namcp: fall managed care forum- 2014 handelsman.pdfnamcp: fall managed care forum- 2014 yehuda...

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NAMCP: Fall Managed Care Forum- 2014

Yehuda Handelsman, M.D., F.A.C.P., F.A.C.E., F.N.L.A.Bellagio Hotel, Las Vegas, NV, Friday, 11/14/2014

Update in the Management of Type 2 Diabetes: A Closer Look at Current &

Emerging Treatment Strategies

Yehuda Handelsman, MD, FACP, FACE, FNLA

Medical Director & Principal investigator

Metabolic Institute of AmericaPresident

American College of EndocrinologyProgram Chair & Director

12 World Congress on Insulin Resistance Diabetes & CVDNovember 20-22, 2014, Los Angeles, CA

Solo practice

Endocrinology, Diabetes & MetabolismTarzana, California

2

Handelsman Disclosures Handelsman Disclosures Research grant- Amgen, AZ, BMS, BI, DSI, Gilead, Grifolis, Hamni, Intarcia,

GSK, Lexicon, Merck, Novo Nordisk, Sanofi, Takeda.

Consultant - Amarin, Amgen, (Amylin) BMS, BI, diaDeux, DSI, Eisai, Gilead, GSK, Halozyme, Janssen, LipoScience, Merck, Novo-Nordisk, Sanofi, Santarus, Vivus

Speaker’s Bureau- Amarin, Astra Zeneca-BMS(Amylin), BI-Lilly, DSI, GSK, Janssen, Novo-Nordisk, Santarus, Vivus

President - American College of Endocrinology

Associate Editor: Journal of Diabetes

Dr Handelsman & his immediate family do not have ownership interest & or stocks of any Pharmaceutical or device company

This lecture may include investigational products & non-approved FDA treatments & medications’ indication. It will be identified

appropriately

T2DM Management focus on Safety & Efficacy

– Glycemic goals of T2DM management

– What agents are available?

– Characteristics of contemporary therapy

– Principles of Therapy- focus on Safety and Efficacy

– Patient’s Centered- individual Goals and personalize treatment plan

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Paula, 62-Year- Old Italian Woman

• Married, 2 children, works as Systems Annalist

• Family history of type 2 diabetes and CVD

• Prior history of elevated BP and lipids, managed with lifestyle

• “No time for exercise”

• Current medications: None

• Review of symptoms– Fatigue– Recent sleep disturbances– Joint pain


Physical Examination– BMI: 32.5 kg/m2

– Waist circumference: 38 inches (96.5 cm)

– Blood pressure: 147/89 mmHg

– Heart rate: 86 bpm

Laboratory Results– TSH: 1.8 mIU/L, FT4: 1.2 ng/dL– BUN: 22 mg/dL, Cr: 1.0 mg/dL– eGFR: 70 mL/min/1.73 m2

– Urinary albumin: 100 mcg/min– A1c: 7.4%, FPG: 153 mg/dL– Lipids

• TC: 189 mg/dL• LDL-C: 112 mg/dL• HDL-C: 42 mg/dL• TG: 175 mg/dL

4

Goals For Glycemic ControlADA-AACE

A1c Goals – Individualized

≤6.5% to ≤6.9% for most; provided safely

<6.5% (5%) As close to normal for new, relatively young, healthy; provided safely

≥7% Less stringent for “less healthy” – multiple co-morbidities, labile, short life expectancy

Algorithm for Individualizing Glycemic Targets

Ismail-Beigi F et al. Ann Intern Med. 2011;154:554-9.

Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems

Less motivated, nonadherent, limited insight, poor self-care capacities, and

weak support systems

Psychosocioeconomic considerations

Hypoglycemia riskLow Moderate High

Patient age, years40 45 50 55 60 65 70 75

Disease duration, years5 10 15 20

Other comorbid conditionsNone Few or mild Multiple or severe

Established vascular complicationsNone Cardiovascular disease

Early microvascular Advanced microvascular

Most intensive Less intensive Least intensive6.0% 7.0% 8.0%

5

Personalized medicine- and goals distribution

Study design

Internet based survey

250 expert diabetologists

151 responses

Organize the parameters for consideration according to relative importance

Suggest target HbA1c for sample patients

Cahn A. et al. Submitted for publication

6


Distribution according to region


7

Study Conclusion

• The target HbA1c for the individual patients still varies

between experts.

• These inconsistencies persist in different regions of the

world.

