Clinical Updates in TYPE 2 DIABETESEvolving Roles of GLP-1 Receptor Agonists

Learning Objectives

• Describe the major pathologic deficits underlying T2DM development with a focus on relationships with incretin hormone signaling

• Individualize therapy for patients with T2DM based on disease severity, therapeutic goals, comorbidities, and treatment-related risks, including hypoglycemia

• Select appropriate patients with T2DM for treatment with short- or long-acting GLP-1 RAs

• Intensify antidiabetes regimens for various patient types to address poor fasting and/or postprandial glycemic control and other relevant clinical parameters

• Educate patients on lifestyle changes, the clinical profiles of GLP-1 RAs, and treatment adherence

GLP-1 RAs = glucagon-like peptide-1 receptor agonists; T2DM = type 2 diabetes mellitus.

Achieving Treatment GoalsRoom for Improvement in T2DM

*P <.01.N = 1497 (1988-1994) and 1447 (2007-2010) adults aged ≥20 years with a self-reported diagnosis of diabetes. Retrospective analysis of data obtained from the National Health and Nutrition Examination Surveys.A1C = glycated hemoglobin; BP = blood pressure; LDL-C = low-density lipoprotein cholesterol.Stark Casagrande S, et al. Diabetes Care. 2013;36:2271-2279.

0

Patie

nts

Ach

ievi

ng G

oal,

%

A1C <7.0% BP <130/80 mm Hg LDL-C <100 mg/dL A1C <7.0%,BP <130/80 mm Hg,

and LDL-C <100 mg/dL

1988-19942007-2010

40

50

60

70

30

20

10

* **

*

Goals Potential Benefits

• Establish a partnership based on exchange of information

• Discuss treatment options• Match therapies with patient

preferences• Prioritize actions required to fulfill

clinical decisions

• Individualized goals and therapy• Improved treatment outcomes• Mitigated behavioral risks and

psychosocial hurdles• Increased treatment adherence• Reduced inappropriate care and

healthcare costs

Shared Decision Making and Coordinated Care in T2DM

Barriers• Time constraints• Patient health literacy• Lack of clinician accessibility and availability• Patient/provider power imbalance

Solutions• Interprofessional care• Patient decision aids

O’Connor PJ, et al. Diabetes Care. 2011;34:1651-1659; Oshima Lee E, et al. N Engl J Med. 2013;368:6-8; Peek ME, et al. J Gen Intern Med. 2009;24:1135-1139; Shojania KG, et al. JAMA. 2006;296:427-440.

AliceAnnual Checkup

• 46-year-old Latina lawyer• Married with no children• BMI, 30.6 kg/m2 (obese)• BP, 141/92 mm Hg• Unhealthy lifestyle

– Little physical activity– Regularly consumes fried

food and red meat– Eats few fruits or

vegetables

• Family history– Father had T2DM

• Medical history– Hypertension diagnosis

5 years ago• Lisinopril 40 mg daily• Atenolol 50 mg daily

– Forgets BP medications at least once weekly

BMI = body mass index.

Screening Asymptomatic Persons for Diabetes

ADA

• Screen at least every 3 years if ≥45 years of age OR BMI ≥25 kg/m2 (≥23 kg/m2 for Asian Americans) with an additional risk factor• Screen more frequently based on results and risk status

AACE• Screen every 3 years if any risk factor is present• Screen annually if ≥2 risk factors are present

Alice’s risk factors

• Sedentary lifestyle • Obese• First-degree relative with T2DM• High-risk race or ethnic group (eg, black, Hispanic)• Hypertension (BP ≥140/90 mm Hg, or therapy)

AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association.ADA. Diabetes Care. 2015;38(suppl 1):S1-S91; Handelsman Y, et al. Endocr Pract. 2015;21:1-87.

