15. rushakoff- current controversies in diabetes … · current controversies in diabetes...

Current Controversies in Diabetes Management

Robert J. Rushakoff, MDProfessor of Medicine

University of California, San Francisco

[email protected]


www.endotext.com

What do you think of when told:

2-2.5 fold increased risk of CHF2-3 fold increase in risk for initial MI3 fold increase in risk for pancreatitisDecreased leukocyte functionRisk for lactic acidosisIncreased risk for cancerIncreased risk for renal failure, retinopathy, neuropathy

Type 2 Diabetes

Hyperglycemia

β

⇑ hepaticglucose output

⇓ Insulinsecretion

⇓ Glucoseuptakeglucose utilization

Hyperglycemia

β α⇑ Postprandial

glucagonsecretion

Hyperglycemia

β α

⇑ FFALipotoxicity

Hyperglycemia

β α

Incretins

Hyperglycemia

β αAlteredglucosereabsorption

Hyperglycemia

β α

AlteredHypothalamic

AppetiteControl

Hyperglycemia

β α

Ominous Octet

Fundamental Questions

Just because a drug may work at one or more of the sites of defect in Type 2 DM - what about:EfficacySide effectsActually improve outcomes or make them worseDecrease mortality or kill people

Fundamental Questions

Is there anything wrong with the “older” group of medications?Do the newer medications fix what is wrong with the older medications?Does it really matter what medication is used first, second, third?Does it really matter what medication is used?

New Drug Truthiness

Often no clinically relevant literature published before medication is releasedStudies performed to obtain FDA approval are useful for FDA approvalClinically useful studies may lag release to market by 5 years, or are never done

Today’s Controversies

How to Diagnose DiabetesGlucose MonitoringWhat are the goals?Lawyers and Diabetes

Oral agentsInsulin and Cancer

Even the algorithm– ADA way, AACE way and of course, MY WAY

Diabetes Care 31:1473–1478, 2008

Relationship Between Plasma Glucose and HgA1c

Diabetes Care 31:1473–1478, 2008


Data in parentheses are 95% CIs.

Diabetes Care 31:1473–1478, 2008


Hemoglobin A1c

50% of level determined in previous month25% by month before 12.5% by month before12.5% by month before

Hemoglobin A1c

False High LevelsThalassemia (Hgb F)Lead poisoningLarge amount of ASAHigh alcohol, Tgbilirubin levelsHemoglobinopathiesJ,K,I,H, Bart’s, Raleigh, Long Island and South Florida

False Low LevelsHemoglobinopathiesS,D,C,E,G, Leporeand O-Arab. Hemolytic anemia, bleedingLarge ingestions of Vitamin C and E

Recommendation of the International Expert Committee for the Diagnosis of Diabetes

Diabetes should be diagnosed when the A1c is ≥ 6.5%. Diagnosis should be confirmed with a repeat A1c test.

Confirmation is not required in symptomatic subjects with plasma glucose levels > 200 mg/dl (>11.1 mmol/l).

If A1c testing is not possible, previously recommended diagnostic methods (eg, fasting plasma glucose or 2-hour OGTT plasma glucose), with confirmation, are acceptable.

A1c testing is indicated in children in whom diabetes is suspected, but the classic symptoms and a casual plasma glucose >200 mg/dl (>11.1 mmol/l) are not found.

The relationship between baseline A1C group and observed reduction from baseline in A1C and in FPG

Baseline A1C (%)

n enrolled in clinical trials

Change in A1C (%)

Change in FPG (mmol/l)

6.0–6.9 410 –0.2 –0.57.0–7.9 1,620 –0.1 –0.88.0–8.9 5,269 –0.6 –1.6

9.0–0.9.9 1,228 –1.0 –2.310.0–11.8 266 –1.2 –3.4

Diabetes Care 29:2137-2139, 2006

Overview on self-monitoring of blood glucose

Martina Montagnana, Marco Caputo, Davide Giavarina, Giuseppe LippiClin Chim Acta 2009 402:7-13.


The SMBG is recommended in patients on insulin therapy. For type 1 diabetes, SMBG should be performed at least 3 times daily. SMBG is also recommended in patients treated with oral hypoglycemic agents and in all the patients not fulfilling the optimal therapeutic target.


The SMBG is recommended in patients on insulin therapy. For type 1 diabetes, SMBG should be performed at least 3 times daily. SMBG is also recommended in patients treated with oral hypoglycemic agents and in all the patients not fulfilling the optimal therapeutic target.

Glucose Checks per day

≤2

≥4

HgA1c

Time 1 Time 2

high

low


When a patient begins insulin therapy, SMBG should be

increased in frequency.

For patients starting basal insulin therapy, the morning fasting

blood glucose levels should be determined daily.

For the patient on premixed insulin, morning and dinner checks.

For each additional injection of insulin, SMBG should be

increased in frequency to ensure successful titration of each

dose


In patients with type 2 diabetes, SMBG can help to achieve a better glycemic control, especially at the beginning of therapy or following adjustments, although there are not sufficient lines of evidence to attest that strict monitoring in these patients is associated with an improved outcome on the long term.

The role of SMBG in patients with type 2 diabetes managed by diet control alone is still unknown.


What are the goals?Microvascular Disease

DCCT - Type 1UKPDS – Type 2

Macrovascular Disease

ADVANCE: Action in Diabetes and Vascular Disease

•11,140 Enrollees•60% male 40% female•Mean age 66

•50% macrovascular dx•10% microvascular

Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazidecombination in >55 y/o Type 2 DM

Baseline HgA1c: 7.51%“standard” : 7.30% Intensive: 6.53%

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

ADVANCE: Relative Effects of Glucose-Control Strategy on All Prespecified Primary and Secondary Outcomes

ACCORD: Action to Control Cardiovascular Risk in Diabetes

10,251 Enrollees60% male 40% femaleMean age 62.2Baseline HgA1c 8.1%BMI - 32

30% macrovasculardxDuration DM: 10 yearsMajority of intensive group on 3-5 oral agents plus insulinHypoglycemia 3 times greater in intensive group

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

Primary and Secondary Outcomes

ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

VADT - Veterans Administration Diabetes Trial

•1742 Enrollees•97% male•Mean age 60.4

•BMI 31.3•Majority had multiple CV risk factors

•72% HTN•40% macrovasculardx•62% retinopathy•43% neuropathy


Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES

Standard: 29.3% (predicted – 40%)Intensive: 27.4% (predicted – 31.6%)


