INSIGHT INTO MANAGING AND TREATING TYPE 2 DIABETES

ISRAEL HARTMAN MD FACE

3

Age-Adjusted Percentage of Adults* With Diagnosed Diabetes in Arizona, 20072

≥ 9.47.6 – 9.36.6 – 7.5≤ 6.5

Type 2 Diabetes Mellitus (T2DM) Is an Epidemic

*≥20 years old.1. Centers for Disease Control Web site. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. 2. Centers for Disease Control Web site. http://apps.nccd.cdc.gov/ddt_strs2/NationalDiabetesPrevalenceEstimates.aspx.

2007Age-adjusted percent of adults* with diagnosed diabetes Trends

• The Centers for Disease Control and Prevention statistics from 2007 estimated that 23.5 million adults in the US had diabetes―10.7% of the US population aged 20 years or older1

– T2DM accounts for 90%-95% of all diagnosed cases of diabetes1

Back to U.S. map

HIIDILINIAKSKYLAMEMD

NMNYNCNDOHOKORPARISC

SDTNTXUTVTVAWAWVWIWY

MAMIMNMSMOMTNENVNHNJ

ALAKAZARCACOCTDEDCFLGA

Obesity Trends* Among U.S. AdultsBRFSS, 2005

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

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

5

Type 2 Diabetes Is a Complex and Progressive Metabolic Disorder 

1. Kendall DM, et al. International Diabetes Center. 2005. 2. Defronzo DA. Diabetes. 2009.3. Fehse F, et al. J Clin Endocrinol Metab. 2005.

Adapted from Kendall DM, Bergenstal RM.

History and Progression of Type 2 Diabetes1‐3

By the time of diabetes  onset, up to 80% of

beta‐cell function may be lost2,3

Diagnosis

Putativetrigger

Circulating autoantibodies (ICA, GAD65)

Cellular autoimmunityCellular autoimmunity

Loss of first‐phase insulin response (IVGTT)

Glucose intolerance(OGTT)

Clinicalonset—only 10% ofβ‐cells remain

Time

β‐Cell mass 100%

“Pre”‐diabetes

Geneticpredisposition

Insulitisβ‐Cell injury

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Diabetes

Natural History Of “Pre”–Type 1 Diabetes

14

IFG and IGTIntermediate Between Normal and Diabetes

Impaired Glucose Tolerance (IGT)

• 2-h PG on OGTT ≥140 but <200 mg/dL

• Predicts increased risk of diabetes and cardiovascular disease

Impaired Fasting Glucose (IFG)

• FPG ≥100 but <126 mg/dL• Predicts increased risk

of diabetes and micro-and macrovascular complications

9

Hyperglycemia Damages Tissues

• Effects of hyperglycemia– Glycation of proteins (eg, hemoglobin, collagen) – Accumulation of sorbitol and fructose (eg, in nerves, lens)– Activation of protein kinase C (eg, on vascular cells)

• Tissue changes– Altered protein function and turnover, cytokine activation– Osmotic and oxidative stress – Reduced motor and sensory nerve conduction velocity– Increased glomerular filtration rate and renal plasma flow

2

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10*Requires confirmation by repeat testing

Symptoms of diabetes plus random plasma glucose ≥200 mg/dL*

orFPG ≥126 mg/dL*

or2-h PG during a 75-g OGTT ≥200 mg/dL*

Making the Diagnosis of Diabetes

20

Classification of Diabetes Mellitusby Etiology

Type 1 β-cell destruction—complete lack of insulin

Type 2 β-cell dysfunction and insulin resistance

Gestational β-cell dysfunction and insulin resistance during pregnancy

Other specific types • Genetic defects of β-cell function• Exocrine pancreatic diseases• Endocrinopathies• Drug- or chemical-induced• Other rare forms

11

Gestational Diabetes

• Hyperglycemia during pregnancy—usually resolvesafter birth

• Complicates ~4% of all pregnancies in the United States• High risk of perinatal morbidity and mortality• High risk of later type 2 diabetes in both mother and baby• Diagnosed by specific glucose tolerance test methods • Requires intensive dietary and glycemic management

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S88-S90 18

Two Defects Contributing to Type 2 Diabetes

Buchanan TA. Clin Ther. 2003;25(suppl 2):B32–B46.Kahn SE. J Clin Endocrinol Metab. 2001;86:4047–4058.