Available Drugs for the Treatment of T2DM - 2014

8

Noninsulin Agents Available for Treatment of Type 2 Diabetes

Class Primary Mechanism of Action Agent Available as

-Glucosidase inhibitors

Delay carbohydrate absorption from intestine

Acarbose Precose or generic

Miglitol Glyset

Amylin analogue

Decrease glucagon secretion Slow gastric emptying Increase satiety

Pramlintide Symlin

Biguanide

Decrease HGP Increase glucose uptake in

muscleMetformin Glucophage or generic

Bile acid sequestrant

Decrease HGP? Increase incretin levels?

Colesevelam WelChol

DPP-4 inhibitors Increase glucose-dependent

insulin secretion Decrease glucagon secretion

Alogliptin NesinaLinagliptin Tradjenta

Saxagliptin OnglyzaSitagliptin Januvia

Dopamine-2 agonist

Activates dopaminergic receptors

Bromocriptine Cycloset

HGP=hepatic glucose production. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

Noninsulin Agents Available for Treatment of Type 2 Diabetes


Glinides Increase insulin secretionNateglinide Starlix or genericRepaglinide Prandin

GLP-1 receptor agonists

Increase glucose-dependent insulin secretion

Decrease glucagon secretion Slow gastric emptying Increase satiety

Exenatide Byetta

Exenatide XR Bydureon

Liraglutide Victoza

Albiglutide Tanzeum

Dulaglutide Trulicity

SGLT2 inhibitor Increase urinary excretion of

glucose

Dapagliflozin Farxiga/ForxigaCanagliflozin InvokanaEmpagliflozin Jardiance

Sulfonylureas Increase insulin secretion

Glimepiride Amaryl or genericGlipizide Glucotrol or generic

GlyburideDiaeta, Glynase, Micronase, or generic

Thiazolidinediones

Increase glucose uptake in muscle and fat

Decrease HGP

Pioglitazone Actos

Rosiglitazone Avandia

9

Combination Agents Available for the Treatment of Type 2 Diabetes

Class Added Agent Available as

Metformin + DPP-4 inhibitor

Alogliptin Kazano

Linagliptin Jentadueto

Saxagliptin Kombiglyze XR

Sitagliptin Janumet

Metformin + glinide Repaglinide PrandimetMetformin + SGLT2 Canagliflozin Invokamet

Metformin + sulfonylureaGlipizide Metaglip and generic

Glyburide Glucovance and generic

Metformin + thiazolidinedionePioglitazone Actoplus Met

Rosiglitazone Avandamet

Thiazolidinedione + DPP-4 inhibitor Pioglitazone + alogliptin Oseni

Thiazolidinedione + sulfonylureaPioglitazone + glimepiride Duetact

Rosiglitazone + glimepiride Avandaryl

Insulin Available for the Treatment of Type 2 Diabetes


Basal

Increase glucose uptake Decrease HGP

Detemir Levemir

Glargine LantusDegludec Tresiba

Neutral protamine Hagedorn (NPH)

Generic

Prandial

Aspart NovoLog

Glulisine Apidra

Lispro Humalog

Regular human Humulin, generic

PremixedBiphasic aspart NovoMix

Biphasic lispro Humalog Mix

Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

10

INCRETINSIn response to equivalent

hyperglycemic stimuli, ORALglucose elicits a greater insulin

response than IV glucose

Glucagon-like Peptide 1 (GLP-1)and

Glucose-Dependent Insulinotrophic Polypeptide (GIP)

Account for ~90% of the incretin effect

Gastric emptying

L-cells

Insulin

SatietyFullness

GIP+

–

++

Glucagon

–GLP-1

K-cells

INCRETIN HORMONE PHYSIOLOGY

11

GLP-1 ANALOGUES

●Exenatide BID●Liraglutide●Exenatide QW●Albiglutide●Dulaglutide

GLP1GLP1

● Effectively reduce HbA1c

● May preserve beta cell function

● Promote weight loss

● Correct known pathophysiologic defects in T2DM

● Do not cause hypoglycemia

● Have an excellent safety profile

Triplitt C, DeFronzo RA. Expert Rev Endo Metab 2006;1:329-41.

12

-1.0-1.1

LEAD 2MET

LEAD 1SU

LEAD 4MET + TZD

LEAD 5MET + SU

-1.3

-1.5

DECREMENT IN HbA1c IN PIVOTAL LIRAGLUTIDE (1.8 mg/d) TRIALS

H

bA

1c (

%)

-1.6

-1.2

-0.8

-0.4

0

LEAD 3Mono RX

-1.1

Per

cen

t R

each

ing

Hb

A1c

< 7

.0%51% 42% 42% 54% 53%

Buse JB et al. Lancet 2009;374:39-47.Garber A et al. Lancet 2009;373:473-81.Marre M et al. Diabet Med 2009;26:268-78.Nauck M et al. Diabetes Care 2009;32:84-90.Russell-Jones D et al. Diabetologia 2009;52:2046-55.Zinman B et al. Diabetes Care 2009;32:1224-30.

