side-effects, 3x/day

dosing

GLP-1 agonists (exenatide)

0.5-1.0% Weight loss Expensive, injections, frequent GI side-effects,

little experience

DPP-4 inhibitors (Sitagliptin)

0.5-0.8% Weight neutral Expensive, little experience

Meglitinides 1-1.5% Short duration Expensive, 3x/day dosing, hypoglycemia

Amylin analogues (pramlintide)

0.5-1.0% Weight loss Expensive, injections, 3x/day dosing, frequent

GI side effects, little experience

Nathan et al, Diabetes Care 31:173-175, 2008

Comparison diabetes medications: newer therapies

Measurement of the incretin effect:

OGTT and matched IV infusion

Nauck MA et al: J Clin Endocrinol Metab 63:492-498; 1986

0

50

100

150

200

-30 0 60 120 180

Time (min)

Glucose (mg/dl) Insulin (pmol/l)

-30 0 60 120 180

Time (min)

0

50

100

150

200OralIV

GLP-1 release and its effects

Brain• Satiety

Islets of Langerhans• Increases insulin secretion • May increase ß-cell mass• Inhibits glucagon secretion

Stomach• Delays gastric emptying

GLP-1 release from L

cells

Meal ingestion

GLP-1 release and inactivation

GLP-1(9-36)Inactive

DPP4

Rapid Inactivation(>80% of pool)

Mixed MealIntestinal

GLP-1Release

GLP-1 (7-36)Active

t1/2 = 1-2 min

Exenetide: glucose control and body weight

Blonde L et al: Diabetes Obes Metab 8:436-447; 2006

0.0

-0.5

-1.5

-1.0

0 20 40 60 80

∆ A1c(%)

Treatment (weeks)

Placebo-controlled

trials

Open-label Extensions(10 µg exenatide bid)

Intent-to-treat (n=551)82-week completer (n=314)

-0.8±0.1%

-1.1±0.1%

0

1

3

2∆ BodyWeight

(kg)

4

50 20 40 60 80

Treatment (weeks)

Placebo-controlled

trials

Open-label Extensions(10 µg exenatide bid)

-4.4±0.3 kg

-3.5±0.2 kg

Incidence of significant adverse events with exenatide and insulin glargine

Heine RJ et al: Ann Intern Med 143:559-569; 2005

Adverse Event Exenatide

(n=282), n (%)

Insulin Glargine

(n=267), n (%)

p

ValueNausea 161 (57.1) 23 (8.6) <0.001

Vomiting 49 (17.4) 10 (3.7) <0.001

Diarrhea 24 (8.5) 8 (3.0) 0.006

Upper abdominal pain 12 (4.3) 2 (0.7) 0.012

Constipation 10 (3.5) 1 (0.4) 0.011

Dyspepsia 10 (3.5) 1 (0.4) 0.011

Anorexia 10 (3.5) 0 (0) 0.002

Decreased appetite 9 (3.2) 1 (0.4) 0.021

Inhibition of DDP-4 increases active GLP-1 levels

GLP-1(9-36)Inactive

DPP4

Rapid Inactivation(>80% of pool)

Mixed MealIntestinal

GLP-1Release

GLP-1 (7-36)Active

t1/2 = 1-2 min

DPP-4 Inhibition Increases GLP-1 Levels and Improves Glucose Tolerance in Type 2 Diabetes

Ahrén B et al: J Clin Endocrinol Metab 89:2078-2084; 2004

2

6

10

14

60

80

100

120

-30 0 30 60 90 1200

100

200

300

Placebo (19)Vildagliptin (18)

125

175

225

275

Glucose(mg/dl)

Insulin(pmol/l)

GLP-1(pmol/l)

Time (min)Time (min)

Glucagon(pmol/l)

-30 0 30 60 90 120

Sitagliptin lowers HbA1c

0

-0.4

-0.8

-1.2

-1.6

Placebo-Subtracted

HbA1c(%)

Baseline HbA1c (%)<7 7 - 8.5 ≥8.5

100 mg qDWeek 12

Herman G et al: Diabetes 54 (Suppl 1):A134; 2005

-0.30 -0.64 -1.13

Kupersmith et al, Health Affairs 26:w156-168w, 2007

Diabetes care: How is the VA doing?

HbA1c measured Foot examvisuala

Foot examsensorya

Eye exam

SOURCE: VHA External Peer Review ProgramNOTE: results for VHA primary care outpatients with DMaData for 2004 and 2005 not provided

0

20

40

60

80

100

%

1995

200020012002200320042005

199719981999

Copyright ©2007 by Project HOPE, all rights reserved.

Kupersmith et al, Health Affairs 26:w156-168w, 2007

A1c: How is the VA doing?

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