Download Type II Diabetes 2007

Type II Diabetes
Gil C. Grimes, MD
Assistant Professor
Community and Family Medicine
Scott and White Memorial Hospital
September 2007
Objectives
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Discuss Complications
Discuss Therapy
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Oral Agents
Insulin
Highlight Texas Flow-sheets Provided
Complications
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Prospective population study 13,105
subjects followed for 20 years 1
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1.5-2 fold increase risk of death in men &
women
1.5-2 fold increase of MI in men
1.5-4.5 fold increase risk of MI in women
1.5-2 fold increase risk of Stroke in men
2-6.5 fold increase risk in stroke in women
1- Arch Intern Med 2004;164:1422 [Level 1c]
Complications
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Prospective cohort 4,662 men aged 4579 followed 2-4 years 1
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Increase HbA1c associated with increasing
mortality
All cause RR 2.2
Cardiovascular disease RR 3.3
Ischemic disease RR 4.2
1- BMJ 2001;322:15 [Level 1c]
Complication Macrovascular
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Macrovascular complications
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75-80% diabetic deaths related to
atherosclerosis
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75% accelerated CAD
25% accelerated CVD and PVD
>50% diabetics hypercholesterolemic
DynaMed accessed March 15 2006
Complication CAD
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Meta-analysis of 37 prospective studies
447,064 patients
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Rate of Fatal CAD 5.4% vs. 1.6% for
diabetics
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Women RR 3.50
Men RR 2.06
BMJ 2006;332(7533):73-8 [Level 1a]
Complication CAD
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Diabetes may be as risky as a prior MI 1
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Prospective cohort 9,434 men age 35-57 followed
25 years
Diabetes similar mortality to prior MI
Diabetics without prior MI= risk of prior MI 2
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Risk of MI
3.5% in non-DM no prior MI
18.8% for prior MI non-DM
20.2% for DM without prior MI
45% for DM with prior MI
1- Arch Intern Med 2004;164:1438 [Level 1c]]
2- NEJM 1998;339:229 [Level 2b]
Complication HTN
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Prospective cohort 49,582 Finish
subjects without stroke or CAD at
baseline followed 19.1 years followed
for stroke
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HTN Stage I HR 1.35 mortality 1.47
HTN Stage II HR 1.98 mortality 2.62
DM HR 2.54 mortality 3.06
HTN I and DM HR 3.51 mortality 5.99
HTN II and DM HR 4.50 mortality 9.27
Stroke 2005;36(12):2538-43 [Level 1b]
Complication PAD
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Prospective cohort 1,294 patients with
DM-2
Subgroup of 531 with sufficient
screening for PAD
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PAD at entry 13.6% (161 patients)
14 developed PAD (75 patients)
Incidence of new PAD 3.7 per 100 pt years
Diabetes Care 2206;29(3):575-80 [Level 2b]
Complication Microvascular
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Microangiopathy
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Retinopathy (RR20)
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#1 cause of new blindness
#3 cause of blindness
Neuropathy (ESRD RR25)
Nephropathy
BMJ 2000;320(7241):1062 [Level 5}
Complication Coma
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Hyperosmolar Coma
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Most common in elderly patients
Also occurs in children
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Causes
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8 case reports in obese children
Infection 20-25%
New onset DM 30-50%
Drugs, Stress (MI etc.)
20-30% mortality
Endocr Pract 2005;11(1):23-9 [Level 4]
Complication Hypoglycemia
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Mild episodes common
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Retrospective cross-sectional analysis of 1,055 outpatients
Prevalence of symptoms
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Diet controlled 12% (9 of 76)
Oral agents 16% (56 of 346)
Insulin use 30% (193 of 633)
Severe Hypoglycemia 0.5% (5 of 1055) all using insulin
Risk factors
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Younger age
Insulin use
Lower HbA1c at follow-up
Arch Intern Med 2001;161(13):654-9 [Level 2b]
Treatment Goals
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American Diabetes Association Recommendations
Control of glycemia is important
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Goal is HgA1c less than 7%
Pre-meal glucose 5-7.2 mmol/l
Post-meal glucose <10 mmol/l
Blood pressure less than 130/80
Lipid control
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LDL < 2.6 mmol/l
Triglycerides <1.7 mmol/l
HDL >1.1 mmol/l
Diabetes Care 2006 Jan;29(suppl 1):S4-S42
Cost-effectiveness
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CDC cost-analysis
Hypothetical cohort patients >25 yo new
diabetes
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Antihypertensive Therapy
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Intensive Glycemic Control
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Improved quality of life and cost savings age 25-84
Very cost-effective 85-94
Increase cost and improved outcome
Decreasing effect on quality of life
Decreasing cost effectiveness with increasing age
Lipid management improved quality of life at
increased cost
JAMA 2002;287(19):2542-51 [Level 2b]
Lifestyle Changes
