Diabetes Mellitus

James W. Mold, M.D., M.P.H.OU-HSCDepartment of Family and Preventive Medicine

Objective

Attendees should be able to: Construct a rational management

plan for an older patient with type 2 DM, taking into account life expectancy, risks for adverse events, and patient goals, preferences, and resources

Format

Lecture (30 minutes) Small group case-discussions (30

minutes) Presentations of case discussions in

large group (30 minutes)

Type 2 Diabetes Mellitus

Insulin resistance plus beta cell failure Insulin resistance (metabolic syndrome)

usually precedes beta cell failure by 10-20 years

Connection between the two is still unclearBeta cell fatigue? Genetically linked?

Inflammation? DM diagnosed when beta cell function

insufficient to control blood glucose levelsFirst manifestation is postprandial hyperglycemia

Insulin Resistance/Metabolic Syndrome

Insulin resistance Hypertension Lipid abnormalities Endovascular inflammation Hypercoagulability

Doubles the risk of:Macrovascular events (MI, CVA)

Metabolic SyndromeNCEP ATP III Criteria (3 or more criteria)

NCEP ATP III. JAMA. 2001;285:2486–2497.

Criteria Defining LevelWaist circumference

Men >40 inchesWomen >35 inches

Triglycerides >150 mg/dL

HDL CholesterolMen <40 mg/dLWomen <50 mg/dL

Blood Pressure >130/>85 mm Hg

Fasting Glucose >110 mg/dL

Metabolic Syndrome: Prevalence by ATP III Criteria — NHANES III Population

Overall 22% for age 20 and older

0

5

10

15

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25

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35

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45

30-39 40-49 50-59 60-69 70

Men

Women

Age (yr)

Pre

vale

nce

(%

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Adapted from: Ford ES et al. JAMA. 2002;287:356–359.

Why Worry About Insulin Resistance

Twice the risk of MI, CVA, PAD Eight times the risk of development of

type 2 DM Substantially reduced life expectancy

(by approximately 8 years)*

*Franco et al. Arch Intern Med 2007;167:1145-1151

Beta Cell Failure

Hyperglycemia increases risk for: Microvascular disease (retinopathy,

nephropathy) Neuropathy Infection

Some small additional risk for: Macro-vascular disease/events

Hypercoagulability Endothelial cell dysfunction

UKDPS: Benefits of Glycemic Control vs BP Control With ACEIs or -Blockers

UKPDS Group. BMJ. 1998;317:703–713. Lancet. 1998;352:837–853.

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+7

-12-8

-56

-44

-21

-32

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-20

-40

-60

Rel

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e R

isk

Red

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ion

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Heart Failure Stroke MI Diabetic Death

Glycemic ControlACEI or BB

Early Detection/Screening

USPSTF: Screen all adults with hypertension or hyperlipidemia for type 2 diabetes mellitus.

Prevention

In at risk patients: The onset of beta cell failure (diabetes) can

be delayed or prevented with exercise, diet, metformin, glitazones, acarbose, an ACEI or an ARB. Exercise and diet are much more efficacious

than medications.

However, The cost effectiveness of delaying the onset

of diabetes has not yet been established.

American Geriatrics Society Offer individualized therapy that

considers Life expectancy Cognitive impairment Patient preferences Functional status Social support

Keep therapy as simple and inexpensive as possible

Goals

Things you would want to make happen for which it makes very little sense to ask, “so that….?”

Examples:A longer life, the ability to communicate

through writing, the ability to make decisions for myself.

Goals of Health Care

Prevent premature death and disability (QALE) Increase life expectancy (LOL) Reduce the risk of disabling complications

(future QOL)

Improve or maintain current quality of life (QOL) Maximize ability to function in ways that

make life worth living

Clinical Decision-making

Strategies in individual cases should depend upon:

1. Outcomes of importance to the patient Desire to continue to try to stay alive Ability to participate in valued life activities

2. Estimated impact of interventions on those outcomes

3. Ability and willingness of the patient to adhere to the interventions

DM and Length of Life

75% of Type 2 diabetics die of cardiovascular events (MI, CVA)

2-4 times more likely to have cardiovascular events

Risk of MI is as high for type 2 diabetics with no prior MI as for non-diabetics with a prior MI

When they have an MI, diabetics are significantly more likely to die or to develop CHF

Lifestyle Modifications

Exercise*** Aerobic: Substantial benefits for both LOL and

QOL Strengthening: Substantial benefits for future

QOL, ??LOL Balance: Reduced falls

Diet Weight reduction: Difficult.** Associated with

better QOL. Be more careful in the elderly. Mediterranean diet: Associated with reduced

macrovascular events. Be careful in the elderly.