AliceWorkup and Diagnosis

• A1C, 8.5%• FPG, 225 mg/dL

– Second test 218 mg/dL• eGFR, 88 mL/min/1.73 m2

• ACR, 2.5 mg/mmol • Normal sensory

examination• Normal fundoscopic

examination

• Lipids– LDL-C, 121 mg/dL– HDL-C, 41 mg/dL– TG, 180 mg/dL– TC, 198 mg/dL

ACR = albumin/creatinine ratio; eGFR = estimated glomerular filtration rate; FPG = fasting plasma glucose; HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides.

Alice receives a diagnosis of T2DM

AliceSetting Glycemic Targets

Age, 46 yearsNewly diagnosed

BMI, 30.6 kg/m2 A1C, 8.5% Father treated for T2DM

Hypertension Mild dyslipidemia Normal renal function

Not adherent to other drug

therapies

What treatment goals would you target for Alice?

Reducing T2DM ComplicationsMultidimensional Treatment Goals

a2014 American College of Cardiology/American Heart Association guidelines: Patients aged 40-75 years with T2DM and initial LDL-C ≥70 mg/dL should receive high-intensity (lower LDL-C by ≥50% if 10-year ASCVD risk is ≥7.5%) or moderate-intensity (lower LDL-C 30%-50% if 10-year ASCVD risk is <7.5%) statin therapy.ASCVD = atherosclerotic CVD; CVD = cardiovascular disease.ADA. Diabetes Care. 2015;38(suppl 1):S1-S91; Handelsman Y, et al. Endocr Pract. 2015;21:1-87; Stone NJ, et al. Circulation. 2014;129(25 suppl 2):S1-S45.

Lifestyle modificationsHealthy diet, exercise, smoking cessation

BPADA

<140/90mm HgAACE

<130/80mm Hg

A1CADA

<7.0%AACE≤6.5%

Lipidsa

LDL-C: <100 mg/dL (<70 mg/dL with CVD)

HDL-C: >40 mg/dL (men)>50 mg/dL (women)

TG: <150 mg/dL

Comprehensive Diabetes Management

BMI<25 kg/m2

AliceInitial Treatment Planning

• Target A1C ≤6.5%• Alice and her clinician discuss lifestyle modifications• Clinician suggests a certified diabetes educator

– Patient education– Detailed dietary and exercise recommendations

Diabetes Education and Lifestyle Modifications

Skills-Based Diabetes Education• Disease process and treatment options• Blood glucose monitoring • Medication safety (eg, hypoglycemia)• Strategies to promote behavior change

Individualized Dietary Recommendations• Dehydration and nutritional deficits• Discuss macronutrient content and eating patterns • Monitor carbohydrate intake• Reduce calories to achieve weight loss

− Initial moderate calorie restriction (500-1000 kcal/d)

Physical Activity• At least 150 min/wk of moderate activity • Aerobic, resistance, flexibility

ADA. Diabetes Care. 2015;38(suppl 1):S1-S91; Evert AB, et al. Diabetes Care. 2014;37(suppl 1):S120-S143; Jensen MD, et al. Circulation. 2014;129(25 suppl 2):S102-S138; Haas L, et al. Diabetes Care. 2014;37(suppl 1):S144-S153.

aP <.001; bP = .01 vs support and education alone.N = 2570 for lifestyle intervention and 2575 for support and education.Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.

Parameter Intensive Lifestyle Intervention

Support and Education

Weight loss, % –6.5a –0.88Treadmill fitness, % metabolic equivalent 12.74a 1.96

A1C, % –0.36a –0.09Systolic pressure, mm Hg –5.33a –2.97Diastolic pressure, mm Hg –2.92b –2.48HDL-C, mg/dL 3.67a 1.97TG, mg/dL –25.56a –19.75

LOOK AHEAD StudyIntensive Lifestyle Intervention and Risk Reduction

Intensive Lifestyle Intervention • Diet modification, exercise, behavioral training• Group support with in-person and telephone follow-ups

Look AHEADIntensive Lifestyle Intervention and Diabetes Remission

Years of Continuous Remission (Partial or Complete)

Remission Prevalence Remission Duration

Year

0

4

8

12

16

Prev

alen

ce, %

1 2 3 4

Intensive lifestyle interventionDiabetes support and education

0

4

8

12

20

Estim

ate,

%

≥1 ≥2 ≥3 4

Intensive lifestyle interventionDiabetes support and education

16

N = 4503 adults with T2DM and BMI ≥25 kg/m2.Gregg EW, et al. JAMA. 2012;308:2489-2496.

