Type II Diabetes

Gil C. Grimes, MDSeptember 2006

Objectives Define Diagnosis of Diabetes Describe Pathogenesis Describe risk factors for Type II

diabetes Outline complications Delineate options for therapy

Definition American Diabetes Association

Fasting plasma glucose is the preferred test Three criteria

Symptoms (polyuria, polydypsia, unexplained weight loss) and glucose ≥ 200 mg/dL

Fasting plasma glucose ≥ 126mg/dL on 2 occasions

2 hour plasma glucose (after 75 g anhydrous glucose in water) ≥ 200 mg/dL

WHO prefers Oral glucose tolerance testNational Guideline Clearing House 2002 Aug 22:6574 [Level 5]

Definition Results of ADA changes

Increased diagnosis of diabetes Most of these ‘new’ diabetics have

normal HgA1c 1

No evidence that Tx at low range impacts quality of life 2

1- JAMA 1999;281:1203 [Level 1c]2- Am Fam Physician 1998;58:1287 [level 5]

Definition Fasting vs. 2 hour glucose

tolerance test Fasting criteria less sensitive for

predicting cardiovascular disease Prospective analysis 4,515 pt over 8

years Cardiovascular Health Study Sensitivity ADA fasting 28% Sensitivity WHO criteria 54%

Lancet 1999;345(9179):622-5 [Level 1b]

Prevalence Estimate 8.3% US adults >20 yo

with diabetes1

Estimate 14.4% have either DM or Impaired Glucose Tolerance1

Estimated Lifetime Risk of Diabetes in US2

32.8% males 38.5% female

1- MMWR 2003;52:833 [Level 1c]2- JAMA 2003;290(14):1884 [Level 2c]

Incidence Disease of middle age Mean age in US 46 years 1

Prevalence similar in men and women

Fourth most common diagnosis during Family Physician visits 2

1- Ann Fam Med 2005;3(1):60 [Level 2c]2- Ann Fam Med 2004;2(5):411 [Level 2c]

Pathophysiology Insulin resistance

Usually a receptor or post-receptor defect Manifests as increased insulin requirement Common cause

Obesity (especially abdominal) Metabolic syndrome Genetics and lifestyle

Decreased insulin secretion Possible accelerated age-related loss beta cell Amyloid deposits in > 70% pancreatic cells diabetics

1

Unclear the role in disease

1- NEJM 2000;343(6);411 [Level 5]

Risk Factor Obesity Prospective cohort 37,878 female

nurses followed 7 years BMI more powerful predictor (HR

3.22) than activity 1

Single most important predictor in prospective cohort 89,941 followed 16 years 2

1- JAMA 2004;292:1188 [Level 1b]2- NEJM 2001;345:790 [Level 1b]

Risk Factor Obesity Adult diabetics

85.2% obese or overweight 54.8% obese 1

Obese children 2

Multicentric cohort 167 children and adolescents

BMI >95% for age 25% age 4-10 impaired glucose tolerance 21% age 11-18 impaired glucose tolerance 4% age 11-18 type II DM

1- MMWR 2004;53:1066 [Level 1c]2- NEJM 2002;346:802 [Level 2c]

Risk Factor IGT Population-based cohort study

1342 participants follow-up 6.4 years 1

Performed FPG and 2 hour GTT Odds Ratio for developing DM

10 for IFG 10.9 for isolated IGT 39.5 for both

1- JAMA 2001;285:2109 [Level 2c]

Risk Factor IGT Prospective cohort study 1,197 VA

patients over 3 years HgA1c.7% led to testing fasting

glucose 73 patients developed dm (6.1%) Annual incidence

0.8% if HbA1c<5.5% 2.5% if HbA1c 5.6-6% 7.8% if HbA1c 6.1-6.9%

J Gen Intern Med 2004;19(12):1175 [Level 1b]

Risk Factor Activity Prospective cohort from Nurses

Health Study 68,497 women without DM 1

1515 new cases of DM Each 2 hours/day sedentary increase

risk obesity 5% and DM 7% TV Watching associated with 23%

increase risk obesity and DM 14%1- JAMA 2003;289(14):1785 [Level 1b]

Risk Factor Diet Western Diet associated with

increased risk of DM 42,504 men age 40-75 followed 12

years 1,321 developed DM Relative Risk 1.59 diet alone Relative Risk 1.96 diet and sedentary

Ann Intern Med 2002;136:201 [Level 1c]