EFFECT OF EXENATIDE VS GLARGINE INSULIN ON INSULIN SECRETION IN T2DM

Subjects: 59 T2DM; Age = 58y; BMI = 30.5 kg/m2

HbA1c = 7.5%; FPG = 9.1 mMRx = Metformin only

Exptl Design: Exenatide*(n=29) vs Glargine (n=30)Treatment goal = HbA1c ≤ 7.0%Actual HbA1c = 6.8±0.1%Hyperglycemic (15 mM) clamps

Study Duration: One year

*Up to 15-20 μg tidBunck MC et al. Diabetes Care 2011;34:2041-7.

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C-PEPTIDE SECRETION DURING HYPERGLYCEMIC CLAMP AFTER 1 YEAR OF EXENATIDE VS GLARGINE INSULIN

0

2

4

6

8

10

Time (min)

C-p

epti

de

(nm

ol/L

)

0

1

2

3

4

Rat

io t

o B

asel

ine P< 0.0001

3.19 1.31

EXEN GLAR

-15 0 10 30 60

Exenatide

ExenatideGlargine

Glucose 15 mM

80

EFFECT OF SAXAGLIPTIN ON HbA1c: CHANGE FROM PLACEBO (BASELINE HbA1c ≈ 8.0%)

Chacra AR et al. Int J Clin Prac 2009;63:1395-406; Rosenstock J et al. Diabetes Obes Metab 2008;10:376-86; DeFronzo RA et al. Diabetes Care 2009;32:1649-55; Hollander P et al. J Clin Endocrinol Metab 2009;94:4810-9.

-1

-0.5

0

DRUG NAIVE METFORMIN

ADDITION OF SAXAGLIPTIN TO:

GLYBURIDE PIO/ROSI

H

bA

1c(%

)

-0.63

-0.76-0.83

-0.64

14

0

0.5

1

1.5

2

ADDITION OF LIRAGLUTIDE VS SITAGLIPTIN IN 665 METFORMIN-TREATED T2DM PATIENTS (HbA1c = 8.4%)

Dec

rem

ent

in H

bA

1c (

%)

1.5%

Pratley RE et al. Lancet 2010;375:1447-56.

1.2%

0.9%

P<0.0001

P<0.0001

SITA LIRA - 1.2 mg LIRA - 1.8 mg

PLEIOTROPIC EFFECTS OF TZDs

Durable HbA1c Reduction

Insulin sensitivity

Insulin secretion

Lipotoxicity

Dyslipidemia

Atherosclerotic CVD

NASH

Nephropathy

15

EIGHT YEAR INCIDENCE OF BLADDER CANCER: ANALYSIS – KPNC REGISTRY

193,099 T2DM patients ≥ 40 years

HR = 0.98, 95% CI = 0.81-1.18

Lewis JD, Kaiser Permanente Northern California (KPNC), August, 2012Lewis JD et al. Diabetes Care 2011;34:916-22.

1,089 T2DM developed bladder cancer

- 137 treated with pioglitazone- 952 never received pioglitazone

SGLT1 and SGLT2 Inhibitors in Clinical Development

Compound Company SGLT1 SGLT2 Stage/Phase

Dapagliflozin BMS/AZ No Yes Approved E.U, USA

Canagliflozin Mitsubishi/JNJ Yes (weak) Yes Approved USA

Empagliflozin BI/Lilly No Yes Approved USA

LX4211 Lexicon Yes Yes Phase 3-ready

Ipragliflozin Kotobuki/Astellas No YesDiscontinued in U.S./E.U.; Phase 3 Japan

Tofogliflozin Chugai No YesDiscontinued by Roche; returned to Chugai (Ph 3 Japan)

Ertugliflozin Pfizer/Merck No Yes Phase 3

Luseogliflozin Taisho No Yes Phase 2

LIK066 Novartis Yes Yes Phase 2 starting

GSK-1614235 Kissei/Dainippon/GSK Yes No Phase 1

16

Intestinal and Renal Role of SGLT1 and SGLT2 in Glucose Absorption

• SGLT1 is the primary transporter for absorption of glucose and galactose in the GI tract