Type 2 Diabetes

Beta cell

Insulinresistance

Beta-cell dysfunction

Muscle tissue Adipose tissue PancreasLiver

300

200

100

0

Plasma glucose (mg/dL)

Postprandialhyperglycemia

Normal

Fasting hyperglycemia

Riddle MC. Diabetes Care. 1990;13:676-686

Time of day0600 1200 1800 2400 0600

A1C Reflects Both Fasting and Postprandial Hyperglycemia

6

14

Appropriate A1C Management Should Consider Both FPG and PPG Levels

• FPG and PPG contributions to A1C differ as A1C levels change– PPG is the major contributor to

A1C in patients with A1C <7.3%

– FPG is the major contributor to A1C in patients with A1C ≥9.3%

Approximate Contribution Approximate Contribution to A1Cto A1C (%)(%)

>10.2

9.3–10.2

8.5–9.2

7.3–8.4

<7.3

A1C (%)FPGPPG

70%*† 30%†

53%‡ 47%‡

45% 55%

40%* 60%

30%* 70%

*Significant difference was observed between FPG and PPG.†Significantly different from all other quintiles.‡Significantly different from >10.2 quintile.All percentages are approximated.Monnier L et al. Diabetes Care. 2003;26:881-885.

FPG and PPG concentrations were measured in 290 patients with T2DM. Patients were divided into quintiles of A1C and these values were used to calculate the relative contribution that each made to the patient’s overall diurnal hyperglycemia. The results were compared across quintiles.

15

Recommended A1C

ADA2 <7.0%

AACE3 ≤6.5%57.1%

Treated Patients with T2DM*

42.9% of patients not at goal

Mean A1C=7.17% (N=491)

Nearly Half of All Adult Patients With T2DM Remain Uncontrolled on Their Current Therapy1

1. Ong KL, et al. Ann Epidemiol. 2008;18:222-229. 2. Nathan DM, et al. Diabetes Care. 2009;32:193-203. 3. Rodbard HW et al. Endocr Pract. 2009;15:540-559.

A1C >7%

A1C <7%

NHANES=National Health and Nutrition Examination Survey.*Data from 2003-2004 NHANES, includes all men and non-pregnant women ≥20 years with valid data on diabetes history and body mass index measurement (N= 4430). Participants with diabetes diagnosed at age <30 years, who were treated with insulin alone, were excluded from the analysis of determinants of glycemic control as they were likely to have type 1 diabetes.

DiabeticRetinopathy

Leading causeof blindnessin adults

DiabeticNephropathy

Major cause of kidney failure

CardiovascularDisease

Stroke

DiabeticNeuropathy

Major cause of lower extremity amputations

CV disease & stroke account for ~65% of deaths in T2D patients 

Type 2 Diabetes Associated with Serious Complications

CV = cardiovascular.National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2005. Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, 2005.*Patients ages ≥20 years.Centers for Disease Control. National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed February 27, 2009.

