12901990 Diabetes Mellitus Today

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DIABETES MELLITUS

DIANA W. GUTHRIE RN, PhD

DEFINITION & THE PROBLEM

• CRITERIA FOR DIAGNOSIS

• DEFINITION

• PATHOPHYSIOLOGY

• PREVALENCE

• OBESITY

METABOLIC SYNDROME

Glucose Tolerance Cate ories

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care.2002;25(suppl):S5

FP 2-hr PG on

100 and <126

140 and

Glucos

Prediabet

Diabetes

Toleranc

Prediabet

Diabetes

mg/d mg/d

Etiologic Classification of

Type 1 -cell destruction withlack of

insulin

Type 2 Insulin resistance withinsulin

deficiency

Other specific Geneticdefects in -cell Types exocrine pancreasdiseases,

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-

Source: Mokdad et al., Diabetes Care 2000;23:1278-83;

Diabetes Trends* Among Adults in theU.S.,

Prevalence of Diabetes in

Obesity Trends* Among U.S. AdultsBRFSS, 1991-2002

No Data <10% 10%–14% 15%–19% 20%–24%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4”

DNPAGraphics:DNPA

Graphics:Diabetes Trends* Among Adults in theU.S.,

Source: Mokdad et al., J Am Med

Source: Behavioral Risk Factor Surveillance System, CDC

(*BMI 30, or ~ 30 lbs overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4”

Obesity Trends* Among U.S. AdultsBRFSS, 2002

• 20.8 million Americans have

diabetes• 1.5 million new cases in 2005

more than 3500 each day

Complications of diabetes area major cause of mortality andmorbidity (2002 statistics)

90% of patients with diabetes are

treated by primary care

Diabetes Today: An Epidemic

ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed April 11, 2005;ADA Diabetes Statistics. Available at http://www.diabetes.org/utils/printthispage.jsp?PageID=STATISTICS_233181. December 29,

Total Cost of Diabetes in the US, 2002Total Cost of Diabetes in the US, 2002

Indirect CostsIndirect Costs$39.8 billion$39.8 billionHealth Care ExpendituresHealth Care Expenditures

$91.8 billion$91.8 billion

DisabilityDisability$18.3 billion$18.3 billion

MortalityMortality$21.5 billion$21.5 billion

Inpatient careInpatient care

$40.3 billion$40.3 billion

Outpatient care/Outpatient care/home health &home health &medicationsmedications$37.1 billion$37.1 billion

Nursing home & hospiceNursing home & hospice$14.4 billion$14.4 billion

Total CostTotal Cost$132 billion$132 billion

American Diabetes Association. American Diabetes Association. Diabetes CareDiabetes Care. 2003;26(3):917-932.. 2003;26(3):917-932.

The Problem

Modern Life Has Both

Illustration taken from: Lambert C, Bing C. The Way We Eat Now. Harvard Magazine. May-June, 2004;50.

METABOLIC SYNDROME

• Obesity- high waist to hip ratio

• Hyperlipidemia

• Hyperinsulinemia

• Hypertension

• Hyperglycemia

Acanthosis Nigricans• PCOS

ACANTHOSIS NIGRICANS

Waist/Hip Ratio

High WHR

Low WHR

American Diabetes Association

Normal Type 2 Diabetes

Courtesy of Wilfred Y. Fujimoto, MD.

Visceral Fat DistributionNormal vs Type 2 Diabetes

And America Continues to Enjoy

Strong Economic Growth……………………………..

Glucose

-1 - 0 5 1 1 2 2 3

Years of Diabetes*IFG=impaired fasting glucose.

Burger HG, Loriaux DL, Marshall JC, Melmed S, Odell WD, Potts JT, Jr., Rubenstein AH. 2001. DiabetesMellitus, Carbohydrate Metabolism, and Lipid Disorders. Chap. in Endocrinology . 4th ed. Edited by Leslie J.

DeGroot and J. Larry Jameson. Vol. 1. Philadelphia: W.B. Saunders Co. Originally published in Type 2 Diabetes BASICS. (Minneapolis, International Diabetes Center, 2000).

Relative

Functio

Fasting Glucose

Postmeal Glucose

Obesit I DiabetUncontrolledHyperglyce

Insulin

-cell Failure

Course of T e 2 Diabetes

*FFA=free fatty acids; TG=triglycerides.

Adapted from: Kahn SE. J Clin Endocrinol Metab. 2001;86(9):4047-4058. Adapted from: Ludwig DS. JAMA. 2002;287(18):2414-2423.