• Reduction of glucose absorption in the proximal intestines leads to more glucose being delivered distally

• L cells respond to increased glucose metabolism by releasing GLP-1 and PYY

• SGLT1 effect fully preserved in all stages of CRF

• SGLT2 is expressed in the proximal PCT where it reabsorbs >90% of filtered glucose

• Enhancing glucose excretion in the kidney will enhance glycemic control

• This mechanism is independent of insulin and may be pancreas-sparing

• SGLT1 is expressed in the distal PCT and reabsorbs <10% of filtered glucose

SGLT2 Inhibitors Increase Urinary Glucose Excretion

a P < 0.01 vs PBO.BID=twice daily; PBO=placebo; QD=once daily; UGE=urinary glucose excretion.1. List J et al. Diabetes Care. 2009;32:650-7. 2. Rothenberg PL et al. 46th EASD Meeting. 2010;876.

LX4211

17

SGLT2 Inhibitors: Monotherapy Efficacy on A1c and FPG

1. Stenlöf K et al. Diabetes Obes Metab. 2013;15:372-82. 2. Ferrannini E et al. Diabetes Care. 2010;33:2217-24. 3. Ferrannini E et al. 46th EASD Meeting. 2010;877. 4. Kashiwagi A et al. 47th EASD Meeting. 2011;149. 5. Rothenberg P et al. 46th EASD Meeting. 2010;876.

Canagliflozin1 Empagliflozin3 Ipragliflozin4Dapagliflozin2

Dapagliflozin2 Empagliflozin3 Ipragliflozin4Canagliflozin5

PBO 256

PBO 5 10 25PBO 100 300

PBO 2.5 5 10PBO 100 200 400

PBO 25

0.1

PBO 5 10 251

PBO 2.5 5 10

-0.8-0.6-0.5-0.4

-23-31-29

-0.77

-29-24

-15-4

-60-65-54

-25

0.14 -0.2

-0.6-0.8

-0.9

-46

-1.03

∆A

1c (

%)

∆F

PG

(m

g/d

L)

0.5

SGLT2 Inhibitors: A1c Efficacy as Add-onto Metformin Therapy

1. Bailey C et al. Lancet. 2010;375:2223-33. 2. Rosenstock J, et al. 70th ADA Scientific Sessions. 2010;77-OR. 3. Seman L et al. 47th EASD Meeting. 2011;147. 4. Bailey C et al. 47th EASD Meeting. 2011;146. 5. Del Prato S et al. 47th EASD Meeting. 2011.

a24 weeks, N = 534, baseline A1c=7.9% - 8.2%. b 12 weeks, N=408, baseline A1c=7.9%. cMean PBO-subtracted ∆ from baseline. d16 weeks, N=129, baseline A1c=8.3%. eP < 0.05 vs PBO.

FPG reductions from baseline also statistically significant vs PBO (P < 0.05)

-0.4 e -0.54

e

Dapagliflozin1,a,c Canagliflozin2,b,c Empagliflozin3,c,d LX 4211c

200 400

-0.43 e

-0.86e

18

Efficacy of SGLT2 Inhibitors Added to Insulin ± Oral Agents

a48 weeks, N=808, baseline A1c=8.53%. b28 days, N=29, baseline A1c=7.9%.1. Wilding J et al. 70th ADA Scientific Sessions. 2010;21-LB. 2. Schwartz S et al. 70th ADA Scientific Sessions. 2010;564-P.

Dapagliflozin1,a Canagliflozin2,b,

Weight Loss: SGLT2 Inhibitors Added to Metformin

1. Bailey C et al. Lancet. 2010;375:2223-33. 2. Rosenstock J et al. 70th ADA Scientific Sessions. 2010;77-OR. 3. Rosenstock J et al. 71st ADA Scientific Sessions. 2011;989-P. 4. Bailey CJ et al. 47th EASD Meeting. 2011;146..

aPBO-subtracted values. bP ≤ .01 vs PBO.

Dapagliflozin (24 wk)1 Canagliflozin (12 wk)2,a Empagliflozin (12 wk)3

19

SGLT2 Inhibitors Added to Metformin: Systolic Blood Pressure Effects

Dapagliflozin- 4.3 mm Hg (52 weeks)1

- 5.1 mm Hg (10 mg, 24 weeks)2

- 6.4 mm Hg (10 mg, 12 weeks)3

Canagliflozin

- 5.1 mm Hg (300 mg, 52 weeks)4

Empagliflozin- 6 mm Hg (25 mg, 12 weeks)5

LX4211

- 6 mm Hg (400 mg, 12 weeks)6

Nauck MA et al. Diabetes Care. 2011;34:2015-22. 2. Bailey C et al. Lancet. 2010;375:2223-33. 3. List JF et al. Diabetes Care. 2009;32:650-7. 4. Schernthaner G et al. Diabetes Care. 2013;36:2508-15. 5. Seman L et al. 47th EASD Meeting. 2011;147. 6. Diabetes. 2013(suppl 1):948.