AliceOverview

• 46-year-old Latina woman with an unhealthy lifestyle

• BMI, 30.6 kg/m2 (obese)• BP, 141/92 mm Hg• A1C, 8.5%

– Target A1C, ≤6.5%• FPG, 225 mg/dL• eGFR, 88 mL/min/1.73 m2

• ACR, 2.5 mg/mmol • Normal sensory and fundoscopic exams

• Lipids– LDL-C, 121 mg/dL– HDL-C, 41 mg/dL– TG, 180 mg/dL– TC, 198 mg/dL

• Father had T2DM• Medical history

– Hypertension• Lisinopril and atenolol• Often forgets medications

What medication(s) would you initially consider for Alice?

AACE/ACE Algorithm for Glycemic Control

Lifestyle Modification

Entry A1C <7.5% Entry A1C ≥7.5% Entry A1C >9.0%

Monotherapya Dual therapya

MetforminGLP-1 RASGLT2 inhibitorDPP-4 inhibitorAG inhibitorTZDSU/GLN

If not at goal in 3 months, proceed to

dual therapy

GLP-1 RASGLT2 inhibitorDPP-4 inhibitorTZDBasal insulinColesevelamBromocriptine QRAG inhibitorSU/GLN

METF

ORMI

N or

othe

r firs

t-line

agen

t Dual therapy

ORtriple

therapy

Insulin ±other

agents

Add or intensify insulinPossible benefits or few adverse eventsUse with caution

aMedications listed in order of suggested hierarchy of usage.ACE = American College of Endocrinology; AG = α-glucosidase; DPP-4 = dipeptidyl peptidase-4; GLN = glinide; QR = quick release; SGLT2 = sodium-glucose cotransporter-2; SU = sulfonylurea; TZD = thiazolidinedione.Garber AJ, et al. Endocr Pract. 2015;21:438-447.

If not at goal in 3 months, proceed to triple therapy

Symptoms

NO YES

AliceTreatment Initiation and Follow-up

• Prescribed metformin 500 mg twice daily – Titrated up to 1000 mg twice daily after 1 week

• At 1-month follow-up appointment– A1C, 7.9%

• Previous value, 8.5%• Target value, ≤6.5%

– FPG, 125 mg/dL• Previous value, 225 mg/dL

– PPG, 219 mg/dL (2-hours postmeal)– No significant changes in any other clinical parameters

PPG = postprandial glucose.

Clinician suggests adding a GLP-1 RA.Should the 2nd agent have been initiated with metformin?

Effects of Incretin Hormones

• GLP-1 and GIP stimulate insulin release in response to food intake• Reduced incretin effect is an early sign of T2DM development• GLP-1 and GIP are rapidly degraded by DPP-4

– Incretin-based therapies include degradation-resistant GLP-1 RAs and inhibitors of DPP-4

N = 8 metabolically healthy control subjects. GIP = gastric inhibitory polypeptide. Elrick H, et al. J Clin Endocrinol Metab. 1964;24:1076-1082; Grunberger G. J Diabetes. 2013;5:241-253; Holst JJ, et al. Diabetes Care. 2011;34 (suppl 2):S251-S257; Nauck M, et al. Diabetologia. 1986;29:46-52; Russell S. Int J Clin Pharm. 2013;35:159-172.

Time, min

15

Insu

lin, m

U/L

60

Oral glucose load (50 g)Intravenous glucose infusion10

5

0–10 –5 120 180

Incretin Effect

GLP-1 RAs Effects on Human Physiology

1. Holst JJ, et al. Trends Mol Med. 2008;14:161-168; 2. Flint A, et al. Adv Ther. 2011;28:213-226; 3. Degn K, et al. Diabetes. 2004;53:1187-1194; 4. Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157; 5. Horowitz M, et al. Diabetes Res Clin Pract. 2012;97:258-266; 6. Vilsbøll T, et al. BMJ. 2012;344:d7771; 7. Niswender K, et al. Diabetes Obes Metab. 2013;15:42-54; 8. Fonseca V, et al. Diabetes. 2010;59(suppl 1):A79(296-OR).