Baseline Predictor of CVD:Age and prior CVD event

On-trial hypoglycemia – low glucose and altered consciousness in the three months prior to an event was predictive of CVD outcome


When duration of DM factored in:Intensive glycemic control showed benefitBenefit declines until about 12-15 years of disease

Ann Intern Med. 2009;150:505-515

Trends In Control of Cardiovascular Disease and DiabetesBlood Pressure Control

Ann Intern Med. 2009;150:505-515

Trends In Control of Cardiovascular Disease and DiabetesGlycemic Control

Ann Intern Med. 2009;150:505-515

Trends In Control of Cardiovascular Disease and DiabetesTotal Cholesterol Control

Explaining Decline in Early Mortality with Type 2 DMTrends in Drug Utilization

Diabetes Care. 2008; 31:1761-1766

5 71%

16 43%

21 55%

43 14%

X(1996) y(2006)% (use in 1st year)

All cause 2 year mortality: 48/1000 person-years (1996) to 25/1000 p-y (2006)

UKPDS: 10 year follow-upGlucose Control

Between-group differences in HgA1c gone after 1 yearIn the sulfonylurea–insulin group, relative reductions in risk persisted at 10 years for:

any diabetes-related end point (9%, P=0.04)microvascular disease (24%, P=0.001)risk reductions for myocardial infarction (15%, P=0.01) death from any cause (13%, P=0.007)

In the metformin group:any diabetes-related end point (21%, P=0.01)myocardial infarction (33%, P=0.005)and death from any cause (27%, P=0.002).

Published at www.nejm.org September 10, 2008

Effect of Metformin-Containing AntidiabeticRegimens on All-cause Mortality in Veterans With Type 2 Diabetes Mellitus

Decreased Hazard Ratio for all cause mortality for patients on metformin

vs no metformin – 0.77 (p<0.01)

Increased Hazard Ratio for all cause mortality for patients on insulin:

1.62 (p<0.001)

Decreased Hazard Ratio for all cause mortality for patients on metformin and insulin vs insulin

0.62 (p<0.04)

Am J Med Sci 2008; 336:241-247

Conventional

Intensive

Sustained 3-Step Change in Secondary Cohort

P<0.001

Kaplan-Meier Estimates of the Risk

of Death from Any Cause and from

Cardiovascular Causes and the Number of

Cardiovascular Events, According to

Treatment Group

Gaede P et al. N Engl J Med 2008;358:580-591

Effect of a MultifactorialIntervention on Mortality

in Type 2 Diabetes

ADA Targets for Glycemic Control

PreprandialPreprandial plasma glucose plasma glucose 8080––130 mg/dl (5130 mg/dl (5--7.2 7.2 mmol/lmmol/l))

Peak postprandial plasma glucosePeak postprandial plasma glucose <180 mg/dl (<10 <180 mg/dl (<10 mmol/lmmol/l))

Hemoglobin AHemoglobin A1c1c <7 (%) <7 (%)

Biochemical IndexBiochemical Index GoalGoal

ADA Targets for Glycemic Control

Key concepts in setting glycemic goals: A1C is the primary target for glycemic control.

Goals should be individualized based on: duration of diabetesage/life expectancycomorbid conditionsknown CVD or advanced microvascular complicationshypoglycemia unawarenessindividual patient considerations

More or less stringent glycemic goals may be appropriate for individual patients.

Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.

Goals for Type 2 Diabetes • For Decreasing Cardiovascular Disease:

– Focus on blood pressure– Lipids– anti-platelet therapy– Smoking cessation.– Early aggressive glucose control

Goals for Type 2 Diabetes • Be cautious in your glucose lowering

strategies in older, high-risk patients with long standing diabetes. Maintaining HbA1c close to 7% (but not necessarily <7%) may be the optimal target for these individuals.

• Avoid hypoglycemia.


• Lawyers and Diabetes–Oral agents

ClassGeneric Name(Brand Name)

Mechanism of Action

Dosage RelativeEffective

-ness

Major Side Effects / Interactions / Uses

Weight Effects

(average)

Cost

Sulfonylureas

Glyburide(Micronase)

Glipizide(Glucotrol)

glimepiride(Amaryl)

Stimulate insulin release from beta cells of the pancreas

2.5-10 mg bid

5-20 mg bid

0.5-4 mg qd

1

1

1

HypoglycemiaGain 2 lbs $


Mechanism of Action


-ness


Weight Effects

(average)

Cost

Sulfonylureas Stimulate insulin release

1 Hypoglycemia Gain 2 lbs

$

Meglitinides

repaglinide(Prandin)

nateglinide(Starlix)


0.5-2 mg tid(before meals)

60-360 mg tid(before meals)

1

.8

HypoglycemiaUseful in pts on glucocorticoids and in pts with renal failure who often have good FBS and high BS over the course of the dayPrandin is short-acting. Starlix is very short-acting

Gain 1 lb $$$

Diabetes Care 27:1265-1270, 2004

Repaglinide Versus Nateglinide Monotherapy


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$

Meglitinides Stimulate insulin .8-1 Hypoglycemiashort-acting Gain 1 lb $$$

Biguanidemetformin(Glucophage)

Primarily inhibits hepatic gluconeogen-esis.

500-2000 mg daily with meals

1Diarrhea, nausea, vomitingIncreased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use

Loss2-3 lbs $

Metformin and Lactic Acidosis• “Metformin may provoke lactic Acidosis which is

most likely to occur in patients with renal impairment. It should not be used with even mild renal impairment” 1

• Metformin probably not as unsafe as previously thought. – 25% users have relative contraindication 2

– Patient’s with lactic acidosis usually have acute renal failure 3

1. Joint Formulary Committee British National Formulary. 2006:3532. Diabet Med 2001; 18:483-4883. Diabet Med 2007; 24:494-497

Metformin and eGFR• 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x

(1.210 if black) • Current Guidelines call for discontinuation of Metformin

serum creatinine >150 umol/l (1.7 mg/dl).• Estimated GFR (eGFR) being introduced as possible

better measure of renal function than serum creatinine alone

• eGFR of 36 ml/min per 1.73m2

would be somewhat neutral to current use

Briet et al. EASD October 2009


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$


Biguanide inhibits hepatic gluconeogenesis.