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Dietary changes and exercise works
20-50% of patients can control their
diabetes with diet, exercise and weight
reduction
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Current trial lookAHEAD is recruiting
patients for lifestyle management study
Exercise
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Exercise training reduces the HgA1c
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Metanalysis of 14 trials duration 8 weeks
HgA1 c 7.65% vs. 8.31% 1
Increased activity reduces risk of MI,
Stroke
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Walking 2 hours/week lower mortality NNT
61 for one year 2
1- JAMA 2001;286:1218 [Level 1a]
2- Circ 2003;163:1440 [Level 1c]
Dietary Advice
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Systematic review of 18 RCT lasting 6
months where dietary advice main
intervention
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Diets examined: low-fat/high –carb, highfat/low-card, low-cal (1,000 kcal/day),
very-low-calorie (500 kcal/day)
Data did no provide robust conclusions on
effectiveness of dietary advice
Exercise improves glycemic control
Cochrane Library 2004 Issue2:CD004097 [Level 1a]
Protein Restriction
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ADA recommendation for patients with
any chronic kidney disease
Limit protein intake 0.8g/kg/day
Grade B
Diabetes Care 2006;29(suppl 1):S4-S42
Medications
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Initial Monotherapy
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Sulfonylureas inexpensive
Metformin inexpensive
Rosiglitazone and pioglitazone are
expensive and lacking long-term data
Nateglinide less effective than repaglinide
Acarobose and miglitol less effective poorly
tolerated
Medical Letter 2002;1:1
Medications
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When monotherapy fails
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Add second drug with different mechanism of
action
Metformin (vs. pioglitazone) probably better
choice for 2nd agent 1
Dual therapy fails add insulin with metformin
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Less expensive than triple oral therapy
No difference in diabetic control compared
1- Diab Care 2004;27:141 [Level 1b]
2- Diab Care 2003;26:2238 [Level 1c]
2
Medications
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Systematic Review of 63 RCTs duration 3
months reporting HbA1c
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Studied sulfonylureas, metformin, alphaglucosidase inhibitors, thiazolidinediones, nonsulfonylurea secreatagogues
Medications at maximal doses were equally
effective (except nateglinide and alphaglucosidase inhibitors)
Only Sulfonylureas and metformin demonstrate
long term vascular risk reduction
Metformin has advantage of lack of weight gain
and lack of hypoglycemia
JAMA 2002;287(3):360-72 Level 1a)
Sulfonylureas
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Increase insulin secretion by pancreas
Take before meals
Contraindicated in sulfa allergic patients
Second generation safer in renal
disease
Multiple drug interactions
Sulfonylureas
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First generation have more interactions
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Acetoheaxmide
Chlorpropamide
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Tolazamide
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Disulfram reaction more likely
May aggravate CHF or fluid retention
May Cause SIADH
Caution in renal dysfunction
Tolbutamide
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BID dosing decreases GI side effects
Sulfonylureas
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Second-generation agents have fewer
interactions
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Glipizide and Glyburide are less likely to
have disulfram reaction
Gluburide is renally eliminated watch in
renal disease
Glipizide little benefit to doses >20mg/day
Sulfonylureas and hypoglycemia
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52 sulfonylurea-treated subjects with DM
mean age 65 RCT glyburide or glipizide 1
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Participated in 23 hour fasting study
1 week placebo vs. 10mg/day or 20 mg/day of
active drug
No hypoglycemia observed in 156 fasting studies
Second study glipizide similar results
1- JAMA 1998;279(2):1442-3 [Level 1b]
2- JAMA 1999;281(12):1084- [Level 1b]
2
Metformin
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Mechanism
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Improves response to insulin
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Decreased endogenous glucose production
Decreased hepatic gluconeogenesis 1
Enhanced insulin-mediated glucose uptake
Increased use of glucose in intestine and adipose
Reduced GI glucose absorption
Does not stimulate insulin secretion
Requires insulin to be effective
1- NEJM 1998;338(13):867-72 Level 1c
Metformin
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Side effects
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Gastrointestinal upset
Nausea, anorexia, diarrhea, abdominal
discomfort, metallic taste
Dose-related
Minimized by taking with meals and
gradually increasing the dose
0.003% lactic acidosis
Metformin
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Risk factors for lactic acidosis
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Renal impairment (Creat> 1.5 mg/dL men >1.4
mg/dL women)
CHF on medications
Hepatic insufficiency
Hypoxia
Perioperative from major surgery
Binge drinking
Iodinated contrast agents
Metformin
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Preventive measures
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Hold prior to procedure