Relationship of A1C to Risk of Microvascular Complications

Adapted with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243

RetinopathyNephropathyNeuropathyMicroalbuminuria

Rel

ativ

e R

isk

A1C (%)

15

1311

9

7

53

16 7 8 9 10 11 12

Who Should Be Tested for Diabetes?Consider if One or More of the Following Apply

• Symptoms suggesting diabetes: weight loss, hunger, urinary frequency, blurred vision

• Age >45 (>30 if patient has other risk factors)• Prior IGT or IFG or family history of diabetes• Prior gestational diabetes or baby weighing >9 lb• Women with polycystic ovarian syndrome (PCOS)• Obesity (BMI ≥25 kg/m2), especially adolescents• African, Latino, Asian, or Native American ancestry• History of vascular disease or hypertension

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14;AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82 19

Type 2 Diabetes Treatment Options Utilize DifferentMechanisms of Action and Target Different Primary Tissues

Liver Adipose Muscle Pancreas

Metformin (MET)1*• Primarily decreases hepatic glucose production

Thiazolidinediones (TZDs)2

• Improve insulin sensitivity

Sulfonylureas (SU)3

• Increase insulin secretion in functioning pancreatic beta cells

DPP-4 Inhibitors4

• Slow inactivation of incretin hormones resulting in: increased synthesis and release of insulin from functioning pancreatic beta cells and lower glucagon secretion from pancreatic alpha cells

1. Glucophage [prescribing information]. Bristol-Myers Squibb; 2. Prescribing information for AVANDIA; 3. Amaryl® (glimepiride) [prescribing information]. Aventis Pharmaceuticals; 4. JanuviaTM (sitagliptin phosphate) [prescribing information]. Merck & Co., Inc.

Not intended to imply a comparison of efficacy or safety of these treatment options.*Also decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization.

Initial Diabetes Management

• Patient Education– Exercise

– Diet

– Glucose Monitoring

– Complication avoidance

• Be sure that the patient understands the ‘game plan’ for their diabetes

Dietary Recommendations

• Determine current BMI and ideal weight– BMI = Weight (lbs) x 703 / (height in inches)^2

• Normal = 20 ‐24.9  • Overweight 25 – 29.9• Obese 30.0 or more

– Ideal weight• Men: 106 for first 60 inches, then 6 # each additional inch.

• Women: 100 for first 60 inches, then 5# each additional inch

Specify a diet

• Refer to a dietitian if at all possible– They have more time than you do

– They can answer questions about specific food preferences better than you can

– They can schedule follow up

– They are usually less expensive than you

• A diet of 13 kcal / pound IBW will usually induce gradual weight loss

Give the patient an exercise prescription

• Be specific– Type of exercise – walking, bicycling, swimming, Gazelle, weightlifting, etc

– How long: Ask them to do 30 minutes, you may get 20 minutes

– How often:  5 or more times a week

– Point out that exercise is effective, and less expensive than many of our medications

24

Lifestyle + MET + PIO + SFU

Lifestyle + MET + PIO + SFU

“If hypoglycemia is particularly 

undesirable…” and/or “promotion of weight 

loss is a consideration…”

“If hypoglycemia is particularly 

undesirable…” and/or “promotion of weight 

loss is a consideration…”

ADA/EASD 2008 Consensus Statement Includes a GLP‐1 Receptor Agonist

STEP 1 At diagnosis: Lifestyle + MET

STEP 2 Tier 1:Well‐validated core therapies*

STEP 3 Lifestyle + MET + intensive insulin

OR

If A1C If A1C ≥≥7%7%

CHF, chronic heart failureMET, metformin PIO, pioglitazone SFU, sulfonylurea

*Validation based on clinical trials and clinical judgment.†Insufficient clinical use to be confident regarding safety.Adapted from Nathan DM, et al. Diabetes Care. 2008. 

Lifestyle + MET + basal insulin

Lifestyle + MET + basal insulin

Lifestyle + MET + SFU

Lifestyle + MET + SFU

Lifestyle + MET + basal insulin

Lifestyle + MET + basal insulin

Tier 2: Less‐well‐validated therapies*

Lifestyle + MET + PIO

Lifestyle + MET + PIO

Lifestyle + MET +GLP-1 receptor

agonist†Lifestyle + MET +GLP-1 receptor

agonist†

Oral Diabetes Meds • Sulfonylureas 

• Glipizide, glyburide, glimipiride, 

• Biguanides / Metformin• Thiazoladinediones

• Avandia, Actos

• α Glucosidase Inhibitors• Precose, Glyset

• Glinides• Starlix, Prandin

• DPP‐IV inhibitors• Januvia, Onglyza

Sulfonylureas

• Introduced in 1955

• Inexpensive  ($4 at Target/Sams/WalMart)