Dapagliflozin in T1DM: Pilot Study

• 2-week, randomized, double-blind, placebo-controlled study

• 70 adults with T1DM (A1c 7%-10%) on stable insulin who received one of four dapagliflozin doses (1/2.5/5/10 mg) or placebo

– Sixty-two patients (88.6%) completed the study

• Mean changes from baseline with dapagliflozin 10 mg by Day 7 were: – Increased glucosuria (493 mmol/24h; 95% CI: 306-680) [88 g/24h; 95%

CI: 55-121]– Reduced daily average blood glucose (−2.29 mmol/L; 95% CI: −3.71 to

−0.87) [−41.3 mg/dL; 95% CI: −66.9 to −15.7]– Reduced mean amplitude of glycemic excursion (−3.77 mmol/L; 95% CI:

−6.09 to −1.45) [−63.1 mg/dL; 95% CI: −111.5 to −14.8]– Reduced total daily insulin dose (−16.2%; 95% CI: −29.4 to −0.5)

• Hypoglycemia was common across all treatments (60.0%-92.3%)

Diabetes. 2013(suppl 1):992.

20

Effect of Dapagliflozin on Plasma Glucagon Concentration and EGP

Abdul-Ghani et al. Diabetes. 2013(suppl 1):607.

Mechanism of Action for Bile Acid Sequestrant (colesevelam) and Dopamine D2 Receptor Agonist (bromocriptine)

Mechanism of Action

Colesevelam • Non-absorbed polymer that binds bile acids in the intestine (lowers LDL-C)

• MOA to reduce glucose has not been elucidated

Bromocriptine • D2 receptor agonist

• Increases early morning dopamine receptor activity (thought to be low in T2DM contributing to glucose and lipid dysfunction)

LDL-C=low-density lipoprotein cholesterol.

21

Colesevelam in Combination Lowers A1c and LDL-C

ITT Population, Last Observation Carried Forward (LOCF), patients on background monotherapy and combination therapy.SFU=sulfonylurea.

-0.54 -0.54 -0.50

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

(n=148)Baseline

A1c=8.1%

(n=218)Baseline

A1c=8.2%

(n = 144)Baseline

A1c=8.3%

P < 0.001 P < 0.001P < 0.001

Mean Change in A1c (%)

Colesevelam Plus

Metformin-Based Therapy

Colesevelam Plus

SFU-Based

Therapy

Colesevelam Plus

Insulin-Based

Therapy

Colesevelam Plus

Metformin-Based Therapy

Colesevelam Plus

SFU-Based Therapy

Colesevelam Plus

Insulin-Based Therapy

Mean LDL-C

Change from

Baseline(%)

5

0

-5

-10

-15

-20

-15.9%P < 0.001

-16.7%P < 0.001

-12.8%P < 0.05

3.7 0.6 0.5

-12.3-16.1

-12.3

Colesevelam

Placebo

Bromocriptine Safety Trial: Evaluation of A1c Change in a 24-week Efficacy Period

Efficacy data in combination with glitazones are limited. Efficacy has not been confirmed in combination with insulin.

Placebo

Bromocriptine

Failing Any OAD(n=412)

Failing Metformin ± OAD(n=282)

Failing Metformin + Sulfonylurea

(n=192)

Failing TZD ± OAD(n=81)

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

A1c changes from baseline vs placebo in patients completing 24 weeks of treatment (per protocol population) (%)

Average baseline A1c=8.3%

∆ -0.57P < 0.0001 ∆ -0.69

P < 0.0001 ∆ -0.69P = 0.0002

∆ -0.91P = 0.0026

22

Comparative InsulinTrials in T2DMSummary of Key Findings

• Any insulin will lower glucose and A1c

• All insulins are associated with some weight gain and some risk of hypoglycemia

• The larger the doses and the more aggressive the titration, the lower the A1c, but often with a greater possibility of adverse effects

• Long-acting insulin analogues reduce the incidence of overnight hypoglycemia

• Rapid-acting insulin analogues reduce postprandial glucose excursions (compared with corresponding human insulins [NPH, Regular]); however, they are associated with more hypoglycemia and weight gain

Inzucchi SE, et al. Diabetologia. 2012;55:1577-96.