Brain5-7

Body weightSatietyEnergy intake

Pancreas1-4

Insulin secretion (glucose-dependent)and β-cell sensitivity Insulin synthesisGlucagon secretion (glucose-dependent)

CV System8

Systolic BP

Liver4

Hepatic glucose output

Stomach1,4

Gastric emptying

FDA-Approved GLP-1 RAsDaily Formulations

Medication Dosage Forms

Adverse Eventsa Dosing

Exenatide twicedaily1

• 5 μg/dose in 1.2-mL prefilled pen

• 10 μg/dose in 2.4-mL prefilled pen

Nausea, vomiting, dyspepsia

1. Start at 5 μg twice daily (1 hour before morning and evening meals)

2. Increase to 10 μg twice daily after 1 month

Liraglutide2 • Prefilled, multidose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg

Nausea, diarrhea,vomiting,

constipation, headache

1. Initiate at 0.6 mg once daily, regardless of meals

2. After 1 week, increasedose to 1.2 mg

3. If glycemic control is not acceptable, dose can beincreased to 1.8 mg

aTreatment-emergent adverse reactions with ≥5% incidence in clinical trials with drug as monotherapy (excluding hypoglycemia). FDA = Food and Drug Administration.1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015.

Shor

t Act

ing

Long

Act

ing

FDA-Approved GLP-1 RAsWeekly Formulations

Medication Dosage Forms Adverse Eventsa Dosing

Exenatide once weekly1

• Single-dose tray with 2-mg vial

• Single-dose 2-mg prefilled pen

Nausea, diarrhea,injection-site nodule, constipation,headache, dyspepsia

1. Administer at 2 mg once every 7 days (weekly), independent of meals

Albiglutide2 • 30-mg or 50-mg lyophilized powder in single-dose pen for reconstitution

Upper respiratory tract infection, diarrhea,nausea, injection-site reaction, cough, back pain, arthralgia, sinusitis, influenza

1. Administer at 30 mg once every 7 days (weekly), regardless of meals

2. If glycemic control is not acceptable, dose can increaseto 50 mg

Dulaglutide3 • Single-dose pen in 0.75-mg or 1.5-mg doses

• Prefilled, single-dose syringe in 0.75-mg or 1.5-mg doses

Nausea, diarrhea, vomiting, abdominal pain, and decreased appetite

1. Initiate at 0.75 mg weekly, regardless of meals or time of day; dose can be increased to 1.5 mg

2. If dose is missed, missed dose must be taken within 3 days

aTreatment-emergent adverse reactions with ≥5% incidence in clinical trials with drug as monotherapy (excluding hypoglycemia).1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf). Accessed May 29, 2015;2. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 3. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015.

Long

Act

ing

Exenatide Twice DailyGlucose Control and Weight Loss

aP <.0001 vs placebo; bP <.001 vs placebo; c16 to 30 weeks, baseline A1C: 7.8%-8.7%. BID = twice daily; MET = metformin.1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460; 2. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100; 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635; 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485; 5. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

ΔA1C,% ΔWeight, kg1 2 3 34 45 521

BackgroundTherapyc

LiraglutideGlucose Control and Weight Loss

aP <.0001 vs comparator; bP <.001 vs comparator; cP <.01 vs comparator; d26 weeks (except 52 weeks for monotherapy), mean baseline A1C: 8.2%-8.6%.1. Garber A, et al. Lancet. 2009;373:473-481; 2. Nauck M, et al. Diabetes Care. 2009;32:84-90; 3. Marre M, et al. Diabet Med. 2009;26:268-278; 4. Zinman B, et al. Diabetes Care. 2009;32:1224-1230; 5. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

ΔA1C,% ΔWeight, kg

Liraglutide 1.8 mg Placebo Sulfonylurea

1 2 3 34 45 521Background

Therapyd

Exenatide Once WeeklyGlucose Control and Weight Loss

P <.005 for all comparators vs exenatide once weekly 2 mg.aOnly sitagliptin comparator shown (study also included MET and pioglitazone as comparators); bCombination therapy allowed.1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258; 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310; 3. Bergenstal RM, et al. Lancet. 2010;376:431-439; 4. Diamant M, et al. Lancet. 2010;375:2234-2243.