• Stimulate insulin release from pancreatic beta cell

• Mean absolute A1c reduction:  1 – 2 %

Sulfonylureas

• Cons: – Weight gain

– Risk of hypoglycemia

– K channel inhibition may worsen arrhythmia risk in patients with coronary artery disease

– Do not delay progression of disease

Non –SU Secretagogues

• Starlix (nateglinide) and  Prandin (repaglinide)

• $125/month

• Increase mealtime beta cell release of insulin

• Shorter duration of action than SU

• A1c Starlix  ‐ 0.4 ~ 1.1 %

• A1c Prandin   ‐ 1.7~1.9%

Non –SU Secretagogues

• Pros• Short half life

• Less hypoglycemia than SU

• Starlix can be used in renal failure patients

• Cons• Weight gain, but not as much as SU

• Must be taken just before meal

• Less long term outcome data

Metformin

• Introduced 1962 (France) 1995 (USA)

• Inexpensive  ($4 at Target/Sams/WalMart)

• Decreases hepatic glucose production primarily gluconeogenesis, probably through effects on AMP‐kinase

• Mean absolute A1c reduction:  1 – 2 %

Metformin

• Pros:

• Modest amount of weight loss

• Modest lipid lowering effect

• Benefit on cardiovascular risk markers

• As monotherapy, had lowest CV risk in UKPDS

• May be useful in prevention of diabetes – DPP

• Treatment option for PCOS

Metformin

• Cons:

• Gastrointestinal side effects

• Contraindicated in renal, liver, cardiac dysfunction because of risk of lactic acidosis

AGI’s

• Acarbose (Precose) Miglitol (Glyset)

• Inhibit enzyme on enterocyte brush border that breaks down complex starches

• Approximately $95 per month

• Mean absolute A1c reduction:  0.5 – 1%

• Reduces postprandial BG more than fasting

• Reduced risk of MI in STOP‐NIDDM

Thiozoladinediones (TZDs)

• Activate nuclear transcription factors PPARγ

• rosiglitazone (Avandia) & pioglitazone (Actos)

• Cost (full dose) $180 ‐ $213 per month

• Improve insulin sensitivity & glucose uptake in adipocytes and muscle

Thiozoladinediones (TZDs)Pros:

• Durable control demonstrated for rosiglitazone (ADOPT)

• May delay progression of disease

• Improved lipid parameters ( pio > rosi ) 

• A1c reduction of 1 ‐2 %

• Rosiglitazone demonstrated to reduce IGT progression to DM by 60% (DREAM)

Thiozoladinediones (TZDs)

• Activate nuclear transcription factors PPARγ

• rosiglitazone (Avandia) & pioglitazone (Actos)

• Cost (full dose) $180 ‐ $213 per month

• Improve insulin sensitivity & glucose uptake in adipocytes and muscle

Thiozoladinediones (TZDs)Cons

• Weight gain

• Edema

• Potential to exacerbate CHF – contraindicated in Class III or IV 

• Controversy over rosiglitazone and cardiovascular risk

ADOPT: A Diabetes Outcome Progression TrialReduced Rate of Monotherapy Failure with AVANDIA (FPG >180 mg/dL)

10781076958

120712051114

139313971337

957950781

844818617

324311218

Patients at riskAVANDIAMETSU

Time (years)0 1 2 3 4 5

Cumu

lative

incid

ence

of

mono

thera

py fa

ilure

(%)

0

10

20

30

40

SU

MET

AVANDIA

Risk reduction with AVANDIA:32% over MET63% over SU

The characteristics of the participants who withdrew did not differ among treatment groups. The subgroup analyses demonstrated some benefit in all subgroups. The analyses suggest that the beneficial effect of AVANDIA vs MET was unlikely to be due to a withdrawal bias.Kahn SE et al. N Engl J Med. 2006;355:2427–2443.