1 Diarrhealactic acidosis

Loss2-3 lbs

$

Alpha-glucosidaseInhibitoracarbose(Precose)

Inhibits enzymes needed to break down complex CHO in the small intestine

50 mg with 1st bite of each meal (start at 12.5 mg and titrate up over weeks)

0.7 Gas/ GI upset Loss1-2 lbs

$$$

Bile Acid Sequestrants• Bile acid sequestrants lower LDL cholesterol

• Colesevelam (Welchol) a bile acid sequestrant, lowers glucose levels and AIC levels in T2D patients


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$

Meglitinides Stimulate insulin 1 Hypoglycemiashort-acting Gain 1 lb $$$



Loss2-3 lbs

$

Alpha-glucosidaseInhibitor

Decreased CHO absorption 0.7

Gas/ GI upset Loss1-2 lbs

$$$

Bile Acid Sequestrants

Colesevelam(Welchol)

unknown3.75 g/d

(3- 625 mg tabs bid)

0.7

esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

neutral $$$

Bromocriptine• Ergot derivative.

Sympatholytic dopamine D2 receptor agonist, inhibits serotonin turnover in CNS.

• Improved glucose control associated with improved glucose tolerance (enhanced stimulated insulin-mediated glucose disposal).

Diabetes Care 2000. 23: 1154-1161


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$


unknown .7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

-- $$$

Bromocriptine improved glucose tolerance (enhanced stimulated insulin-mediated glucose disposal).

0.25– 0.5 mg/d .7

Nasal Stuffiness, Nausea, headache, constrictive pericarditis, neuroleptic malignant syndrome, hypotension

---- $$

–The bad–The good–The very ugly

Thiazolidenediones

TZDs and Liver Disease• From troglitazone – contraindicated in

patients with liver disease• Diabetes patients frequently have fatty

liver (NASH---Non- Alcoholic Steatorrhoeic Hepatosis) with elevated LFT

• TZDs decrease liver fat and improve NASH

• TZDs may be best treatment for NASH and preventing cirrhosis

Rushakoff RJ: Normalization of abnormal liver function tests in Type 2 diabetic patients after administration of Troglitazone. Diabetes 48 supplement 1999

Current TZD Side Effects• Weight Gain: 5-12 lbs in 1 year

– Blunted with metformin– Worse with insulin

• Edema: 4-30%– Unresponsive to diuretics

• BUT:– Increased Cardiac Index– Increased Stroke volume– Decreased systemic resistance– Decreased Blood Pressure

Prevention of Type 2 Diabetes With Troglitazone in the Diabetes Prevention Program

Diabetes 54:1150-1156, 2005Diabetes 54:1150-1156, 2005

Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous

Coronary Intervention

Diabetes Care 30:384-388, 2007

Positive Side to TZDs• Reduction in glucose• Reduces BP• Reduces albuminuria• Reduces CRP• Possible DM

prevention• Reduces NASH• Reduces LFT

• Reduces IMT• Reduces stent failure• Reduces death after

CHF

• Increases adiponectin• Increases HDL

The NEW ENGLANDJOURNAL of MEDICINE

ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24

Effect of Rosiglitazone on the Risk of Myocardial InfarctionAnd Death from Cardiovascular Causes

Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.

Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death…that had borderline significance.

CONCLUSIONS

Limitations to Analysis• No access to actual data.

– No time to event calculation

– No confirmation of events– No combined analysis

(some may have had multiple events)

• 42 studies– 11 peer reviewed– 26 never published

• Small number of events• Trials of short duration• Trials not designed to

capture or adjudicate events, thus events not endpoints, just investigator reports

• Many studies only zero or 1 report

• Hypothesis generating, not testing

Meta-analysis of MI and Death risk with rosiglitazone

Nissen SE, Wolski K. N Engl J Med. 2007;356.

n = 15,560 on rosiglitazone; n = 12,283 on comparator drug or placebo

Rosiglitazone group

Control group

Study No. of events/Total no. (%)Odds ratio (95% CI) P

Myocardial infarction

Small trials combined

DREAM

ADOPT

Overall

44/10,280 (0.43)

15/2635 (0.57)

27/1456 (1.85)

22/6105 (0.36)

9/2634 (0.34)

41/2895 (1.44)

1.45 (0.88–2.39)

1.65 (0.74–3.68)

1.33 (0.80–2.21)

1.43 (1.03–1.98)

0.15

0.22

0.27

0.03

Cardiovascular death


DREAM

ADOPT

Overall

25/6557 (0.38)

12/2365 (0.51)

2/1456 (0.14)

7/3700 (0.19)

10/2634 (0.38)

5/2854 (0.18)

2.40 (1.17–4.91)

1.20 (0.52–2.78)

0.80 (0.17–3.86)

1.64 (0.98–2.74)

0.02

0.67

0.78

0.06

Meta-analysis of MI and Death risk with rosiglitazone

Nissen SE, Wolski K. N Engl J Med. 2007;356.

n = 15,560 on rosiglitazone; n = 12,283 on comparator drug or placebo

Rosiglitazone group

Control group

Study No. of events/Total no. (%)Odds ratio (95% CI) P

Myocardial infarction


DREAM

ADOPT

Overall

44/10,280 (0.43)

15/2635 (0.57)

27/1456 (1.85)

86

22/6105 (0.36)

9/2634 (0.34)

41/2895 (1.44)

72

1.45 (0.88–2.39)

1.65 (0.74–3.68)

1.33 (0.80–2.21)

1.43 (1.03–1.98)

0.15

0.22

0.27

0.03

86/14371 (.60%) 72/11634 (0.62%)Relative Risk = 86/72 = 1.19

Absolute Risk = -.02%

Comparison of RSG to SU or MET MI/CV Death/Stroke

Meta-analysis database (ICT), ADOPT and RECORD

Myocardial Infarction

Overall pooled data(N=26011)

ADOPT (N=4351)

DREAM (N=5269)

Small trials combined(N=16391)

0 1 2 3 4Odds ratio

Uncorrected (Peto)

1.45 (0.88-2.39)

1.43 (1.03-1.98)

0 1 2 3 4Odds ratio

Corrected (MH/CC)