Factors That May Drive the

InsulinResistanc

Hyperglycemia(glucose

“Lipotoxicity”(elevated FFA*,

Progression to Type 2 Diabetes

Kruszynska Y, Olefsky JM.Kruszynska Y, Olefsky JM. J Invest Med J Invest Med ..1996;44:413-428.1996;44:413-428.Weyer C, et al.Weyer C, et al. J Clin Invest.J Clin Invest. 1999;104:787-794.1999;104:787-794.

Insulin

Hyperinsuline

Compensated insulinresistance

Impaired glucose

ß-cell

Type 2

Genetic Factors

Acquired:•Obesity

•Sedentary lifestyle•Aging

ß-cell

Glucose and/or fat toxicity

Over 90% of type 2 diabetics are Insulin Resistant

InsulinResistance

Hypertensi

Type 2

Disordered

ComplexDyslipidem

Endothelial Systemic

Inflammati

Atheroscleros

Viscer al

Adapted from the Consensus Development Conference of the AmericanDiabetes Association.

The Importance of Targeting Insulin

ETIOLOGY OF T1DM

DQ* D C B A

SHORT ARM # 6 CHROMOSOME

IMPORTANCE OF GLUCOSECONTROL

• DCCT

• KUMAMOTO

• UKPDS

• IN-PATIENT CONTROL

BrainCerebrovascular disease

• Transient ischemicattack

• Cerebrovascular accident

• Cognitive impairment

Complications of Diabetes

HeartCoronary artery disease

• Coronary syndrome• Myocardial infarction• Congestive heart

ExtremitiesPeripheral vascular disease

• Ulceration• Gangrene• Amputation

Macrovascul Microvascul

EyeRetinopathyCataractsGlaucoma

KidneyNephropathy

• Microalbuminuria• Gross albuminuria• Kidney failure

NervesNeuropathy

• Peripheral• Autonomic

Retinopathy

Nephropathy

Neuropathy

Macrovascular disease

* not statistically significant

Kumamoto

17-21%

24-33%

Diabetes Control and Complications Trial (DCCT) Research Group.Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med N Engl J Med . 1993;329:977-986.. 1993;329:977-986.

Ohkubo Y et al.Ohkubo Y et al. Diabetes Res Clin Pract Diabetes Res Clin Pract . 1995;28:103-117.. 1995;28:103-117.UK Prospective Diabetes Study Group (UKPDS) 33:UK Prospective Diabetes Study Group (UKPDS) 33: Lancet Lancet .. 1998;352:837-853.1998;352:837-853.

Good Glycemic Control (Lower

Glycemic Goals For Diabetes

IN-HOSPITAL MANAGEMENT

• PREVALENCE

• SURGERY

• MI

• INFECTION

• ICU

Consensus:

• Intensive care unit

–110 mg/dL (6.1 mmol/L)

Medical/surgical floors –110 mg/dL (6.1 mmol/L) preprandial

–140 mg/dL (7.78 mmo/L) maximal

glucoseValues above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levelsmore frequently to determine the direction of any glucose trend and theneed for more intensive intervention. Achieving these targets may requireconsultation with an endocrinologist or diabetes specialist.

American Association of Clinical Endocrinologists. Available at:http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.

Diabetes in Hospitalized

• Fourth most common co-morbidcondition among hospitalizedpatients

• 10–12% of all hospital discharges

• 29% of all cardiac surgery patients

1–3 days longer hospital stay

Hogan P, et al. Diabetes Care. 2003;26:917–932. American Association of Clinical Endocrinologists. Available at:

http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.

Hyperglycemia in Patients

• Hyperglycemia occurred in 38% of patientsadmitted to the hospital – 26% had known history of diabetes

12% had no history of diabetes• Newly discovered hyperglycemia was associated

– Higher in-hospital mortality rate (16%) compared with

patients with a history of diabetes (3%) and patientswith normoglycemia (1.7%; both P < 0.01)

Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–

Higher Costs:Higher Costs:

• Higher rate of hospitalizationHigher rate of hospitalization

• Longer staysLonger stays

• More procedures, meds.More procedures, meds.

• Chronic complicationsChronic complications

• More arteriosclerotic disease-More arteriosclerotic disease-• More infectionMore infection

Hyperglycemia Is an Independent Marker of

Adapted from Umpierrez GE, et al. J Clin Endocrinol Metab. 2002;87:978–

In-hospitalMortality Rate

NewlyDiscovered

Hyperglycemia

PatientsWith Historyof Diabetes

PatientsWith

Normoglycemia

P < 0.01

Hospital Mortality Rate and

MortalityRate (%)

Mean Glucose Value (mg/dL)

Retrospective review of 1,826 consecutive intensive care unitpatients

at The Stamford Hospital in Stamford, Connecticut.