Primary Endpoint

RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes

Study Results: Primary Endpoint

Home PD et al. Lancet. 2009. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60953-3/fulltext. Published June 5, 2009. Accessed June 6, 2009.

Time to CV Death or First Event of CV Hospitalization

People at riskRosiglitazone 2220 2086 1981 1883 1795 1720 918 156Metformin/SU 2227 2101 1995 1895 1798 1697 908 169

Cumulative Incide

nce (%

, SE)

Rosiglitazone (321 events)Metformin/SU (323 events)

HR: 0.99 (95% CI 0.85, 1.16)

Time (years)

ROSIGLITAZONE ISSUES

• Neither increased or decreased risk of CV events is established.

• “…excluding trials from a meta‐analysis with zero events probably exaggerated risk estimates”

• “available evidence does not justify what the authors of the original meta‐analysis (as well as the media, the US Congress and worried patient groups decried as “urgent need for comprehensive evaluations”

Ann Int Med 147;8:578‐582 October 16, 2007

Five Long‐term Studies Showed No Increased Risk of Total Mortality with Rosiglitazone1–7

Duration of Relevant Studies

1. Prescribing Information for AVANDIA; 2. Kahn SE et al. N Engl J Med. 2006;355:2427–2443; 3. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC et al. Lancet. 2006;368:1096–1105; 4. Home PD et al. Lancet. 2009. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60953-3/fulltext. Published June 5, 2009. Accessed June 6, 2009. 5. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545–2559; 6. NHLBI. http://www.nih.gov/news/health/ feb2008/nhlbi-06.htm. Accessed February 12, 2009; 7. American Diabetes Association Web site. http://www.diabetes.org/for-media/pr-intense-blood-glucose-control-yields-no-significant-effect-on-cvd-reduction.jsp. Accessed February 12, 2009; 8. Duckworth W et al. N Engl J Med. 2009;360:129–139.

*Mean duration: 41 months.†Not prospectively designed to assess the safety of rosiglitazone. 

‡Independent, non‐GSK‐sponsored studies.

Randomized, long‐term prospective trials with rosiglitazone

Randomized, long‐term trials that included patients on rosiglitazone

A Com

parison of Relevant S

tudies

N=5269 patients

N=4360 patients

N=4447 patients

DREAM*†1,3

ADOPT*†1,2

RECORD*1,4

0 1 2 3 4 5 6

Duration, years

N=10,251 patientsACCORD†‡ (Interim Studies)5,6

N=1791 patientsVADT†‡7,8

4–6 years

5–7 years

Incretins

• EXENATIDE

• LIRAGLUTIDE

• SITAGLIPTIN 

• SAXAGLIPTIN

43

GLP‐1 Is a Glucoregulatory Hormone With Multiple Physiological Actions

Pancreas β‐cells:Glucose‐dependent insulin 

secretion

Brain:Promotes satiety* 

Food intake

Liver:Hepatic glucose

Stomach:Gastric emptying

*In animal models. Adapted from: 1. Flint A, et al. J Clin Invest. 1998. 2. Larsson H, et al. Acta Physiol Scand.1997. 3. Nauck MA, et al. Diabetologia. 1996. 4. Drucker DJ. Diabetes. 1998. 

Pancreas α‐cells: Postprandial glucagon

44

• Increases glucose‐dependent insulin secretion

• Restores first‐phase insulin response

• Suppresses glucagon release

• Delays gastric emptying

• Reduces food intake

GLP‐1 Receptor Agonists Address GLP‐1 Deficiencies and Leverage the GLP‐1 

Effect 

1. Nielsen LL, et al. Regul Pept. 2004. 2. Kolterman OG, et al. J Clin Endocrinol Metab. 2003. 3. Fehse F, et al. J Clin Endocrinol Metab. 2005.