Benefits of Insulin Analogues

• Mimics physiological insulin more predictably than NPH1,2

• PK/PD profiles are not affected by factors such as injection site that affect NPH3

• Fewer hypoglycemic episodes due to limited peak effects4,5

• Reduced variability between patients1

• Rapid onset1

• Longer mean duration of action1

1Evans M, et al. Diabetes Obes Metab. 2011;13:677-84.2Rosenfalck AM, et al. Acta Diabetol. 2000;37:41-6.3 Morello CM. Int J Gen Med. 2011;4:827-35.4Hamaty M. Cleve Clin J Med. 2011;78:332-42. 5Hermansen K, et al. Diabetes Care. 2006;29:1269-74.

23

Adding Insulin to OADs Improves Glycemic Control for Many Patients: Results of Large RCTs

7.82

7.2

7.49

7.6

7.5

7.1

7.24

7.3

7.7

7.19

7.2

0 2 4 6 8 10 12

Davidson et al (2011)

DURABLE (2011)

Riddle et al (2011)

4-T (2007)

STEPwise (2011)

Average A1C (%)

a A second type of insulin could be added beginning at 24 weeks if A1c ≥ 8.0% on 2 consecutive readings or A1C > 10%.b P < .001 vs. DET QD; c P < .05 vs. BIASP; d P < .025 vs. BIASP.

Meneghini L, et al. Endocr Pract. 2011;17:727-36.Holman RR, et al. N Engl J Med. 2007;357:1716-30.

Riddle MC, et al. Diabetologia. 2011;54(suppl 1):S421:1036. Buse JB, et al. Diabetes Care. 2011;34:249-55.

Davidson MB, et al. Endocr Pract. 2011;17:395-403.

DET QDaBIASP BIDaASP TIDa

BIASP BID

GLAR QD

GLAR QD + GLU QDGLAR QD + 0-3 GLU

52 weeks

60 weeks

24 weeks

14 weeks

GLAR QDLM75/25 BID

Baseline A1c (%)

48 weeks

DET + 0-3 ASP (Measured PPG)DET + 0-3 ASP (Estimated meal size)

bb

cd

8.98.7

8.68.68.4

9.439.359.28

8.78.6

10.2

Addition of Basal Insulin vs. a Third Oral Agent to Combination Oral Therapy

*P < 0.05 for glargine vs. rosiglitazone

240 4 8 12 16 20

9.0%

8.5%

8.0%

7.5%

7.0%

6.5%

A1c

Time (weeks)

GlargineRosiglitazone

Baseline A1c

07% 8% 9% 10% 11%

GlargineRosiglitazone

A

1c

**

**

-0.5%

-1.0%

-1.5%

-2.0%

-2.5%

-3.0%

-3.5%

Glycemic ControlOver Time

Glycemic Control by Baseline A1c

Rosenstock J, et al. Diabetes Care. 2006;29:554-9.

24

12,612

>6000 standard step-therapy>6000 early glargine

FPG goal: <95 mg/dL(<5.3 mmol/L)

A1c goal: <7%

Start: 2003 Follow-up: Extended to 7 years Final results: 2011

ORIGIN Trial: Study Design

• Prediabetes and early T2DM with CVD

• CV event-reduction outcome study

• Opportunity to assess -cell preservation

If positive…insulin replacement can be considered right from the outset!

Gerstein H, et al. Am Heart J. 2008;155:26-32.

Median A1c Levels

6.4

5.96 6

6.16.2

6.36.2

6.4

6.26.3

6.4 6.46.5 6.5 6.5

5.5

6.0

6.5

7.0

0 1 2 3 4 5 6 7

A1

c (

%)

Year

Glargine

Standard

IQR 5.5 – 6.5

IQR 5.8 – 6.9

25

ATLANTUSInsulin glargine titrated by 2 units q3 days by patient or weekly by physician based on traditional adjustment algorithm

Davies M, et al. Diabetes Care. 2005;28:1282-8.