1.16 (0.76-1.78)

1.28 (0.95-1.72)

Rosiglitazone and Cardiovascular EventsMeta-Analytic Subgroups

Rosiglitazone and Cardiovascular EventsMeta-Analytic Subgroups

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchJoint Meeting of the Joint Meeting of the EndocrinologicEndocrinologic and Metabolic Drugs Advisory Committee and the and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeDrug Safety and Risk Management Advisory CommitteeJuly 30, 2007July 30, 2007

David Graham, MD MPH

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchJoint Meeting of the Joint Meeting of the EndocrinologicEndocrinologic and Metabolic Drugs Advisory Committee and the and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeDrug Safety and Risk Management Advisory CommitteeJuly 30, 2007July 30, 2007

David Graham, MD MPH

PANIC

RECORD: Kaplan-Meier Plots of time to the Primary Endpoint (Cardiovascular Death or Cardiovascular Hospitalization)

Lancet. 2009 Jun 5. [Epub ahead of print]

The BARI 2D Study Group. N Engl J Med 2009;360:2503-2515

BARI 2D: Enrollment and Randomization

BARI 2D: Rates of Survival and Freedom from Major Cardiovascular Events


BARI 2D: Kaplan-Meier Estimates for Event Rates at 5 Years


Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From

ADOPT

Diabetes Care Publish Ahead of Print, published online on February 5, 2008

Changes in BMD during pioglitazone or placebo treatment in patients with PCOS

J Clin Endocrinol Metab. 2008 Feb 19 [Epub ahead of print]


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$

Thiazolidine-diones

rosiglitazone(Avandia)

pioglitazone(Actos)

Insulin sensitizers—Activate receptor molecules inside cell nuclei to decrease insulin resistance

4-8 mg daily

15-45 mg daily

1

1

Weight gain, edema which is resistant to diuretic therapy, CHF.

Associated with bone loss and fractures.

Gain 12 lbs $$$


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$


unknown .7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

-- $$$


0.25– 0.5 mg/d .7


---- $$

Thiazolidine-diones


pioglitazone(Actos)


4-8 mg daily

15-45 mg daily

1

1



Gain 12 lbs $$$

Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes

114 drug naïve patientsInitial HgA1c Duration DM about 3 yearsInitial Hga1c 10%Body mass index 25

Diabetes Medicine 2005; 22:980-985

Time course of reduction in glycated haemoglobin (HbA1c) in patients receiving pioglitazone (O), metformin (●), or glimepiride ( ). Data are mean ±sd. *P < 0.05; **P < 0.01; ***P < 0.005 vs. baseline.

Diabetes Medicine 2005; 22:980-985

-80-60-40-20

02040

0 7 14 21 28Weeks

Mea

n Ch

ange

(mg/

dl)

Continuedglyburide(n=209)

Switched tometformin(n=210)

Metformin +glyburide(n+213)

Fasting Plasma glucose: Mean Change From Baseline

Diabetes 452:146, 1993

Generic Oral Hypoglycemic Slide

HgA1c

Time

Change from Drug A to B, C, or D

Add Drug A to B, or B to A

Add Drug C

Add Drug D

3.94

-5.29

7.32

10.84

-6-4-202468

1012

Change in Weight

SulfonylureaMetforminInsulinTZD

Weight Changes Associated with Anti-Hyperglycemic Therapies for Type 2 Diabetes

ADA Scientific Meeting 2005 ABS 13-or

Postprandial Glucose Control

Shin J et al. Abstract 424-P. ADA; 2004: New Orleans, La.

Postprandial Glucose Excursions in Subjects With or Without Diabetes

350

300

250

200

150

100

50

0–1 0 1 2 3 4 5 6 7 8

Time (hours)

Seru

m G

luco

se V

alue

(mg/

mL) Without diabetes

Type 1 diabetesType 2 diabetes

Meal Event

Subjects

Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles

n=58 n=58 n=58 n=58n=58

Monnier L et al. Diabetes Care. 2003;26:881–885.

0

20

40

60

80

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Postprandial glucose Fasting glucose

A1C

Con

trib

utio

n, %

INCRETINS

• Gut factors that promote insulin secretion in response to nutrients

•Major incretins: GLP-1, CCK, GIP

Oral Glucose Promotes More Insulin Release than IV Glucose - Indicating a

Role for Incretins

Non-Diabetic Diabetic

Plasma Insulin Responses to Oral and Intravenous Glucose

J Clin Invest 1967; 46:1954-1962

OralIntravenous

OralIntravenous

60

Insu

lin (μ

U/m

L)

30

00 60 120 18030 90 150 0 60 120 18030 90 150

90

Insu

lin (μ

U/m

L)

60

30

0

90

MinutesMinutes

Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes

Glucose

Glucagon When glucose levels approach normal values, glucagon levels rebound.

When glucose levels approach normal values,insulin levels decreases.

*P <0.05Patients with type 2 diabetes (N=10)

mm

ol/L

15.012.510.07.55.0

25020015010050

mg/dL* * * * * * *

pmol

/L

25020015010050

403020100

mU

/L

* ** * * * * *

Infusion

Minutes

pmol

/L

201510

5

0 60 120 180 240

* * * *

pmol/L

201510

5

Placebo

GLP-1

Insulin

2.50

0

0 0

0

Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.

–30

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme

Meal

Intestinal GIP and GLP-1 release

GIP and GLP-1 Actions

DPP-4 (Dipeptidyl Peptidase IV)Enzyme

GIP-(1–42)GLP-1(7–36)

Intact

GIP-(3–42)GLP-1(9–36)Metabolites

Rapid Inactivation

Half-life*GLP-1 ~ 2 minutes

GIP ~ 5 minutes

Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.