Risk Factor Diet Western Diet associated with

increased risk of DM 69,554 women age 38-63 followed 14

years 2,699 developed diabetes Relative Risk 1.49 diet Relative Risk per increase serving

Red meat 1.38 Processed meat 1.73

Arch Intern Med 2004;164(20):2235 [Level 1c]

Risk Factor Diet High glycemic index foods low fiber

diet associated with increased risk of DM 1

Prospective cohort 91,249 women, 741 cases of DM, followed 8 years

Higher glycemic index higher the risk for developing diabetes (RR 1.27)

Higher cereal fiber reduces risk (RR 0.64)1- Am J Clin Nutr 2004;80:348 [Level 1c]

Risk Factor Gestational DM Prospective cohort 696 women with GDM

1

Followed with GTT post-partum and every 5 years

Risk of abnormal GTT 42.4% at 11 years Risk of DM 13.8%

Prospective cohort 481 women with diet controlled GDM 2

40% incidence after10 years 27% impaired GTT

1- Diabetes Care 2003;26:1199 [Level 1c]2- Diabetes Care 2004;27:1194 [Level 1c]

Risk Factor PCOS Prospective cohort 67 women with

PCOS for 6.2 years 1

54 with normal GTT subsequently 17% developed DM

13 with impaired GTT subsequently 54% developed DM

1- Hum Reprod 2001;16:1995 [Level 1c]

Risk Factor Medications Prospective double blind RCT 44

postmenopausal women not on HRT Raloxifen or estrogen vs.. placebo Looked at effects on insulin

sensitivity Used glucose tolerance test to check

for insulin sensitivity Insulin Sensitivity decreased in

raloxifeneJ Am Geriatric Soc 2003;51(5):683-8 [Level 2b]

Risk Factor Medications Gatifloxacin et al may affect glycemic

control as seen in two case control studies 788 case patients in ED or

hospital with hypoglycemia Gatifloxacin OR 4.3 Levofloxacin OR 1.5

470 case patients with hospital diagnosed hyperglycemia

Gatifloxacin OR 16.7 Moxifloxacin OR 1.7

NEJM 2006 March 30 early release on-line [Level 3b]

Complications Prospective population study 13,105

subjects followed for 20 years 1

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 Prospective cohort 4,662 men

aged 45-79 followed 2-4 years 1

Increase HgA1c 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 Macrovascular complications

75-80% diabetic deaths related to atherosclerosis

75% accelerated CAD 25% accelerated CVD and PVD

>50% diabetics hypercholesterolemic

DynaMed accessed March 15 2006

Complication CAD Meta-analysis of 37 prospective

studies 447,064 patients Rate of Fatal CAD 5.4% vs. 1.6% for

diabetics Women RR 3.50 Men RR 2.06

BMJ 2006;332(7533):73-8 [Level 1a]

Complication CAD Diabetes may be as risky as a prior MI 1

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

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 Prospective cohort 49,582 Finish

subjects without stroke or CAD at baseline followed 19.1 years followed for stroke 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 Prospective cohort 1,294 patients

with DM-2 Subgroup of 531 with sufficient

screening for PAD PAD at entry 13.6% (161 patients) 14 developed PAD (75 patients) Incidence of new PAD 3.7 per 100 pt

yearsDiabetes Care 2206;29(3):575-80 [Level 2b]

Complication Microvascular Microangiopathy

Retinopathy (RR20) #1 cause of new blindness #3 cause of blindness

Neuropathy (ESRD RR25) Nephropathy

BMJ 2000;320(7241):1062 [Level 5}

Complication Coma Hyperosmolar Coma

Most common in elderly patients Also occurs in children

8 case reports in obese children Causes

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 Mild episodes common

Retrospective cross-sectional analysis of 1,055 outpatients

Prevalence of symptoms 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 Younger age Insulin use Lower HbA1c at follow-up

Arch Intern Med 2001;161(13):654-9 [Level 2b]

Treatment Goals American Diabetes Association

Recommendations Control of glycemia is important

Goal is HgA1c less than7%Grade B Pre-meal glucose 90-130mg/dL Post-meal glucose <180mg/dL Blood pressure <130/80

Lipid control LDL <100 mg/dL Triglycerides <150 mg/dL HDL >40 mg/dL men or >50 mg/dL women