Fasting Plasma Glucose A1c Change (%)

Weeks since randomization

FB

G (

mg

/dL

)

Insu

lin d

ose

(IU

)

0 2 4 6 8 10 12 14 16 18 2022 2490

110

130

150

170 50

45

40

35

30

25

20

†

*

FBG Insulin dosePhysicianPatientPatient

Physician

-1.08-1.22

P < 0.001

-1.25

-1.00

-0.75

-0.50

-0.25

0

Physician(n = 2315)

Patient(n = 2273)

A1c

(%

)

Insulin Glargine Plus Exenatide: Phase III Data

8.5 8.3

7.4

6.7

5

6

7

8

9

Glargine + placebo

Glargine + exenatide

A1c

(%

)

Baseline

30 weeks

P < 0.001*

P < 0.001*

P = 0.001†

*vs. baseline; †Between treatment groups.Buse J, et al. Diabetes. 2010;59(suppl 1):A10-LB.

34

14

68

49

0

20

40

60

80

Pat

ien

ts a

chie

vin

g t

arg

ets

(%)

Glargine + placebo

Glargine + exenatide

P < 0.001†

P < 0.001†

A1c <6.5% A1c <7.0%

Significant post-prandial effects and weight loss with exenatide

26

Insulin Therapy Summary• When

– Whenever needed to achieve A1c control

– Avoid futile strategies

– Are there benefits from early use – ORIGIN?

• Why– Individualize therapy

– Get patients to goal

– Prevent complications

• Which– All insulins are efficacious

– Consider side effect profiles

– Ultimately, choice depends on patient and provider preferences

– Combination with new agents – particularly effective


• Married, 2 children, works as Systems Annalist

• Family history of type 2 diabetes and CVD

• Prior history of elevated BP and lipids, managed with lifestyle

• “No time for exercise”

• Current medications: None

• Review of symptoms– Fatigue– Recent sleep disturbances– Joint pain

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Which statement about the “ADA-EASD 2012 Position Statement on Management of Hyperglycemia in T2DM” is correct?

1. Treatment is based on baseline A1c

2. Medications which cause hypoglycemia should not be used

3. It includes off-label recommendations

4. It recommends several treatment goals

5. Answers 1 and 4

6. Answers 2 and 3

7. Answers 1, 2, 3, and 4

ADA-EASD Position Statement (2012): Management of Hyperglycemia in T2DM

1. PATIENT-CENTERED APPROACH

“...providing care that is respectful of and responsive to individual patient preferences, needs, and values -ensuring that patient values guide all clinical decisions.”

• Gauge patient’s preferred level of involvement

• Explore, where possible, therapeutic choices

• Utilize decision aids

• Shared decision making – final decisions re: lifestyle choices ultimately lies with the patient

Inzucchi SE et al. Diabetes Care. 2012;35: 1364-79.

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ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach

2. ANTIHYPERGLYCEMIC THERAPY• Implementation Strategies

– Initial drug therapy– Advancing to dual combination therapy– Advancing to triple combination therapy– Transitions to and titrations of insulin

3. OTHER CONSIDERATIONS• Age• Weight• Sex/racial/ethnic/genetic differences• Comorbidities (coronary artery disease, heart failure, chronic

kidney disease, liver dysfunction, hypoglycemia)



29

Which statement about the AACE Diabetes Management Algorithm 2013 is correct?

1. Treatment is based on baseline A1c

2. Medications which cause hypoglycemia should not be used

3. It includes off-label recommendations

4. It recommends several treatment goals

5. Answers 1 and 4

6. Answers 2 and 3

7. Answers 1, 2, 3, and 4

30

Principles of AACE/ACE 2013 Diabetes Algorithms for Glycemic Control

• Comprehensive approach addressing all CV risk factors

• Minimize risk of hypoglycemia

• Minimize risk of weight gain

• Individualize and personalize management plan

• Consider both fasting and postprandial glucose levels

• Consider total cost of therapy, not just acquisition cost of the drug– Hypoglycemic events– Drug-related adverse events– Treatment of complications from nonadherence– Additional laboratory tests

• Include all major classes of FDA-approved glycemic medications

• Select therapy stratified by A1c level

• Select therapy by A1c-lowering potential

Rodbard HW et al. Endocr Pract. 2009;15:540-59. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

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Physical Examination– BMI: 32.5 kg/m2

– Waist circumference: 38 inches (96.5 cm)



Laboratory Results– TSH: 1.8 mIU/L, FT4: 1.2 ng/dL– BUN: 22 mg/dL, Cr: 1.0 mg/dL– eGFR: 70 mL/min/1.73 m2

– Urinary albumin: 100 mcg/min– A1c: 7.4%, FPG: 153 mg/dL– Lipids

• TC: 189 mg/dL• LDL-C: 112 mg/dL• HDL-C: 42 mg/dL• TG: 175 mg/dL

Which treatment is best for Paula?