Incretin DrugsGLP Agonists

ExenatideLiraglutideSemaglutideAlbiglutideTaspoglutideExenatide LarLixsenatide

DPP 4 InhibitorsVildagliptinSitagliptinSaxagliptinAlogliptinLinagliptinDutogliptinmetogliptin

Diabetes Care 28:1083-1091, 2005

Glycemic Control in Subjects with Type 2 Diabetes Treated with Metformin and a sulfonylurea Plus Exenatide or Placebo

BYETTA Sustained A1C Reductions at 2.5 Years

Open-label ExtensionBYETTA 10 mcg BID (n = 241) Baseline A1C = 8.3%

2.5-y completers; Mean ± SE Data on file, Amylin Pharmaceuticals, Inc. See accompanying Prescribing Information and safety information included in this presentation

-1.1 ± 0.1%

ΔA

1C (%

)

-1.5

-1.0

-0.5

0.0

0 10 20 30 40 50 60 70 80 90 100 110 120 130Time (wk)

BYETTA Continued to Reduce Weight at 2.5 Years

-11.2 ± 0.8 lbs

Open-label ExtensionBYETTA 10 mcg BID (n = 241)

-12

-10

-8

-6

-4

-2

0

ΔW

eigh

t (lb

s)

2.5-y completers; Mean ± SE; Weight was a secondary endpointData on file, Amylin Pharmaceuticals, Inc. See accompanying Prescribing Information and safety information included in this presentation

0 10 20 30 40 50 60 70 80 90 100 110 120 130Time (wk)

N

ON H 2

NN

C F 3

F

F

F

N

Sitagliptin

Vildagliptin

N

O

N

NH

OH

Improvements in HbA1C With Initial Co-administration of Sitagliptin and Metformin

Placebo

Sita 100 mg QD

Sita 50 mg BID + Met 500 mg BIDSita 50 mg BID + Met 1000 mg BID

Met 1000 mg BID

Met 500 mg BID

* Placebo-subtracted LS mean change form baseline at Week 24.Sita=sitagliptin; Met=metformin.

-2.5

-2.0

-1.5

-1.0

-0.5

HbA

1C(%

)* -0.8-1.0

-1.3-1.6

-2.1

Mean Baseline HbA1C = 8.8%N=1091

Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.

Proportion of Patients Achieving HbA1C Goals

0

10

20

30

40

50

60

70

Placebo

Sita 100 mg QD

Sita 50 mg BID + Met 500 mg BID

Sita 50 mg BID + Met 1000 mg BID

Met 1000 mg BID

Met 500 mg BID

HbA1C <7.0%HbA1C <6.5%

To G

oal (

%)

Sita=sitagliptin; Met=metformin.Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen.

110

bid=twice a day; LSM=least-squares mean; qd=once a day. aResults include only randomized patients who agreed to enter the extension study, had not received glycemic rescue therapy through week 54, took at least 1 dose of study medication after week 54, and had at least 1 post-54-week A1C measurement.bValues represented are rounded, actual values 1.15 for Sitagliptin 100 mg qd and 1.06 for Metformin 500 mg bid.Data available on request from Merck & Co., Inc. Please specify 20852883(1)-JAN.

LSM

A1C

Cha

nge

From

Bas

elin

e, %

–2.0

–1.5

–1.0

–0.5

0.0

–1.1 –1.1–1.3

Initial Combination Therapy With Sitagliptin Plus Metformin Study: A1C Results at 104 Weeks

(Extension Study)a

Sitagliptin 100 mg qd

Metformin 1,000 mg bid

Metformin 500 mg bid

Sitagliptin 50 mg bid + metformin 1,000 mg bid

Sitagliptin 50 mg bid + metformin 500 mg bid

n=50 n=64 n=87

104-week resultsMean baseline A1C = 8.5%–8.7%

–1.4

–1.7

n=96 n=105

b b

DPP-4 Study Summary

Vildagliptin plus insulin− Patients on >30 U/d, added 100 mg/d− Baseline HgA1c 8.5− Drop in HgA1c 0.5% vildagliption, 0.2% placebo− >65 y/o-- Drop in HgA1c 0.7% vildagliption, 0.0% placebo− Hypoglycemia: Placebo: 45patients; 185 events; 6 severe

Vildagliptin: 33patients; 113 events; 0 severe

• Sitagliptin vs glipizide added to metformin − 52 weeks, 100 mg/d vs 20 mg/d− Baseline HgA1c 7.5− Both 0.67% reduction in HgA1c− Both about 60% reached HgA1c <7− Hypoglycemia – glipizide: 32% sitagliptin: 4.9%


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$

Thiazolidinediones Insulin 1 Weight gain, edema, fractures Gain 12 lbs

$$$

Incretins

exenatide(Byetta)

sitagliptin(Januvia)

saxagliptin(Onglyza)

Mimics GLP-1 (gut hormone which affects insulin, glucagon, gastric emptying and satiety)

DPP-4 inhibitor (enzyme that breaks down GLP-1)

5-10 mcg bid SQ

100, 50, or 25 mg daily (dose by Cr Cl)

5, 2.5 mg (for decrease creat)

1

0.7-1

Nausea, Vomiting, constipation, pancreatitis (?)Weight loss achieved through appetite suppression

Side effects are rare. Occ GI side effects.

Loss 8 lbs

Neutral

$$$

$$$

DPP-4 Inhibitor Concerns

DDP-4 effects on T-cell activation and proliferation− No clinical indication of suppression of immune system− Decrease in T-cell proliferation appears associated with inhibition

of DPP-8,9− DPP-3 appears important in neutrophil proliferation

• Other substrates− Increase action of peptide YY− Increase GHRH− Neuropeptide Y – Increased BP− Increase substance P – Increased BP− Chemokines – general inflammation and allergic reactions

Incretin Drugs: PancreatitisPatients without Diabetes

General Population in US0.33-0.44 events per 1000 adults per year (1)Severe disease in 15-20% of these cases (2)Death in 2-4% of cases (2)

Type 2 Diabetes PatientsEpidemiology study shows 3 times risk compared to subjects without diabetes (3)

1. Frey et al Pancreas. 2006. 33:336-3442. Forsmark et al Gastroenterology 2007 132:2022-2044

3. Noel et al Diabetes Care 2009 May;32(5):834-8

Incretin Drugs: PancreatitisRate of pancreatitis in exenatide patients 0.39 events per 1000 patient yearsInitial Studies:

Exenatide: 1.7/1000 subject-yearsPlacebo: 3.0/1000 subject-yearsInsulin: 2.0/1000 subject-years


Cancer and Diabetes

Meta-Analyses on the Relative Risk (RR) of Cancer in Different Organs of Diabetic Patients

Cancer Relative Risk

Liver 2.5

Pancreas 1.9

Kidney 1.7

Endometrium 2.2

Colon-rectum 1.4

Bladder 1.4

NonHodgkin’s lymphoma 1.4

Breast 1.2

Prostate 0.9

Role of Oral Agents in Risk of Cancer in Diabetic Patients

Most diabetic patients are treated for years or decades with a variety of drugsData are not conclusive because the large majority of diabetic patients change the drug dosage and/or the type many times during the course of the disease. . Moreover, many are treated with more than one drug. Epidemiological studies on this issue, therefore, are difficult to interpret and often inconclusive.