ΔA1C,% ΔWeight, kg

Exenatide once weekly Exenatide twice daily SitagliptinPioglitazone Insulin glargine

1,a 2,b 3 34 41,a 2,b

BackgroundTherapy

AlbiglutideGlucose Control and Weight Loss

aP <.0001 vs comparator; bP <.001 vs comparator; cP = .0086 vs insulin glargine and met noninferiority margin; dData represent only patients treated with albiglutide 50 mg; eData represent only patients treated with albiglutide 30 mg. 1. Reinhardt R, et al. 49th Annual Meeting EASD, 2013. ePoster #903; 2. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148; 3. Reusch J, et al. Diabetes Obes Metab. 2014;16:1257-1264; 4. Weissman PN, et al. Diabetologia. 2014;57:2475-2484.

ΔA1C,% ΔWeight, kg

Albiglutide 30 mg or 50 mg Placebo Insulin glargine

1 2 3 3 44 21

BackgroundTherapy

DulaglutideGlucose Control and Weight Loss

aP <.05 vs comparator and met superiority margin; bP <.001 vs comparator and met superiority margin; cMet superiority margin vs comparator; dData shown are for weeks 26 or 52; eComparators added to insulin lispro and background conventional insulin therapy.GLIM = glimepiride; INS = insulin; PIO = pioglitazone.1. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176; 2. Nauck M, et al. Diabetes Care. 2014;37:2149-2158; 3. Wysham C, et al. Diabetes Care. 2014;37:2159-2167; 4. Giorgino F, et al. 74th ADA Scientific Sessions, 2014. Abstract 330-OR; 5. Jendle J, et al. 74th ADA Scientific Sessions, 2014. Abstract 962-P.

ΔA1C,% ΔWeight, kgBackground

Therapyd

Dulaglutide 1.5 mg Exenatide twice daily SitagliptinInsulin glargine Metformin

1 2 3 4 5,e 1 2 3 4 5,e

Long-Term Efficacy and Safety5-Year Data for Exenatide Once Weekly

• Significant improvements in FPG, body weight, lipid levels, and diastolic BP• Nausea and injection-site reactions decreased vs initial 30-week trial• No major hypoglycemia or new safety signals

N = 153 of 258 extension-phase patients (59.3%) who completed 5 years of treatment (exenatide once weekly2 mg or exenatide twice daily 10 μg for 30 weeks ± oral antidiabetes drugs, followed by 4.4 years on exenatide once weekly 2 mg ± oral drugs). DURATION = Diabetes therapy Utilization: Researching changes in A1C, weight and other factors Through Intervention with exenatide ONce weekly; SE = standard error. Wysham CH, et al. Mayo Clin Proc. 2015;90:356-365.

Open-Ended, Uncontrolled Extension of 30-Week DURATION-1Baseline A1C, 8.1%

32.7

43.9

0

10

20

30

40

50

≤6.5% <7.0%A1C Targets

Prop

ortio

n of

Pa

tient

s, %

Year

Mea

n A

1C (S

E), %

6.56.8 6.8 6.9 7

6

6.5

7

7.5

8

8.5

0 1 2 3 4 5

In an 82-week exenatide completer cohort, weight loss was 1) similar across degrees of nausea, 2) progressive despite stable

nausea incidence, and 3) unlikely to be driven by nausea.3

Weight Loss With GLP-1 RAsNot Driven by Gastrointestinal Adverse Events

aP <.05 vs baseline; bP <.05 vs placebo. EXN = exenatide; LIRA = liraglutide; NVD = nausea, vomiting, diarrhea; PBO = placebo; QW = once weekly.1. Russell-Jones D, et al. 70th ADA Scientific Sessions, 2010;1886-P; 2. Drucker DJ, et al. Lancet. 2008;372:1240-1250; 3. Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.