Low-Dose Aspirin

Reduced risk of MI; greater in men Reduced risk of CVA; greater in

women

USPSTF recommends low dose aspirin for men 45 to 79 and women 55 to 79

DM and LOL

ACE inhibitor (ramipril): 24% reduction in overall mortality over 4.5 years (16% after controlling for effects of BP reduction)

Overall mortality reduced in patients with HTN and LVH with ARBs. 42% reduced risk of CVA even if little change in BP. ARBs reduce cardiovascular events more than atenolol.

HOPE Study Investigators. Lancet 2000; 355 (9200): 253-259 LIFE Study Investigators. Lancet 2002; 359: 1004-1010

DM and LOL

Possible reasons for benefits of ACEIs: Anti-ischemic

Stimulate endothelial nitric oxide Decrease myocardial O2 consumption

Anti-atherogenic Reduce systemic vascular resistance and

BP ?Reduce cardiac remodeling

RRR and ARR

Base Risk X RRR = Absolute Risk Reduction

If base risk = 10%, and RRR = 50%, then ARR = 5%

If base risk = 50%, and RRR = 50%, then ARR = 25%

Therefore, the actual benefit of risk reduction is often greater in the elderly assuming equal RRR (because base risk is higher).

Effects of DM on QOL

RCT of glipizide XL vs. placebo for 12 weeks

594 patients; mean age 58.5 (range: 30-85) Glipizide XL titrated upward as needed Home glucose monitoring Final mean A1c’s: 7.5% (glipizide) vs. 9.3%

(placebo) Final average fasting BS’s: 126mg/dl

(glipizide) vs. 168 mg/dl (placebo)

Effects of DM on QOL

Global QOL directly related to A1c level

Glipizide group had significantly (p<0.001) less: Weakness; fatigue Urinary frequency; nocturia Thirst; polydipsia Dryness of mouth, eyes, or nose Sweet taste in mouth

Effects of DM on QOL (cont.)

Glipizide group also had significantly (p<0.01) less: Foot cramps; foot pain Sweating Numbness of lips or mouth Blurred or double vision Crabbiness; short-temperedness

Effects of DM on QOL (cont.)

Glipizide group also had (p<0.05) less: Headaches Tiredness, drowsiness Muscle cramps Vertigo (spinning sensation) Lightheadedness when standing up Chest pain with exertion Confusion

Effects of DM on QOL (cont.)

Glipizide group also had fewer: Days absent from work Days spent in bed Days of restricted activity

Testa MA, et al. JAMA 1998; 280 (17): 1490-1496

Micro-vascular Disease

Greater benefit from reduction of A1c from 9 to 8 than from 8 to 7

It takes 8-10 yrs of glycemic control to realize the benefits for micro-vascular disease

ESRD

End Stage Renal Disease (ESRD) by age at diagnosis of DM:

Age at Dx A1c Lifetime Risk_ 55 7.0 0.9% 55 9.0 1.6%

65 7.0 0.3% 65 9.0 0.6%

Blindness

Blindness from DM Retinopathy by age at diagnosis of DM:

Age at Dx A1c Lifetime Risk 55 7.0 0.1% 55 9.0 1.2%

65 7.0 <0.1% 65 9.0 0.5%

Diabetic Peripheral and Autonomic Neuropathies Proposed mechanisms: sorbitol,

myoinosital, ischemia, glycosylation, osmotic

Improved glucose control probably slows progression, but size of effect is unknown

Some evidence of minor benefits from: C-peptide, Vitamin E, other antioxidants, nerve growth factors

Why Not Control Everything? Law of diminishing returns

Less benefit from successive interventions Diminishing ability to correctly adhere to

more complicated regimens Increased side effects and drug

interactions from more meds (exponential increase above 4-5)

Impact of testing and interventions on lifestyle

Math

ARR = RRR (baseline risk)

Most interventions that can reduce risk of heart attack have RRR of about 25%.