Role of Oral Agents in Risk of Cancer in Diabetic Patients

TZD: 33% risk reduction in lung cancer versus non-users (1)

Metformin: inhibits breast Ca cell proliferation. Clinical studies ongoing.

1. Journal of Clinical Oncology (2007;25:1476-81)

Insulin Treatment and Risk of Cancer1. Hemkens LG, Grouven U, Bender R et al. Risk of malignancies in patients with diabetes treated with humaninsulin or insulin analogues: a cohort study. Diabetologia 2009;52:1732-44.2. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use andshort-term incidence of alignancies—a population based follow-up study in Sweden. Diabetologia 2009;52:1745- 4.3. Currie CJ, Poole CD, Gale EAM. The influence of glucose lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766–77.4. Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:1755-65.

Insulin Treatment and Risk of Cancer

Four studiesStudies involve convoluted statistical manipulation of epidemiologic dataThere are fundamental internal disagreements and multiple inconsistencies.

Does Diabetes Therapy Influence the Risk of Cancer?

● German study1: N=127,031– Glargine vs human insulin - a decrease in all cancers with

Glargine

– After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (P<.0001): the adjusted HR was 1.09 for a daily dose of 10 IU, 1.19 for 30 IU, and 1.31 for 50 IU

– No increased risk was found for aspart or lispro compared with human insulin

– did not take into account body mass index and the duration of time that the patients were on insulin.

– time on insulin was very short, only about 1.6 years, 1. Hemkens LG, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1418-4.


● Swedish study1: N=114,841

– No statistically significant difference in cancer incidence between patients on insulins other than glargine, and those on glargine plus other insulins

– Women on glargine alone, however, had a higher risk of breast cancer than those on insulins other than glargine, with an RR of 1.99

4 Large Observational Studies

1. Jonasson JM, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1444-2.


● Swedish study1: N=114,841

• In Sweden, an increased risk of breast cancer was reported only in women who used glargine insulin alone, but not in those women who used glargine insulin plus other types of insulin


1. Jonasson JM, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1444-2.

Does Diabetes Therapy Influence the Risk of Cancer? (cont)

● Scottish study1: N=49,197

– Glargine with rapid-acting insulin had a slightly lower rate of cancer progression than did human insulin (HR 0.8, P<.26), but glargine alone had a higher overall rate (HR 1.55, P=.045)

– The number of site-specific cancers was small, but more cases of breast cancer were noted with glargine alone, compared with nonglargine insulins (HR 3.39, P=.004)


1. Colhoun HM; for the SDRN Epidemiology Group. Diabetologia. 2009. doi:10.1007/s00125-009-1453-1.


● Scottish study1: N=49,197

– Glargine – overall, no increase in cancer

– Breast Cancer – no increase for all glargine users

– Breast Cancer - Increase for glargine only -only 6 cases


1. Colhoun HM; for the SDRN Epidemiology Group. Diabetologia. 2009. doi:10.1007/s00125-009-1453-1.


● UK study1: N=62,809

– Metformin monotherapy carried the lowest risk of cancer; adjusted HR was 1.08 for metformin + sulfonylurea, 1.36 for sulfonylurea monotherapy, and 1.42 for insulin-based regimens; adding metformin to insulin reduced progression to cancer (HR 0.54); risk for patients on basal human insulin alone vs glargine was 1.24

– Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69) or pancreatic cancer (HR 4.63) but did not influence the risk of breast or prostate cancer; sulfonylureas were associated with a similar pattern of risk as insulin


1. Currie CJ, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1440-6.

A Long-term Safety Study: Insulin Glargine vs NPH insulin

● An open-label, 5-y, randomized, multicenter, stratified, parallel-group study1

– T2D patients with either no or nonproliferative retinopathy who were treated with OHAs alone, insulin alone, or OHAs with insulin for ≥3 mo

– Randomized to twice-daily NPH insulin (n=509) or once-daily insulin glargine (n=515)

● A post-hoc analysis did not find a difference in the overall number of patients with neoplasms occurring during the trial between the 2 treatment groups2

1. Rosenstock J, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1415-7.2. Rosenstock J, et al. Diabetologia. 2009. doi.10.1007/s00125-009-1452-2.

ETDRS, Early Treatment Diabetic Retinopathy Study.

Combined randomised controlled trial experience of malignancies in studies

using insulin glargine.● 31 studies: 12 in type 1 diabetes and 19 in type 2

diabetes● 10,880 people were included in the analysis (insulin

glargine, 5,657; comparator, 5,223

● insulin glargine was not associated with an increased incidence of cancer, including breast cancer, compared with the comparator group

Home P LagarenneJ , Diabetologia. Published online: 15 September 2009

No evidence of increased risk of malignancies in patients with diabetes treated with insulin

detemir: a meta-analysis.

● 8693 subjects

● Median exposure, weeks (range) – Detemir: 24.0 (0.1–114.6) NPH 23.9 (0.1–107.9)– Detemir 51.0 (0.1–64.1) glargine 51.1 (0.1–57.1)

● Very few cancers● Short duration● No real difference between groups

Dejgaard et al: Diabetologia. Published online: October 2009

Insulin Treatment and Risk of Cancer

Many types of cancer are increased in diabetic patients

Recent retrospective observational studies suggest that long-acting insulin analog glargine may increase and that biguanide metformin may decrease cancer risk

The evidence provided by these studies is weak and disputable because of many experiment and analysis limitations. Therefore it is possible neither to confirm nor to exclude the effect of these drugs on cancer in diabetic patients.