Intensive Insulin Therapy in

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

Conventional: insulin when blood glucose > 215 mg/dL.Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110

Survival

in ICU (%)

0 20 40 60 80 100 120 140 160

Intensive treatment

Conventional treatment

Days After Admission

Intensive Insulin Therapy in Critically

• Intensive therapy to achieve blood glucose levels of 80–110 mg/dL reduced mortality (-34%), sepsis (-46%),dialysis (-41%), blood transfusion (-50%), andpolyneuropathy (-44%)

van den Berghe G, et al. N Engl J Med . 2001;345:1359–1367.

Reduction(%)

Mortality Sepsis Dialysis neuropathy

Transfusion

46%41%

Hyperglycemia and Risk of

• Glucose > 220 mg/dL onpostoperative day 1 is

– A sensitive predictor of nosocomialinfection

– Associated with•

2.7 times higher rate of infection• 5.9 times higher rate of severe infection

Pomposelli JJ, et al. J Parenter Enteral Nutr. 1998;22:77–

Glucose Control Lowers Risk of Wound

Reprinted from Zerr KJ, et al. Ann Thorac Surg . 1997;63:356–361 with permission from

Society of Thoracic Surgeons.

Deep WoundInfectionRate (%)

13%16%

Day 1 Blood Glucose

P = 0.002

Portland Diabetic Project:Incidence of DSWI and Impact of

DSWI = deep sternal wound infection; CII = continuous insulin infusion.

DSWI(%)

87 88 89 90 91 92 93 94 95 96 97

Patients with diabetes

Patientsdiabetes

Reprinted from Furnary AP, et al. Ann Thorac Surg . 1999;67:352–362 with permission

from Society of Thoracic Surgeons.

Cost-Effectiveness in First

For every 9 patients treated withintensive insulin regimen, one life was

Almbrand B, et al. Eur Heart J. 2000;21:733–739.

DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction.

Indications for Intravenous

• Diabetic ketoacidosis• Nonketotic

hyperosmolar state

Critical care illness(surgical, medical)• Postcardiac surgery• Myocardial infarction

or cardiogenic shock• NPO status in Type 1

diabetes

• Labor and delivery

• Glucose exacerbatedby high-dose

glucocorticoidtherapy

• Perioperative period

• After organ

transplant

American Association of Clinical Endocrinologists. Available at:

http://www.aace.com/pub/ICC/inpatientStatement.php. Accessed March 17, 2004.

Yale Insulin Infusion Protocol

Insulin infusion: Mix 1 U regular human insulin per 1 mL0.9% NaCl Administer via infusion pump inincrements of 0.5 U/h

START INSULIN AT O.O5 U/KG/HR

Subsequent rate adjustments:Changes in infusion rate are determined by the current infusion

rateand the hourly rate of change from the prior BG level; see table

for instructionsOR ORDER-TITRATE TO KEEP BG 70-140 MG/DL

Goldberg PA, et al. Diabetes Care. 2004;27:461–

Insulin Requirements in Health

Healthy Sick/Eatin Sick/NPO

Correction

Nutritional

PrandialBasal

TREATMENT OF DIABETES

• IV INSULIN THERAPY

• ORAL HYPOGLYCMIC AGENTS

• INSULINS

• NEW AGENTS – SYMLIN

– BYETTA

– DPP-IV INHIBITORS

– ALPHA-GAMMA TZD

GlucosGlucos

RelativeRelativeFunctionFunction

-1 - 0 5 1 1 2 2 3

Years of Diabetes Years of Diabetes

InsulinInsulin

FastingFasting

Beta cellBeta cell

Post MealPost Meal

At riskAt riskfor for

Timeline for Utilization of

LifestyleLifestyle InsulinInsulin

Metformin, TZD, AGIMetformin, TZD, AGI

SUMeglitinide

Oral Agents

Drug Class

Sulfonylureas

Examples

GlimepirideGlipizideGlyburide

RepaglinideMeglitol

Principal Mode of Action

Stimulate insulinsecretion frompancreatic ß-cells

Key Issues

HypoglycemiaWeight gain

Examples

Metformin

RosiglitazonePioglitazone

AcarboseMi litol

Principal Mode of ActionDecreases hepaticglucose

Improve peripheral

insulin sensitivity

Dela carboh drate

Key Issues

GI upsetRenal dis.

Liver enzymes

Weight gain

Flatulence

Oral Agents•

•Drug Class

•Biguanides

•TZD

• Alpha-lucosidase

Mi i ki N t With I li

Mimicking Nature With Insulin

Ph siolo ic Insulin Secretion

s u l i n

U / m L

G l u c

/ d L )

7 8 9 1 11 1 1 2 3 4 5 6 7 8A PTime of Day

§ Suppresses glucose productionbetween meals and overnight

§ Nearly constant levels

§ 50% of daily needs

Basal insulin

Adapted with permission from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology.