GLP-1 RAs and CV Outcomes Ongoing Trials

Trial Agent Patients (N)

Duration (y)

Patient-Years

Estimated Completion

REWIND(NCT01394952) Dulaglutide 9622 6.5 62,543 2019

EXSCEL(NCT01144338)

Exenatide once weekly 14,000 7.5 105,000 2018

LEADER(NCT01179048) Liraglutide 9340 5 46,700 2015

ELIXA(NCT01147250) Lixisenatide 6075 3.9 23,693 2015

SUSTAIN 6(NCT01720446) Semaglutide 3297 2.8 9232 2016

National Institutes of Health. www.clinicaltrials.gov. Accessed May 29, 2015.

Safety Concerns With Antidiabetic Therapies Hypoglycemia

aIncludes saxagliptin, linagliptin, and sitagliptin; bIncludes canagliflozin, dapagliflozin, and empagliflozin; cIncludes NPH insulin, insulin glargine, and insulin detemir; dHypoglycemia risk is higher when used with sulfonylurea or insulin. NPH = neutral protamine Hagedorn.1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 4. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 5. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015; 6. Boland CL, et al. Ann Pharmacother. 2013;47:490-505; 7. Nauck MA. Drug Des Devel Ther. 2014;8:1335-1380.

Drug A1C Reduction, % Hypoglycemia Incidence, %

Exenatide twice daily1 0.5-0.7 3.8-10.7d

Exenatide once weekly2 1.6 0-3.7d

Liraglutide3 0.8-1.1 3.7-10.9d

Albiglutide4 0.8-1.0 2-3d

Dulaglutide5 0.7-0.8 2.6-5.6d

DPP-4 inhibitors6,a 0.4-0.8 0.3-5SGLT2 inhibitors7,b 0.7 0-6d

Sulfonylureas6 1-2 18-30Pioglitazone6 0.5-1.4 0-3.7Basal Insulin6,c 1.5-3.5 29.9-61.2

ADVANCESevere Hypoglycemia vs Adverse End Points

aAdjusted for multiple baseline covariates; bPrimary end points. Major macrovascular event = CV death, nonfatal myocardial infarction, or nonfatal stroke.Major microvascular event = new or worsening nephropathy or retinopathy.HR = hazard ratio.Zoungas S, et al. N Engl J Med. 2010;363:1410-1418.

15.9

11.5

19.5

9.5 10.010.2 10.1 9.0

4.8 4.3

0

5

10

15

20

25

Major Macrovascular

Event

Major Microvascular

Event

Death From Any Cause

CV Disease Non-CV Disease

Patie

nts

With

≥1

Hyp

ogly

cem

ic E

vent

, %

Severe Hypoglycemia (n=231) No Severe Hypoglycemia (n=10,909)

HR (95% CI):3.53 (2.41-5.17)a

HR (95% CI):2.19 (1.40-3.45)a

HR (95% CI):3.27 (2.29-4.65)a

HR (95% CI):3.79 (2.36-6.08)a

HR (95% CI):2.80 (1.64-4.79)a

b b

Safe Prescribing With GLP-1 RAsAcute Pancreatitis

Precautions1-5

• Cases of pancreatitis have been reported

• Consider treatments other than GLP-1 RAs in patients with history of pancreatitis

Recommendations1-5

• Ask about pancreatitis history• Discontinue promptly if

pancreatitis symptoms occur • If acute pancreatitis develops,

do not restart GLP-1 RA• Report cases of pancreatitis to

www.fda.gov/medwatch

1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 4. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 5. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015.