1. GLP-1 agonist

2. TZD

3. Sulfonylurea

4. SGLT2 inhibitor

5. Metformin

6. DPP-4 inhibitor

7. Answers 4 and 6

8. Answers 1 and 4

9. Answers 1, 2, and 5

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Paula, 62 Year- Old Italian Woman

• Recommendations after last visit– Obesity: lifestyle change

– Hypertension: valsartan

– Elevated lipids: atorvastatin

• Within the first year– Target weight loss and glucose reductions were not achieved with

lifestyle change

• Paula refused weight-loss medication

• Is taking Metformin

– Hydrochlorothiazide added to valsartan to achieve target BP

• During year 2, Paula did not return for follow-up– 13 months have passed since Judith’s last office visit

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Paula, 64 Year Old Italian Woman

• Medications

– Atorvastatin 20 mg

– Valsartan 320 mg/HCTZ 25 mg

– Metformin 2000 mg/day

• Review of symptoms: Continues to have

– Fatigue; Sleep disturbances; Joint pain

• Physical Examination

– BMI: 33.5 kg/m2

– Waist circumference: 39 in (99 cm)



Laboratory Results

• BUN: 24 mg/dL

• Cr: 1.1 mg/dL

• eGFR: 63 mL/min/1.73 m2

• Urinary albumin: 150 mcg/min

• K+: 4.4 mg/dL

• A1c: 7.8%

• FPG: 140 mg/dL

• Lipids– TC: 174 mg/dL– LDL-C: 94 mg/dL– HDL-C: 52 mg/dL– TG: 139 mg/dL

Paula finally returns to office, ~2 years after first visit


1. Replace Metformin with GLP-1 agonist

2. Add TZD

3. Add Sulfonylurea

4. Add SGLT2 inhibitor

5. Add GLP-1 agonist

6. Add DPP-4 inhibitor

7. Answers 4 and 6

8. Answers 1 and 4

9. Answers 2 and 5

34

Paula, a 66 year old Italian Woman

• Paula was prescribed a DPP-4 inhibitor in addition to metformin She declined injectable glucose-lowering therapy

• Follow-up Glycemic targets were maintained the first 6 months

Paula did not return for another 18 months

• Current visit Age: 66 years

Weight increased from last visit

A1C: 8.0%

68

35


• Paula’s glucose remained above target for the next year– She still declined injectable glucose-lowering therapy

• After last visit, Paula was given triple therapy with metformin, a DPP-4 inhibitor, and a thiazolidinedione

• Follow-up– Glycemic targets were improved for few months– Paula again returned by 2 years

• Current visit– Age: 68 years; Blood pressure: 138/84 mmHg; Heart rate: 94 bpm– Weight increased from last visit– A1c: 8.3%; BUN: 26 mg/dL; Cr: 1.3 mg/dL– eGFR: 51 mL/min/1.73 m2; K+: 4.8 mg/dL– Urinary albumin: 250 mcg/min

36


1. Stop all medications and start basal insulin

2. Add basal and meals insulin

3. Add sulfonylurea

4. Add SGLT2 inhibitor

5. Replace the DPP-4 inhibitor with a GLP-1 agonist

6. Replace the DPP-4 inhibitor with a GLP-1 agonist and basal insulin

7. Answers 4 and 6

8. Answers 1 and 4

9. Answers 2 and 5

37

Common Principles in AACE-ACE and ADA-EASD T2DM Treatment Algorithms

• Individualize glycemic goals based on patient characteristics

• Promptly intensify antihyperglycemic therapy to maintain blood glucose at individual targets

– Combination therapy necessary for most patients

– Base choice of agent(s) on individual patient medical history, behaviors and risk factors, ethno-cultural background, and environment

• Insulin eventually necessary for many patients

• SMBG vital for day-to-day management of blood sugar– All patients using insulin

– Many patients not using insulin

Inzucchi SE et al. Diabetes Care. 2012;35:1364-79. Garber AJ et al. Endocr Pract. 2013;19:327-36.

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Summary: DM Contemporary Care

• Identify individual treatment goals

• Institute personalized comprehensive care for people with diabetes Institute intensive treatment for glycemic control while

concomitantly starting medications

Choose medications based on safety, efficacy and characteristics

Monitor every three months and intensify/advance treatment as needed

Introduce Insulin when appropriate, observe for Hypoglycemia and weight gain

Consider combining Insulin and GLP1 as necessary to improve control and reduce side effects

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THANK YOU

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Thank You Questions?

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