Diabetes Care 2006 Jan;29(suppl 1):S4-S42

Cost-effectiveness CDC cost-analysis Hypothetical cohort patients >25 yo new

diabetes Antihypertensive Therapy

Improved quality of life and cost savings age 25-84 Very cost-effective 85-94

Intensive Glycemic Control 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 Dietary changes and exercise

works 20-50% of patients can control

their diabetes with diet, exercise and weight reduction Current trial lookAHEAD is recruiting

patients for lifestyle management study

Exercise Exercise training reduces the HgA1c

Metanalysis of 14 trials duration 8 weeks

HgA1 c 7.65% vs. 8.31% 1

Increased activity reduces risk of MI, Stroke 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 Systematic review of 18 RCT lasting

6 months where dietary advice main intervention Diets examined: low-fat/high –carb,

high-fat/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 controlCochrane Library 2004 Issue2:CD004097 [Level 1a]

High Fiber Diet 13 patients with DM-2 randomized in

crossover fashion 6 week each arm ADA diet 8gm soluble fiber 16 gm insoluble fiber High-fiber 25 gm soluble fiber and 25 gm

insoluble fiber Mean pre-prandial glucose 142 vs. 130 (p=0.04) Mean HbA1c 7.2% vs. 6.9% (p=0.09) Mean LDL 142 mg/dL vs. 133 mg/dL (p=0.11) May not be generalizable due to meals etc.

NEJM 2000;342(19):1392-8 [Level 1b]

Glycemic Index 8 men with DM-2 at VA facility

randomized in crossover trial Low-biologically-available-glucose diet HbA1c 9.8% vs. 7.6% Took place in research center 1

Low glycemic meals may reduce hyperinsulinism Evidence limited Small studies with methodological problems

1- Diabetes 2004;53(9):2375-82 [Level 1b]2- JAMA 2002;287(18):2414-23 [Level 3a]

Protein Restriction 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 Initial Monotherapy

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 toleratedMedical Letter 2002;1:1

Medications When monotherapy fails

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 Less expensive than triple oral therapy No difference in diabetic control compared 2

1- Diab Care 2004;27:141 [Level 1b]2- Diab Care 2003;26:2238 [Level 1c]

Medications Systematic Review of 63 RCTs duration 3

months reporting HbA1c Studied sulfonylureas, metformin, alpha-

glucosidase inhibitors, thiazolidinediones, non-sulfonylurea secreatagogues

Medications at maximal doses were equally effective (except nateglinide and alpha-glucosidase 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 Increase insulin secretion by

pancreas Take before meals Contraindicated in sulfa allergic

patients Second generation safer in renal

disease Multiple drug interactions

Sulfonylureas First generation have more interactions

Acetoheaxmide Chlorpropamide

Disulfram reaction more likely May aggravate CHF or fluid retention May Cause SIADH

Tolazamide Caution in renal dysfunction

Tolbutamide BID dosing decreases GI side effects

Sulfonylureas Second-generation agents have

fewer interactions 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 52 sulfonylurea-treated subjects with

DM mean age 65 RCT glyburide or glipizide 1

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 2

1- JAMA 1998;279(2):1442-3 [Level 1b]2- JAMA 1999;281(12):1084- [Level 1b]

Metformin Mechanism

Decreased endogenous glucose production Decreased hepatic gluconeogenesis 1

Improves response to insulin 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 Side effects

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 Risk factors for lactic acidosis

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 Preventive measures

Hold prior to procedure Restart after 48 hours if renal function is

normal Dissent on contraindications exists 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 0.541- CMAJ 2005 30:173(5):502-05 Level 52- BMJ 2003;326(7379):4 Level 53- Diabetes Care 2005;28(10):2345 Level 2b

Metformin Systematic review 29 RCT 5,259

patients mean follow-up 3 years 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

Glitazones Mechanism of action

Decrease insulin resistance at peripheral sites and liver

Decrease hepatic glucose production Adverse Effects

Fluid retention and heart failure Retrospective study 5,441 patients DM-2 on

glitazones vs. 28,103 controls Mean follow-up 9 months CHF 2.3% treatment group vs. 1.4% controls NNH 111

Diabetes Care 2003;26(11):2983-9 Level 2b

Glitazones Adverse Effects

Hepatotoxicity Extracted to some degree from data

on troglitazone and case reports Review 22 studies >6,000 patients

LFT measured q4weeks x3 months then q6-12 weeks

ALT Levels >3x ULN 0.32% rosiglitazone 0.17% placebo 0.4% sulfonylurea, metformin, insulin

