Diabetes Mellitus

1
Diabetes Mellitus

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

2
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

3
Format

• Lecture (30 minutes)
• Small group case-discussions (30 minutes)
• Presentations of case discussions in large group
  (30 minutes)

4
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 unclear
• Beta cell fatigue? Genetically linked?
  Inflammation?
• DM diagnosed when beta cell function insufficient
  to control blood glucose levels
• First manifestation is postprandial hyperglycemia

5
Insulin Resistance/Metabolic Syndrome

• Insulin resistance
• Hypertension
• Lipid abnormalities
• Endovascular inflammation
• Hypercoagulability
• Doubles the risk of
• Macrovascular events (MI, CVA)

6
Metabolic SyndromeNCEP ATP III Criteria (3 or
more criteria)

• Criteria Defining Level
• Waist circumference
• Men gt40 inches
• Women gt35 inches
• Triglycerides gt150 mg/dL
• HDL Cholesterol
• Men lt40 mg/dL
• Women lt50 mg/dL
• Blood Pressure gt130/gt85 mm Hg
• Fasting Glucose gt110 mg/dL

NCEP ATP III. JAMA. 200128524862497.
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Metabolic Syndrome Prevalence by ATP III
Criteria NHANES III Population
Overall 22 for age 20 and older
Prevalence ()
?
Age (yr)
Adapted from Ford ES et al. JAMA.
2002287356359.
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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 20071671145-1151

9
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

10
UKDPS Benefits of Glycemic Control vs BP Control
With ACEIs or ?-Blockers
20
Heart Failure
Stroke
MI
Diabetic Death
0
7
-8
-9
-12
Relative Risk Reduction
-20
-21
-32
-40
Glycemic Control ACEI or BB
-44
-60
-56
UKPDS Group. BMJ. 1998317703713. Lancet.
1998352837853.
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Early Detection/Screening

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

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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.

13
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

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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.

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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

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Clinical Decision-making

• Strategies in individual cases should depend
  upon
• Outcomes of importance to the patient
• Desire to continue to try to stay alive
• Ability to participate in valued life activities
• Estimated impact of interventions on those
  outcomes
• Ability and willingness of the patient to adhere
  to the interventions

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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

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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.

19
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

20
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

21
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

22
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).

23
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 A1cs 7.5 (glipizide) vs. 9.3
  (placebo)
• Final average fasting BSs 126mg/dl (glipizide)
  vs. 168 mg/dl (placebo)

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Effects of DM on QOL

• Global QOL directly related to A1c level
• Glipizide group had significantly (plt0.001) less
• Weakness fatigue
• Urinary frequency nocturia
• Thirst polydipsia
• Dryness of mouth, eyes, or nose
• Sweet taste in mouth

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Effects of DM on QOL (cont.)

• Glipizide group also had significantly (plt0.01)
  less
• Foot cramps foot pain
• Sweating
• Numbness of lips or mouth
• Blurred or double vision
• Crabbiness short-temperedness

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Effects of DM on QOL (cont.)

• Glipizide group also had (plt0.05) less
• Headaches
• Tiredness, drowsiness
• Muscle cramps
• Vertigo (spinning sensation)
• Lightheadedness when standing up
• Chest pain with exertion
• Confusion

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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

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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

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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
  

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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 lt0.1
• 65 9.0 0.5

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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

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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

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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)

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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

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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

36
Problems with Hypoglycemia

• Case-control study involving 111
  community-dwelling adults gt75 years of age
• Strong correlation between A1clt7 and increased
  risk of falls
• NHLBI-funded ACCORD study, a RCT with 10,251
  participants
• Intensive treatment group had an excess number of
  deaths

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Simulation

• Fictitious 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.

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Case

• Mr. 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.

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Diabetes Personal Health Decisions (PHD) Engine

• Archimedes program
• Attempts to model diabetes by including gt100
  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

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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

41
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
  (r0.99)
• Correlation between absolute differences in
  outcomes also amazing (r0.97)

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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
43
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