While waiting for more careful studies we have no evidence-based rationale for changing treatment approach to diabetic patients

132

ADA and AACE Statements on Insulin Glargine and Cancer

● ADA Statement1 – June 26, 2009“Four different population-based studies were reported and published in Diabetologia and the data within these studies and between these studies are conflicting and confusing. Until more information is available, the American Diabetes Association advises patients using insulin not to stop taking it”

● AACE Response2 – June 29, 2009“The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. AACE supports further research into the effectiveness and safety of all diabetes therapies and will continue to update recommendations as further data become available. Individual patient concerns should be discussed with their physicians”

1. American Diabetes Association.http://www.diabetes.org/diabetesnewsarticle.jsp?storyId=20358264&filename=20090626/comtex20090626iw00001849KEYWORDMissingEDIT.xml. Accessed August 4, 2009.

2. American Association of Clinical Endocrinologists. http://www.aace.com/newsroom/alerts/index.php. Accessed August 4, 2009.

133

FDA Early Communication About Safety of Insulin Glargine

● FDA Communication – July 1, 2009“Based on the currently available data, the FDA recommends that patients should not stop taking their insulin therapy without consulting a physician, since uncontrolled blood sugar levels can have both immediate and long-term serious adverse effects. Patients should also contact their healthcare professional if they have concerns about the medicines they are taking”

– The 4 observational studies evaluated large patient databases and all reported some level of association between the use of insulin glargine, and other insulin products, and various types of cancer. The duration of patient follow-up in all 4 studies was shorter than what is generally considered necessary to evaluate for cancer risk from drug exposure. Further, inconsistencies in findings within and across individual studies raise concerns as to whether an association between the use of insulin glargine and cancer truly exists. Additionally, differences in patient characteristics across the treatment groups may have contributed to a finding of increased cancer risk

– The FDA is currently reviewing many sources of safety data for insulin glargine, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of insulin glargine

U.S. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169722.htm. Accessed August 4, 2009.

DIGAMI2 (European Heart J. Prepublication Feb 2005)

Group 1 – IV insulin then long term SQ insulinGroup 2 – IV insulin then standard treatmentGroup 3 – Standard treatment

Mortality

Effect of different updated glucose lowering treatments on mortality and morbidity

Mellbin, L. G. et al. Eur Heart J 2008 29:166-176

Conventional Therapies Do Not Influence β-Cell Failure: UKPDS

UKPDS 34. Lancet 1998; 352: 854-865

UKPDS 16: Diabetes 1995; 44: 1249-1258

cohort, median values

06

7

8

9

10

-1 0 2 4 6 8 10Years from randomization

ChlorpropamideConventionalGlibenclamideInsulin

Metformin

HbA

1c(%

)

0

20

40

60

80

100

0 1 2 3 4 5 6 7

ßce

ll fu

ncti

on (

%)

0

20

40

60

80

100

0 1 2 3 4 5 6 7

ßce

ll fu

ncti

on (

%)

Years from randomizationConventional Sulphonylurea Metformin

OverweightNon-OverweightOverweight


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$


$$$

Incretinsexenatide

sitagliptin

Increase insulin, decrease glucagon

11

NauseaWeight loss

Side effects are rare.

Loss 8 lbs

Neutral

$$$

Insulin Titrated to need

1+ Hypoglycemia Gain 8 lbs

$$

Insulin Therapy in Type 2 Diabetes: What is the evidence

Mariëlle J. P van Avendonk and Guy E. H. M Rutten

Diabetes, Obesity and Metabolism.

2009. epub.

Insulin Therapy in Type 2 Diabetes: Bottom Line

Basal InsulinPremixed InsulinBasal Bolus


Basal InsulinContinuing metformin and/or sulphonylurea after start of therapy with basal long-acting insulin results in better glycemic control with less insulin requirements, less weight gain and less hypoglycemic events.

Long-acting insulin analogues in combination with oral medication are associated with similar glycemic control but fewer hypoglycemic episodes compared with NPH insulin.


Premixed InsulinMost of the trials demonstrated better glycemic control with premix insulin therapy than with a long-acting insulin once daily, but premix insulin causes more hypoglycemic episodes. Analogue premix provides similar HbA1c, but lower postprandial glucose levels compared with human premix, without increase in hypoglycemic events or weight gain.


Basal BolusDrawing conclusions from the limited number of studies concerning basal-bolus regimen seems not possible. Some studies showed that rapid-acting insulin analogues frequently result in a better HbA1c or postprandial glucose without increase of hypoglycemia than regular human insulin.


A once-daily basal insulin regimen added to oral medication is an ideal starting point. All next steps, from one to two or even more injections per day should be taken very carefully and in thorough deliberation with the patient, who has to comply with such a regimen for many years


Mechanism of Action

Dosage RelativeEffective-

ness


Weight Effects

(average)

Cost

Sulfonylureas

Glyburide(Micronase)

Glipizide(Glucotrol)

glimepiride(Amaryl)


2.5-10 mg bid

5-20 mg bid

0.5-4 mg qd

1

1

1

HypoglycemiaGain 2 lbs $


Mechanism of Action


ness


Weight Effects

(average)

Cost



$

Meglitinides

repaglinide(Prandin)

nateglinide(Starlix)


0.5-2 mg tid(before meals)

60-360 mg tid(before meals)

1

.8

HypoglycemiaUseful in pts on glucocorticoids and in pts with renal failure who often have good FBS and high BS over the course of the dayPrandin is short-acting. Starlix is very short-acting

Gain 1 lb $$$


Mechanism of Action


ness


Weight Effects

(average)

Cost



$


Biguanidemetformin(Glucophage)

Primarily inhibits hepatic gluconeogen-esis.

