New Perspectives in the Management of

Type 2 DiabetesHerold Merisier, MD, FAAFP

Voluntary Assistant Professor of Family MedicineMiller School of Medicine, University of Miami

Plantation, FL

DisclosureSpeaker: Novartis PharmaceuticalsSpeaker: Novo-Nordisk

Diabetes 2010 Epidemiology Diagnosis Screening Management of Type 2 Diabetes

Patient Education Therapeutic Lifestyle Changes (TLC) Pharmacotherapy Treatment of co-morbid conditions

Diabetes in the US 23.6 million children and adults affected (7.8% of the

population)Diagnosed: 17.9 million peopleUndiagnosed: 5.7 million people1.6 million new cases in adults > 20y/o in 20074300 new cases every dayPre-Diabetes: 57 million people2-4 fold increase in cardiovascular mortality and stroke

Center for Disease Control and PreventionAvailable at: http://www.cdc.gov/diabetes/pubs/estimates07.htm#1

Diabetes in Canada1.8 million adults with DiabetesPrevalence: 4.8% (1998): 1 054 000 adult

CanadiansPrevalence: 5.5% (2005)

Available at: http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf

23.0 M36.2 M↑57.0%

14.2 M26.2 M↑85%

48.4 M58.6 M↑21%

43.0 M 75.8 M ↑79%

7.1M15.0 M↑111%

39.3 M81.6

M

↑108%

M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific

Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

Global Projections for the Diabetes Epidemic: 2003-2025

World2003 = 194 M2025 = 333 M↑ 72%

AFR

NA

SACA

EUR

SEAWP

19.2 M39.4 M↑105%

EMME

2003 2025

DiagnosisNormoglycemi

aImpaired Glucose

MetabolismDiabetes

FPG < 100 mg/dlFPG ≥ 100 mg/dl

< 126 mg/dlIFG

FPG ≥ 126 mg/dl(x 2)

2hPPG < 140 mg/dl

2hPPG ≥ 140 mg/dl< 200 mg/dl

IGT

2hPPG ≥ 200 mg/dl

or RPG ≥ 200 mg/dl w/ sx of

Diabetes

HbA1c ≥ 6.5 (x 2)Adapted from Clinical Practice Recommendations. Diabetes Care, 2010

IFG: Impaired Fasting Glucose FPG: Fasting Plasma Glucose RPG: Random Plasma GlucoseIGT: Impaired Glucose Tolerance PPG: Post-Prandial Glucose

Screening All individuals ≥ 45y/o, particularly if BMI ≥ 25

if normal, repeat every 3 years Start screening at younger age if BMI ≥ 25 and:

physically inactive first-degree relative with Diabetes high risk ethnic group h/o IFG, IGT, Gestational Diabetes, PCOS Dyslipidemia or h/o cardio-vascular disease

Fasting glucose or 2-hour OGTT Diabetes Risk Calculator

Diabetes Risk CalculatorGenderAgePrior history of elevated blood glucoseHeight and weightDietSmoking historyPhysical activityFamily history

Diabetes Care. 2008 May;31(5):1040-5

Diabetes Risk Calculator

Available at: http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/

Diabetes Risk Calculator

Available at: http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/

QD Score (http://www.qdscore.org)

BMJ 2009;338:b880. Available at: http://bmj.com/cgi/content/full/338/mar17_2/b880

Management of Type 2 Diabetes

Patient EducationTherapeutic Lifestyle Changes (TLC)Pharmacotherapy Treatment of co-morbid conditions

Pharmacotherapy: Oral AgentsClass Drugs Mechanism of actionα-Glucosidase Inhibitor

AcarboseMiglitol

Decrease carbohydrate absorption in GI tract

Biguanides Metformin Decrease hepatic neoglucogenesis

Secretagogues Sulfonylureas Meglitinides

Glyburide, Glipizide, GlimepirideRepaglinide, Nateglinide

Stimulate β-cell to increase insulin output

ThiazolidinedionesPioglitazone (Actos®)Rosiglitazone (Avandia®)

Improve insulin sensitivity, decrease insulin resistance

DDP-4 InhibitorsSitagliptin (Januvia®)Saxagliptin (Onglyza®)

Slow incretin metabolism, Increase insulin synthesis/release, Decrease glucagon levels

DPP-4 Inhibitors

Rosiglitazone (Avandia®)

Contraindicated in patients with CHFMeta-analysis of 42 clinical studies:

Mean duration 6 months; 14,237 total patients Rosiglitazone vs. placebo Increased risk of risk of myocardial ischemic events

Three other studies Mean duration 41 months; 14,067 total patients Rosiglitazone vs. other oral diabetes medications or

placebo Increased of MI neither confirmed nor excluded this

risk

18

Progressive -cell Failure in Type 2 Diabetes

-12 -6 0 6 120

20

40

60

80

100

-ce

ll Fu

nctio

n(%

)

Based on data of UKPDS 16: conventional (diet) treatment group. Diabetes. 1995.

Years

Diagnosis

Pharmacotherapy: Non-Insulin Injectables

Class Drug Mechanism of action

GLP-1 Analog(Incretin Mimetic)

Exenatide (Byetta®)

Liraglutide (Victoza®)

increases beta-cell responsedecreases glucagon secretiondelays gastric emptying

Amlynomimetic

Pramlintide (Symlin®)

slows gastric emptyingdecreases glucagon secretionearly satiety → weight loss

Insulin Preparation Onset Peak Duration

Short actingRegular 30-60

min. 3-4h 6-8hIntermediateNPHLenteUltralente

2-4h3-4h4-6h

6-10h6-12h10-16h

14-18h16-20h20-24h

Combinations70% NPH / 30% reg75% NPH / 25% reg

30-60 min.

15-60 min.