DPP‐4 Activated GLP‐1 receptor1‐3

ActiveGLP‐1

InactiveGLP‐1

Binds to knownGLP‐1 receptor

GLP‐1receptor agonist

45

EXENATIDE Reduces A1C With Potential Weight Loss

Placebo BID (n=483)EXENATIDE 10 mcg BID (n=483)             Baseline A1C=8.5%

ΔWeight (lb)

-1.5

-1.0

-0.5

0.0

0.5

ΔA1

C (%

)

Time (wk)0 2 4 6 12 18 24 30 0 2 4 6 12 18 24 30

-5

-4

-3

-2

-1

0

Time (wk)

*

**

* * **

†

*

**

* *

Mean ± SE; compared to placebo. *P<0.0001, †P=0.006. Data on file. BYETTA is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.

Change in A1C (%) Change in Weight (lb)

-1.4 lb

-4.2 lb

+0.2%

-0.8%

Three 30‐Week, Double Blind, Phase 3 StudiesEXENATIDE 10 mcg With Metformin and/or a Sulfonylurea

46

EXENATIDE Monotherapy Provided Consistent Improvement in A1C and Weight Loss

Least squares means are adjusted for screening A1C strata and baseline value of the dependent variable.BYETTA is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.

24‐Week, Double‐Blind, Placebo‐Controlled StudyEXENITIDE 10 mcg Monotherapy

7.0

7.5

8.0

Mean

A1C

(%)

-0.9

EXENATIDE10 mcg BID

P<0.01184

186

188

190

-6.4 lb

Placebo

Mean A1C Reduction From Baseline Mean Weight Loss From Baseline

EXENATIDE10 mcg BID Placebo

-0.2

7.8

-3.3 lb

182

∆W

eight

(lb)

47

Please see full US Prescribing Information available at this presentation

SAXAGLIPTIN™ 5 mg Provided Complementary A1C Reductions

Significant A1C Reduction Across Clinical Trials at 6 MonthsWhen Partnered With MET, GLY, a TZD, or as Monotherapy

Significant A1C Reduction Across Clinical Trials at 6 MonthsWhen Partnered With MET, GLY, a TZD, or as Monotherapy

SAXAGLIPTIN Was Weight and Lipid Neutral

P<0.0001(n=186)

P<0.0001(n=306)

P<0.0001(n=250)

P<0.0001(n=183)

P<0.0001(n=103)

Initial Combo With MET

Baseline A1C: 9.4%Add-On to METBaseline A1C: 8.1%

Add-On to the SU Glyburide

Baseline A1C: 8.5%Add-On to a TZDBaseline A1C: 8.4%

MonotherapyBaseline A1C: 8.0%

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Diff

eren

ce F

rom

Com

para

tor (

%)

-1.0

–0.8%

–0.5%

–0.7%–0.6% –0.6%

In addition to diet and exercise

GLY=glyburide.

Treat to which target?

• AAFP – “Inappropriate to set a uniform target”

• ADA – “ in general is less than 7%”

• Am Geriatrics Society• Good functional status – 7%

• Frail “a less stringent target, such as 8%”

• Canadian Diabetes Assn • 7% or lower 

• If it can be safely achieved <6.0% should be considered

Treat to which target?

• Institute for Clinical Systems• < 7% , should be individualized

• Natl Institute for Health and Clinical Excellence

• Between 6.5 – 7.5 % on the basis of vascular risk

• Scottish Intercollegiate Guidelines Network• “around 7.0”

• Veterans Health Administration• “target should be 7.0%”

Treat to which target?

• AACE

• Current targets for glycemic control are:– A1C <6.5%

– Fasting/Preprandial <110 mg/Dl

– 2‐hr Postprandial <140 mg/dL

Can we do it?

Quest Diagnostics Data

State  2001 2006  % change

Texas  7.82 7.38  ‐5.60 

USA 7.56 7.20  ‐4.9