Safe Prescribing With GLP-1 RAsPossible Thyroid and Endocrine Risk

• Recommendations• Counsel patients regarding MTC risk and symptoms of thyroid tumors• Value of routine calcitonin and/or ultrasound monitoring is uncertain; such monitoring may

lead to unnecessary procedures• Patients with thyroid nodules or elevated serum calcitonin levels identified for other reasons

should be sent to an endocrinologist• Report MTC to state cancer registry, regardless of treatment

http://www.naaccr.org/Membership/MembershipDirectory.aspx

Contraindications1-5 Albiglutide Dulaglutide Exenatide Twice Daily

Exenatide Once Weekly Liraglutide

Do not use if personal/ family history of MTC or presence of multiple endocrine neoplasia syndrome type 2

X X X X

MTC = medullary thyroid carcinoma.1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 4. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 5. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015.

Recommendations for GLP-1 RA UsePossible Renal Impairment Risk

• Recommendations– Use with caution in patients with renal impairment or renal transplantation, especially

when initiating or escalating doses– Hypovolemia due to nausea/vomiting may worsen renal function

Precautions Albiglutide Dulaglutide Exenatide Twice Daily

Exenatide Once Weekly Liraglutide

Renal issues1-5

Use with caution

Use with caution

Use with cautionShould not be used with severe renal impairment (CrCl <30 mL/min) or ESRD

Use with cautionShould not be used with severe renal impairment (CrCl <30 mL/min)or ESRD

Use with caution

CrCl = creatinine clearance; ESRD = end-stage renal disease.1. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 4. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 5. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015.

AliceTreatment Tailoring

• Treated with metformin 1000 mg twice daily • A1C, 7.9%

– Target value, <6.5%• FPG, 125 mg/dL• PPG, 219 mg/dL (2-hours postmeal)• Alice expresses some concerns about GLP-1 RAs

– Worried that the injections will be painful– Has read comments online about cancer risks

Her clinician discusses the available options for GLP-1 RA medications

Comparing GLP-1 RAsShorter-Acting vs Longer-Acting Formulations

aNot approved by the FDA for use in the United States.Brunton S. Int J Clin Pract. 2014;68:557-567; Fonseca VA. Clin Ther. 2014;36:477-484; Kalra S. Diabetes Ther. 2014;5:333-340.

Shorter Acting Longer Acting

CompoundsExenatide twice

daily, lixisenatidea

Albiglutide, dulaglutide, exenatide once weekly, liraglutide, semaglutidea

Half-life 2-5 hours 12 hours to several daysEffects• FPG reduction• Postprandial hyperglycemia

reduction• Fasting insulin secretion stimulation• Glucagon secretion• Weight reduction• Potential for nausea

ModestStrong

ModestReduction

YesYes

StrongModest

StrongReduction

YesYes

Nausea and VomitingPooled Results From Placebo-Controlled Trials

• Potential approaches to reduce risks for nausea and vomiting3,6

– Educate patients on meal size, eating pace, and dose timing relative to meals– Use incremental dosing, particularly with shorter-acting agents– Prescribe short-term antiemetic therapy for select patients

1. Albiglutide prescribing information. www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed May 29, 2015; 2. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed May 29, 2015; 3. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf. Accessed May 29, 2015; 4. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf. Accessed May 29, 2015; 5. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf. Accessed May 29, 2015; 6. Ellero C, et al. Diabet Med. 2010;27:1168-1173.

Medication Nausea Incidence, % Vomiting Incidence, %Albiglutide1 11 4Dulaglutide2 12-21 6-13Exenatide twice daily3 8-44 4-18Exenatide once weekly4 11-27 11Liraglutide5 8-35 6-17

GLP-1 RAs vs Basal Insulin

Buse JB, et al. Diabetes Obes Metab. 2015;17:145-151; Diamant M. Lancet Diabetes Endocrinol. 2014;2:464-473; Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