DualDual

14-18h14-18h

Pharmacotherapy: Insulin(Older Agents)

Pharmacotherapy: Insulin(Newer Agents: Insulin Analogs)

Insulin Preparation Onset Peak Duration

Rapid actingLispro (Novolog®)Aspart (Humalog®)Glulisine (Apidra®)

15-30 min.

15-30 min.

15-30 min.

30-90 min.

30-90 min.

30-90 min.

4-6h4-6h4-6h

Long actingGlargine (Lantus®)Detemir (Levemir®) 1-2h

1-2hflatflat

24h24h

Combinations70% / 30% lispro75% / 25% aspart50% / 50% aspart

30-60 min.

15-60 min.

15-60 min.

DualDualDual

14-18h14-18h14-18h

Therapy for Type 2 Diabetes: Sites of Action

Liver

Pancreas

Glucose

Hyperglycemia↑HGO*

↑Sulfonylureas↑RepaglinideTZD

↑Metformin±Thiazolidinediones

Gut

Muscle↑Metformin↑Thiazolidinediones

↓ α-Glucosidase inhibitors

Adiposetissue

↓ Glucoseuptake

AcarboseMiglitol

RosiglitazonePioglitazone

*HGO=hepatic glucose output.Adapted from DeFronzo RA. Ann Intern Med. 1999;131:281-303.Package Inserts for AVANDIA® (rosiglitazone maleate, GlaxoSmithKline), Actos® (pioglitazone HCl, Takeda), Prandin® (repaglinide, Novo Nordisk), Precose® (acarbose tablets, Bayer), Glyset® (miglitol, mfd. by Bayer for Pharmacia & Upjohn).

23

+ +

Diet &exercise

Oral monotherapy

Oral combination

Oral plus insulin

Insulin

+

Stepwise Management of Type 2 Diabetes

Adapted from Williams G. Lancet 1994; 343: 95-100.

PharmacotherapyStepwise Management

Glycemic targets often not met Monotherapy often not effective long

term Therapy fails to address multiple

impairments Step-wise approach tends to perpetuate

“failure”

New Treatment ParadigmTreatment designed to address multiple

impairmentsSimultaneous rather than sequential therapyCombination therapy from the outsetEarly titrations to meet glycemic targets

Combination Oral Diabetic Agents

Glucovance® ( Glyburide + Metformin)Metaglip® (Glipizide + Metformin)Avandamet® (Rosiglitazone + Metformin)Avandaryl® (Rosiglitazone + Glimepiride)ActoPlus Met® (Pioglitazone + Metformin) Janumet® (Januvia + Metformin)

ADA/EASD Consensus Algorithm 2009

Nathan and Associates: Diabetes Care, Vol. 32, Number 1, January 2009

At Diagnosis

Lifestyle+Metformin

Tier 1: Well-validated core therapiesStep 1

Lifestyle + Metformin+Sulfonylurea

Lifestyle + Metformin+Basal Insulin

Step 2

Lifestyle + Metformin+Pioglitazone

Lifestyle + Metformin+GLP1- Agonist

Tier 2: Less well validated therapies

Lifestyle + Metformin+Intensive Insulin

Step 3

Lifestyle + Metformin+Pioglitazone+Sulfonylurea

Lifestyle + Metformin+Basal Insulin

ACCE Diabetes Algorithm 2009

Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6)

Type 2diabetes

Postprandial hyperglycemia

Basal hyperglycemia

Glucose Dynamics: Basal and Prandial

Riddle MC. Am J Med. 2004;116(suppl):3S-9.

Plasma glucose (mg/dL)

Time of day

200

250

150

100

50

00600 1200 1800 06002400

Normal

Basal-Bolus Combination Therapy

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00Time

Bolusinsulin

Bolusinsulin

Bolusinsulin

Plasma Insulin Levels

Basalinsulin

Treatment of co-morbid conditions

Dyslipidemia Hypertension

Diabetes CV Risk Calculator

Available at: http://www.dtu.ox.ac.uk/riskengine/

Diabetes CV Risk Calculator (Canada)

http://www.diabetes.ca/documents/about-diabetes/FINAL_PATIENT_TOOL_FOR_WEBSITE.pdf

The ABCs of Diabetes CareA1C

ADA recommends < 7% in general, < 6% for selected individuals

AACE/IDF recommend ≤ 6.5% Blood pressure

< 130/80 mm HgCholesterol

LDL-C: < 100 mg/dL (< 70 mg/dL in very high-risk patients) HDL-C: > 40 mg/dL in men and > 50 mg/dL in women Non-HDL-C: < 130 mg/dL (< 100 mg/dL in high-risk

patients) Triglycerides: < 150 mg/dL

American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41. American Association of Clinical Endocrinologists. Endocr Pract. 2007;13(suppl 1):3-68. International Diabetes Federation. Diabet Med. 2006;23:579-593.

Additional Recommendations Individualized Medical Nutrition Therapy Exercise Aspirin (75-325 mg/d) Smoking cessation Screening for microvascular complications

(eyes, kidneys, feet) Immunization ( Flu vaccine, Pneumovax) Recommended cancer screening

ADA. Diabetes Care. 2005;28(suppl 1):S1-79.

• Proper nutrition

• Physical activity program

• Smoking cessation

• Weight control

• HbA1c <7%

• Glucose (mg/dL): Preprandial 90–130Postprandial <180

• Dyslipidemia: Statin

• Hypertension: ≥2 drug classes, include ACEI or ARB

• Microalbuminuria:ACEI or ARB

• Use of aspirin

• CHD: ACEI, -blocker

• CVD/high risk: ACEI

Lifestyleinterventions

Intensive glycemic control

Aggressive Rx forCV risk reduction

Optimal Care of the Diabetic Patient

Thank You For Your Attention