Restart after 48 hours if renal function is normal
Dissent on contraindications exists
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1-3
Use in pt with CHF associated with decreased
mortality
1,883 patients with DM and CHF
HR 0.66 for metformin vs. sulfonylurea and
metformin 0.54
1- CMAJ 2005 30:173(5):502-05 Level 5
2- BMJ 2003;326(7379):4 Level 5
3- Diabetes Care 2005;28(10):2345 Level 2b
Metformin
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Systematic review 29 RCT 5,259
patients mean follow-up 3 years
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Reduction of mortality from MI in obese or
overweight patients
Improves glycemic control, weight, lipids,
insulinemia, and diastolic pressure
Cochrane Library 2005 Issue 3:CD002966 Level 1c
Insulin Therapy
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Bedtime NPH with sulfonylurea
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Better than NPH alone for control
Allows for lower insulin dose
Based on metanalysis of 16 studies 1
Metformin as well reduces weight gain 2
Addition of PNH vs.. 70/30 reduces
hypogylcemia, reduces weight gain, not as
effective 3
1- Arch Intern Med 1996;156:259 [Level 1c]
2- Cochrane 2004:CD003418 [Level 1a]
3- J Fam Pract 2004;53:393 [Level 2a]
Insulin Therapy
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Long acting glargine insulin
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With sulfonylurea/metformin may be better
than NPH for glycemic control 1
Second study 70/30 associated with
improved control vs. glargine but more
hypoglycemic episodes 2
1- Diabetes Care 2005;28:254 [Level 3]
2- Diabetes Care 2005;28:260 [Level 3]
Aspirin
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Prospective 5.2 year follow up on 2,368
pts with CAD and DM-2
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Observational study
Cardiac mortality 10.9% those taking
Aspirin
Cardiac Mortality 15.9% for those not
taking aspirin
Am J Med 1998;105(6):494-9 Level 2c
ACE Inhibitors
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Reduce albumin excretion rate in
normotensive diabetics but no evidence of
effect on ESRD, glomerular filtration rate, or
side effects 1
Enalipril has long term reduction of frequency
and severity of albuminuria and reduces the
rate of rise of creatinine 2
HOPE trial discloses that ACE inhibitors help
with a wide range of morbidity and mortality 3
1- Cochrane 2001;1:CD002183 [Level 1a]
2- Arch Intern Med 1996;156:286 [Level 1c]
3- Lancet 2000;355:253 [Level 1c]
Cardiovascular Disease Prevention
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Meta-analysis of placebo controlled RCTs
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7 lipid lowering trials
6 hypertension trials
5 glucose control trial
Results for risk reduction combined outcome
coronary heart disease death and non-fatal MI
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Lipid lowering 0.75 (0.61-0.93)
Hypertension control 0.73 (0.57-0.94)
Glucose control 0.87 (0.74-1.01)
69-300 person-years of Lipid tx or HTN tx to prevent
one cardiovascular event
Am J Med 2001;111(8):633-42 Level 1a
American College of Physicians EB
guidelines
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Recommendation 1: Lipid-lowering therapy should be used
for secondary prevention of cardiovascular mortality and
morbidity for all patients (both men and women) with known
coronary artery disease and type 2 diabetes.
Recommendation 2: Statins should be used for primary
prevention against macrovascular complications in patients
(both men and women) with type 2 diabetes and other
cardiovascular risk factors.
Recommendation 3: Once lipid-lowering therapy is initiated,
patients with type 2 diabetes mellitus should be taking at least
moderate doses of a statin.
Recommendation 4: For those patients with type 2 diabetes
who are taking statins, routine monitoring of liver function tests
or muscle enzymes is not recommended except in specific
circumstances.
Ann Intern Med 2004;140(8):644-649 Level
Lipid Management
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Statin therapy for patients with DM-2
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Coronary artery disease (Grade A)
Age >40 plus CV risk factors LDL>2.59
mmol/l with lifestyle changes (Grade A)
Routine use in others (Grade C)
Am Fam Physician 2005;72(5):866 FPIN questions
Lipid Management
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2,838 Patients 40-75 with DM-2 for 6 months
LDL <4.182 mmol/lL 1 other risk factor, no
prior CAD
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RCT of Atorvastatin 10 mg vs. placebo
Median f/u 3.9 years
Risk Reduction Tx vs. placebo
3.6% vs. 5.5% for composite (MI, USA, CHD
Death, Cardiac arrest)
1.7% vs. 2.4% coronary revascularization
1.5% vs. 2.8% stroke
5.8% vs. 9% primary end point (any of above)
NNT31
Lancet 2004;364(9435):685-96 Level 1c
Control the Blood Pressure
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Aggressive blood pressure control pays
off for diabetics 1
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Goal of less than 135 and less than 80
Decreases clinically relevant macrovascular
events
Decreases clinically relevant microvascular
events
Prolongs life
1- Ann Intern Med 2003;138:593 [Level 1a]
Blood pressure and Lipids
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Meta-analysis of 18 trials looking at
Lipid control, HTN control, and Glucose
control
Primary aggregate end point (CHD,
death non-fatal MI)
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Lipid management RR 0.75 NNT 106
HTN management RR 0.87 NNT 157
Glucose management RR0.87 NS
Am J Med 2001;111:633-42 Level 1a
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