500-2000 mg daily with meals

1Diarrhea, nausea, vomitingIncreased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use

Loss2-3 lbs $


Mechanism of Action


ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$

Alpha-glucosidaseInhibitoracarbose(Precose)

Inhibits enzymes needed to break down complex CHO in the small intestine

50 mg with 1st bite of each meal (start at 12.5 mg and titrate up over weeks)

0.7 Gas/ GI upset Loss1-2 lbs

$$$


Mechanism of Action


ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$


Colesevelam(Welchol)

unknown3.75 g/d

(3- 625 mg tabs bid)

0.7

esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

neutral $$$


Mechanism of Action


ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$

Bile Acid Sequestrants unknown .7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

-- $$$


0.25– 0.5 mg/d .7


---- $$


Mechanism of Action


-ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$

Thiazolidine-diones


pioglitazone(Actos)


4-8 mg daily

15-45 mg daily

1

1



Gain 12 lbs $$$


Mechanism of Action


ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$

Bile Acid Sequestrants unknown .7 esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation

-- $$$


0.25– 0.5 mg/d .7


---- $$

Thiazolidine-diones


pioglitazone(Actos)


4-8 mg daily

15-45 mg daily

1

1



Gain 12 lbs $$$


Mechanism of Action


ness


Weight Effects

(average)

Cost



$




Loss2-3 lbs

$




$$$


$$$

Incretins

exenatide(Byetta)

sitagliptin(Januvia)

saxagliptin(Onglyza)

Mimics GLP-1 (gut hormone which affects insulin, glucagon, gastric emptying and satiety)

DPP-4 inhibitor (enzyme that breaks down GLP-1)

5-10 mcg bid SQ

100, 50, or 25 mg daily (dose by Cr Cl)

5, 2.5 mg (for decrease creat)

1

0.7-1

Nausea, Vomiting, constipation, pancreatitis (?)Weight loss achieved through appetite suppression

Side effects are rare. Occ GI side effects.

Loss 8 lbs

Neutral

$$$

$$$

Drug Cost Comparison

Drug and Dose Cost/month

Glucose Strips (2 per day) $60

Sulfonylurea Generic $4-14Brand $50

Rapaglinide 2 mg tid $175Acarbose 100 mg tid $88Metformin 1000 bid Generic $ 4-32

Brand $132Rosiglitazone 8 mg qd $223Pioglitazone 45 mg/d $222Sitagliptin $181Exenatide 5mcg $230

10mcg $255Colesevelam 3750 mg/d $212Bromocriptine 2.5-5mg $62-130Glargine, 45 U/d $150

24 hour fitness center $44YMCA $60

No Meds

1 Drug

2 Drugs

3 Drugs

Insulin added

7

9

10

8

HgA1c

Diabetes Care. Published online Oct 22, 2008

2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm

An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.

Road Maps to Achieve Glycemic ControlIn Type 2 Diabetes Mellitus

ACE/AACE Diabetes Road Map Task Force

ChairpersonsPaul S. Jellinger, MD, MACE, Co-Chair

Jaime A. Davidson, MD, FACE, Co-Chair

Task Force MembersLawrence Blonde, MD, FACP, FACE

Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE

Yehuda Handelsman, MD, FACP, FACERichard Hellman, MD, FACP, FACE

Harold Lebovitz, MD, FACEPhilip Levy, MD, FACE

Victor L. Roberts, MD, MBA, FACP, FACE

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproducedor distributed in any form without the express permission of AACE.

Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)

InitialA1C%

Achieve ACEGlycemic Goals†

( FPG, PPG, and A1C ) Intervention

ContinuousTitration of Rx( 2 - 3 months )

If ≤ 6.5% A1C GoalNot Achieved

Assess FPG

and PPG

Initial Therapy

Monitor / adjust Rx to

maximal effective dose to meet ACE

Glycemic Goals

Intensify Lifestyle Modification

Intensify or combine Rx including incretin mimetic*1

Target: PPG

and FPG

Monitor / adjust Rx to

maximal effective dose to meet ACE

Glycemic Goals

Combine Therapies 6,7Intensify Lifestyle

Modification

Intensify or combine Rx, including incretin mimetic

with SU, TZD, and/or metformin

6 - 7

7 - 8

Lifestyle M

odificationLifestyle

Modification

If ≤ 6.5% A1C GoalNot Achieved

Alternatives• Glinides• SU (low dose)• Prandial insulin5,8

Preferred:• Metformin4

• TZD10,11

• AGI• DPP-4 Inhibitor

Alternatives• Prandial insulin5,8

• Premixed insulinpreparations8

• Basal insulinanalog9

• Metformin• Glinides• AGI• TZD• SU• DPP-4 Inhibitor

© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

ACE/AACE Diabetes Road Map Task Force

Paul S. Jellinger, MD, MACE, Co-ChairJaime A. Davidson, MD, FACE, Co-ChairLawrence Blonde, MD, FACP, FACEDaniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACERichard Hellman, MD, FACP, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, FACEVictor L. Roberts, MD, MBA, FACP, FACE

Endocr Pract. 2007;13:260-268

†ACE Glycemic Goals ≤ 6.5% A1C< 110 mg/dL FPG < 110 mg/dL Preprandial< 140 mg/dL 2-hr PPG

Access Roadmap at:www.aace.com/pub

* Available as exenatide1 Indicated for patients not at goal despite SU and/or

metformin or TZD therapy; incretin mimetic is notindicated for insulin-using patients

4 Preferred first agent in most patients5 Rapid-acting insulin analog (available as lispro, aspart and

glulisine), inhaled insulin, or regular insulin6 Appropriate for most patients7 2 or more agents may be required8 Analog preparations preferred9 Available as glargine and detemir

10 A recent report (NEJM; 6/14/07) suggests a possible link ofrosiglitazone to cardiovascular events that requires further evaluation.

11 Cannot be used in NYHA CHF Class 3 or 4

Start onsulfonylurea or insulin

TYPE 2 DIABETES

SYMPTOMATICAnd very highNO YES

Referral for:•Diet•HGM•Exercise•Foot Care

Goal Met

Start Metformin

Referral for:•Diet•HGM•Sick Day Rules•Exercise (+/- EST)•Foot Care

NO

Continue Current TreatmentAdd

Medication

YESConsidertransitionto metformin

TYPE 2 DIABETESMetformin

OBESE THIN

Exenatide Sulfonylurea

Add Sulfonylurea(consider TZD)

•Start insulin – use pens•Add levemir , glargine or PM NPH (isolated fasting hyperglycemia or insurance)

•? of which existing meds to continue, generally all •Change to bid premixed insulin

•? of which existing meds to continue, generally just metformin•Change to basal and with premeal insulin

•? of which existing meds to continue, generally just metformin

Goal Not Met

Sitagliptin

Thin or no injection

Sitagliptin(consider TZD)

Goal Not Met

Add Sulfonylurea(consider TZD)

Goal Not Met

Goal Not Met

Roden M. N Engl J Med 2009;10.1056/NEJMe0908706

Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 Years

Three-Year Efficacy of Complex Insulin Regimens in Type 2 Diabetes

15. rushakoff- current controversies in diabetes … · current controversies in diabetes...

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