Diabetes Care 2002;25(5):815-21 Level 2b

Glitazones Adverse Effects

Macular Edema case reports usually in patients with peripheral edema 1

Drug Interactions Gemfibrozil inhibits metabolism or

rosiglitazone and possibly pioglitazone Randomized crossover trial 10 health

volunteer 2

1- FDA MedWatch 2006 Jan5 Level 42- Diabetologia 2003;46(10):1319-23 Level 2c

Alpha-glucosidase inhibitors

Works by inhibiting post-prandial absorption of glucose

Side effects Flatulence, cramps, abdominal distention,

borborygmus, diarrhea May interfere with glucose therapy for

hypoglycemia 2

Improved glycemic control and insulin levels

No effect on lipids or body weight Unknown effectiveness on morbidity

and mortality 11- Cochrane Library 2005 Issue 2:CD003639 Level 1c2- The Medical Letter 1996;38(967):9

Pramlintide Symlim Synthetic analog of human amylin Use with insulin therapy Injected prior to major meals Mechanism of action

Modulates gastric emptying Increases feeling of satiety

Injection medication Adverse effects

Hypoglycemia especially in DM-1 or gastroparesis Should not be used in pt unable to determine when blood

sugar is low Nausea, vomiting, abdominal pain, headache, fatigue,

dizziness

FDA Talk Paper 2005 March 17

Pramlintide Drug Interactions

May decrease absorption of oral drugs

Not recommended with anticholinergics, acarbose, or miglitol

Cost AWP $79.50 per month

Am J Health Syst Pharm 2005;62(8):816-22 Level 2b

Exenatide Byetta Used with metformin or sulfonylurea or both Injected prior to morning and evening meal Mechanism of action

Incretin mimetic, stimulates glucagon-like peptide-1 receptor

Stimulates production of insulin in the presence of high blood glucose

Inhibits release of glucagon Slows gastric emptying Associated appetite suppression and weight loss

Prescriber’s Letter 2005 Detail Document 210603

Exenatide Adverse Effects

Hypoglycemia seen in patients on sulfonylurea (14.4-35.7% dose dependent)

Nausea, vomiting, diarrhea, dizziness, headache, dyspepsia

Withdrawal due to adverse effects 7% vs. 3%

May alter absorption of oral medications Cost $147-172 per moth

Prescriber’s Letter 2005 Detail Document 210603

Insulin Therapy Bedtime NPH with sulfonylurea

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 Long acting glargine insulin

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]

Inhaled Insulin Exubera Inhaled 10 minutes prior to meal dosed

in milligrams 0.05 mg/kg rounding down 1mg ≈ 3 units regular & 3mg ≈ 8 units Three 1mg doses is not equal to one 3mg

dose Mechanism of action

Small particle size 1-3 microns dry powder Deposited in alveoli Absorbed into capillary bloodstream 6-10% of inhaled insulin reached systemic

circulationPrescriber’s Letter 2006 Detail Document 220308

Inhaled Insulin Adverse Effects

Hypoglycemia Related to rate of absorption and duration of action Similar rate to injection insulin

Cough Mild and non-productive Occurs within second to minutes Decreases with continued use

Dry Mouth Mild to moderate severity

Prescriber’s Letter 2006 Detail Document 220308

Inhaled Insulin Contraindications

Hypersensitivity to human insulin Smoking within the last 6 months Unstable or poorly controlled lung

disease Speed of onset similar to rapid

acting insulin

Prescriber’s Letter 2006 Detail Document 220308

Aspirin Prospective 5.2 year follow up on

2,368 pts with CAD and DM-2 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 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 Meta-analysis of placebo controlled RCTs

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

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 eventAm J Med 2001;111(8):633-42 Level 1a

American College of Physicians EB guidelines 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 Statin therapy for patients with

DM-2 Coronary artery disease (Grade A) Age >40 plus CV risk factors LDL>100

with lifestyle changes (Grade A) Routine use in others (Grade C)

Am Fam Physician 2005;72(5):866 FPIN questions

Lipid Management 2,838 Patients 40-75 with DM-2 for 6

months LDL <161.5 mg/dL 1 other risk factor, no prior CAD 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 Aggressive blood pressure control

pays off for diabetics 1

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 Meta-analysis of 18 trials looking

at Lipid control, HTN control, and Glucose control

Primary aggregate end point (CHD, death non-fatal MI) 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

Control the Blood Pressure “We do not intend to suggest that

glycemic control is an ineffective intervention, but rather that treatment of hypertension should be prioritized and stressed as the most important intervention for the average population of persons with type 2 diabetes”

1- Ann Intern Med 2003;138:593 [Level 1a]