Comparison of Human Insulins

Onset of Duration of Insulin Preparations Action Peak Action

Lispro,Asparte,Apidra 5 to 15 min 1 to 2 hr 4 to 6 hr

Human Regular 30 to 60 min 2 to 4 hr 6 to 10 hr

Human NPH 1 to 2 hr 4 to 6 hr 10 to 16 hr

Glargine 2 hr none 22 to 24 hr

* The time course of action of any insulin may vary in different individuals, or at different times in the same individual.

Because of thisvariation, time periods indicated here should be considered as general guidelines only.

I n s u l i n

B DL H

Endogenous

Adapted with permission from McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY:

Marcel Dekker, Inc; 2002:193

Short Acting Insulin Analogs:

Short-Acting Insulin Analogs:

Human InsulinHuman Insulin

Insulin aspart

Aspartate at positionB28 instead of proline

Insulin lispro

Positions of proline andlysine reversed at B28 and

Adapted with permission from Barnett A, Owens D.Lancet. 1997;349:47

Bolli G et al. Diabetologia. 1999;42:1151

GLULISINE-APIDRA

GLULISINE APIDRA VS

GLULISINE-APIDRA VS

APIDRA VS HUMALOG VS

Insulin Glargine

Bolli GB, Owens DR. Lancet.

Produced by recombinant DNA technology; 2 modifications in amino acid sequence of insulinmolecule create stable molecule

Clear solution pH

Microprecipitati

Dissolutio

Capillary

Injectionacidic solution (pH

Microprecipitation of

glargine in SC(pH

Slow dissolutionstabilized

Protracted

Seipke G et al. Diabetologia. 1992;35:A4; Hilgenfeld R et al. Diabetologia. 1992;35:A193

Mechanism of Action

Insulin in

INSULIN TACTICS

Gl i NPH I li i T

Glargine vs NPH Insulin in Type

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

Time (h) After SC

End of observation

Glargin

G l u c o s e U t i l i z a t i o n R a t e

/ k / h

Insulin detemir

LysB29(N -tetradecanoyl)des(B30)human insulin

Insulin detemir

INSULIN IN DIABETES

• INSULIN REQUIREMENTS – 1-2 UNITS/KG/DAY FOR CHILDREN-1/2-

1UNITS/KG/DAY FOR ADULTS DEPENDINGON DEGREE OF KETOSIS &/OR GROWTHRATE

– DISTRIBUTION FOR INJECTABLE INSULIN• BREAKFAST 20% OF TOTAL AS FAST ACTING

• LUNCH 13% OF TOTAL AS FAST ACTING

• SUPPER 17% OF TOTAL AS FAST ACTING• BEDTIME 50% OF TOTAL AS LONG ACTING

EXAMPLE – 24 Units/day

CASE K.M.

EXUBERA INHALABLE INSULIN

Photograph reproduced with permission of

Continuous Glucose Monitoring SystemContinuous Glucose Monitoring System

Continuous Glucose Monitoring SystemContinuous Glucose Monitoring System(CGMS)(CGMS)

3 Interstitial fluid

glucose(G2) is ?comparable with

Interstitial Fluid Measurement

Adapted from Unger RH, Foster DW. Williams Textbook of Endo (8th edition) 1992; 1273-1275

Amylin the Hormone

• Reported in 1987

• 37-amino acid peptide

• Co-located and co-secreted with insulin

from pancreatic β-cells• Neuroendocrine hormone

• Deficient in diabetes

GILA MONSTER ORIGINAL

GILA MONSTER-ORIGINAL

Prescribing Consideration

•2 fixed-dose prefilled pens – 60 doses per pen (30-day supply)

– Ready to use, easy to teach

See Important Safety Information included in this presentation

Summary

• The evidence is overwhelming that goodcontrol does count

• Morbidity and mortality can be reduced

• There is nothing inevitable about thecomplications of diabetes

S ( t)

Summary (cont)

• The cost of diabetes is in its complications

• Any expense paid up front in better management will pay off handsomely in

the long run• The tools for good diabetes care already

•No tool is more important than theservices of a certified diabetes educator

S ( t)

Summary (cont)

• Assessment tools include Self Monitoringof Blood Glucose and HbA1C

• Targets should be established for each of

these for each patients within the nationalguidelines

• When targets are not reached the help of

a specialist should be sought• Christopher D. Saudek MD. Pres. ADA

Summary

• Insulin administration should mimic nature

• Natures way is basal insulin 24 hrs. a day

• And bolus insulin with every feeding

• Insulin lispro, asparte or glulisine cansupply bolus

• Insulin glargine or detemir can supply the

basal with one injection per day• Control of blood sugar will prevent the

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