-0.8-1.2 -1.3

-2.3

-0.6-0.9

-1.3

-2.1

-4

-3

-2

-1

01st 2nd 3rd 4th

Exenatide QWGlargine

Cha

nge

in A

1CFr

om B

asel

ine,

% -0.9 -1.1-1.4

-1.8

-0.5-0.9

-1.2-1.5

-4

-3

-2

-1

01st 2nd 3rd 4th

LiraglutideGlargine

Baseline A1C, % 7.1 7.1 7.7 7.8 8.4 8.5 9.9 9.8

End of TrialA1C, % 6.4 6.6 6.6 6.8 7.1 7.1 7.5 7.7

n 55 49 54 59 59 59 60 53

7.2 7.1 7.9 7.9 8.5 8.6 9.5 9.4

6.3 6.6 6.8 7.0 7.2 7.4 7.7 7.9

61 63 55 69 49 44 59 49

Patient Quartiles Based on Baseline A1C

Combining GLP-1 RA and Basal Insulin

aPercenatge achieving <7% across baseline A1C quartiles for liraglutide and exenatide once weekly vs insulin glargine.Buse JB, et al. Diabetes Obes Metab. 2015;17:145-151; Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15:3-14; Vora J, et al. Diabetes Metab. 2013;39:6-15.

• Simple to initiate• Can control FPG and PPG• Do not impair α-cell response

to hypoglycemia (reduce risks of severe hypoglycemia)

• Weight-lowering• Achieve A1C target in ~60%a

• Simple to initiate• Control nocturnal hyperglycemia

and FPG• Lower hypoglycemia risk than NPH• Can cause weight gain• Achieve A1C target in ~50%a

Potential for better overall A1C control

Basal insulin analogs GLP-1 RAs

Additive effects

Complementary actions

Weighted Mean Difference (95% CI)

Buse et al (2011) –0.70 (–0.72 to –0.68)DeVries et al (2012) –0.43 (–0.68 to –0.18)Li et al (2012) –0.13 (–0.32 to 0.06)Seino et al (L-Asia; 2012) –0.88 (–0.93 to –0.83)Riddle et al (Duo-1; 2013) –0.30 (–0.58 to –0.02)Riddle et al (L; 2013) –0.30 (–0.58 to –0.02)Diamant et al (2014) –0.03 (–0.17 to 0.11)Lane et al (2014) –0.26 (–0.52 to 0.00)Mathieu et al (2014) –0.35 (–0.48 to –0.22)Rosenstock et al (2014) –0.16 (–0.33 to 0.01)Shao et al (2014) –0.11 (–0.23 to 0.01)Wit et al (2014) –0.78 (–1.10 to –0.46)Ahmann et al (2014) –1.19 (–1.36 to –1.02)Rosenstock et al (LixiLan; 2014) –0.20 (–0.40 to 0.00)Seino et al (LIRA-ADD2INSULIN; 2014) –0.80 (–0.96 to –0.64)

Overall (I2 = 96.6%, P <.0001) –0.44 (–0.60 to –0.29)

GLP-1 RAs Plus Basal InsulinMeta-Analysis of Randomized Controlled Trials

15 studies were eligible and included in the analysis (N = 4348 participants).Eng C, et al. Lancet. 2014;384:2228-2234.

–1 –0.5 0 0.5 1Favors GLP-1 RA + Basal Insulin Favors Comparator

ΔA1C, %

AliceKey Points

• Individualize goals and treatment intensity for T2DM– Consider comorbidities– Address psychosocial factors – Take steps to reduce risk of hypoglycemia

• Monitor multiple metabolic targets for comprehensive management and reduction of CV risk– A1C, lipids, BP

• Consider appropriate roles of GLP-1 RAs– Clinically relevant reductions in A1C– Relatively low risks of hypoglycemia– Potential for weight loss and other CV benefits

PCE Action Plan

Routinely screen for T2DM with a frequency that reflects patient age, family history, and other risk factors

Ensure lifestyle modifications are the foundation of any treatment regimen for T2DM

Counsel patients about the risks, signs, and symptoms of pancreatitis before initiating treatment with a GLP-1 RA

Select GLP-1 RAs for T2DM based on the patient’s hyperglycemia profile and preferences

Recommend that patients eat smaller meals and more slowly when initiating treatment with a GLP-1 RA