If 10-yr base = 20%, then the first intervention results in an ARR of 5%, the second in an ARR of 3.75% (25% of 15%), and so on (diminishing returns)

Diminishing Returns Equal RRRs

Prior risk 0.3000

Intervention RRR

Incremental ARR

Resulting risk

Cumulative ARR

Cumulative RRR

1 0.1929 -0.0579 0.2421 -0.0579 0.1929

2 0.1929 -0.0467 0.1954 -0.1046 0.3485

3 0.1929 -0.0377 0.1578 -0.1422 0.4742

4 0.1929 -0.0304 0.1273 -0.1727 0.5756

5 0.1929 -0.0246 0.1028 -0.1972 0.6574

6 0.1929 -0.0198 0.0830 -0.2170 0.7235

7 0.1929 -0.0160 0.0670 -0.2330 0.7768

RRR = Relative Risk Reduction; ARR = Absolute Risk Reduction

Diminishing ReturnsTreatments Chosen from Best RRR to Worst

Prior risk 0.3000

Intervention RRR

Incremental ARR

Resulting risk

Cumulative ARR

Cumulative RRR

1 0.35 -0.1050 0.1950 -0.105 0.35

2 0.30 -0.0585 0.1365 -0.1635 0.545

3 0.20 -0.0273 0.1092 -0.1908 0.636

4 0.20 -0.0218 0.0874 -0.21264 0.7088

5 0.15 -0.0131 0.0743 -0.225744 0.75248

6 0.10 -0.0074 0.0668 -0.2331696 0.777232

7 0.05 -0.0033 0.0635 -0.2365111 0.7883704

RRR = Relative Risk Reduction; ARR = Absolute Risk Reduction

Problems with Hypoglycemia

Case-control study involving 111 community-dwelling adults >75 years of age Strong correlation between A1c<7 and

increased risk of falls NHLBI-funded ACCORD study, a RCT

with 10,251 participants Intensive treatment group had an excess

number of deaths

SimulationFictitious 79 year-old woman with DM, COPD, HTN,

OA, and osteoporosis.Researchers applied relevant clinical practice

guidelines using a conservative approach and generics.

Required 12 medications $406 per month (pre-Medicare D) Taken at 5 different times per day Multiple potential interactions

Boyd CM, et al. JAMA 2005; 294(6): 716-724.

CaseMr. M is a 65 yo man with type 2 diabetes mellitus

diagnosed a yr. ago. Sedentary lifestyle; no cigarettes or alcohol. Recent onset of fatigue, decreased libido, polyuria and polydipsia, and increasing pain in his joints. He currently takes no medications. Past and family history are unremarkable. His primary care physician finds: body mass index (BMI) of 30.5, BP 200/100 mmHg, osteoarthritis involving fingers and knees, hemoglobin A1c 10%, LDL cholesterol 140 mg/dl, HDL cholesterol 40 mg/dl, total cholesterol 260 mg/dl, ALT and AST slightly elevated, and serum testosterone low.

Diabetes Personal Health Decisions (PHD) Engine

Archimedes program• Attempts to model diabetes by including

>100 biological variables, symptoms, signs, tests, treatments, and outcomes

• Uses differential equations and object-oriented programming to model the links between variables

• Keeps all continuous variables continuous

Diabetes Personal Health Decisions (PHD) Engine

• Addresses co-morbidities and treatments with multiple effects

• Includes not only individual patients, but also aspects of the helath care delivery system (facilities, equipment, policies and procedures, costs, and utilities)

• Data based upon knowledge of pathophysiology, clinical trials, and data from Kaiser Permanente

PHD Validation• Subjected to a series of 74 validation

exercises involving 18 clinical trials, 10 of which were not used in the construction of the engine

• Correlation between results of PHD simulations and clinical trials overall was astounding (r=0.99)

• Correlation between absolute differences in outcomes also amazing (r=0.97)

Mr. Waldman (Diabetes PHD Risk Engine)Life expectancy is about 7 years.7-yr. Risk MI CVA

40% 17%

ARR Sum ARR Sum

Aspirin 11% 2% Moderate Exercise 10% 20% 5% 6%BP to 130 with ACEI 7% 24% 3% 9%Lower LDL to 100 5% 27% 0% 9%Lower A1c to 6.5% 1% 28% 0% 9%Reduce BMI to 26 9% 31% 3%

11%www.diabetes.org

Objective

Attendees should be able to: Construct a rational management

plan for an older patient with DM, taking into account goals and preferences, life expectancy, abilities, and resources