Clinical Updates in Type 2 Diabetes

Clinical Updates in TYPE 2 DIABETES Evolving 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 Goals Room for Improvement in T2DM Patients Achieving Goal, %

70 60

*

*

* 1988-1994

50

2007-2010

40 30

*

20 10 0 A1C <7.0%

*P

BP <130/80 mm Hg

LDL-C <100 mg/dL

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

<.01.

N = 1497 (1988-1994) and 1447 (2007-2010) adults aged â&#x2030;Ľ20 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.

Shared Decision Making and Coordinated Care in T2DM 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

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.

Alice Annual 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

BMI = body mass index.

• 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

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 • Sedentary lifestyle

Alice’s risk factors

• 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.

Alice Workup and Diagnosis • Lipids • A1C, 8.5% – LDL-C, 121 mg/dL • FPG, 225 mg/dL – HDL-C, 41 mg/dL – Second test 218 mg/dL – TG, 180 mg/dL • eGFR, 88 mL/min/1.73 m2 – TC, 198 mg/dL • ACR, 2.5 mg/mmol • Normal sensory examination • Normal fundoscopic examination

Alice receives a diagnosis of T2DM 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 Setting Glycemic Targets

Age, 46 years Newly 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 Complications Multidimensional Treatment Goals Comprehensive Diabetes Management BP

A1C

ADA <140/90 mm Hg AACE <130/80 mm Hg

ADA <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

Lifestyle modifications

Healthy diet, exercise, smoking cessation 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.

BMI <25 kg/m2

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

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

Support and Education

Weight loss, %

–6.5a

–0.88

Treadmill fitness, % metabolic equivalent

12.74a

1.96

A1C, %

–0.36a

–0.09

Systolic pressure, mm Hg

–5.33a

–2.97

Diastolic pressure, mm Hg

–2.92b

–2.48

HDL-C, mg/dL

3.67a

1.97

–25.56a

–19.75

Parameter

TG, mg/dL 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.

Look AHEAD Intensive Lifestyle Intervention and Diabetes Remission Remission Prevalence 16

Remission Duration 20

Intensive lifestyle intervention

Intensive lifestyle intervention

Diabetes support and education

Diabetes support and education 16

Estimate, %

Prevalence, %

12

8

4

0

12

8

4

1

2

3

Year

N = 4503 adults with T2DM and BMI ≥25 kg/m2.

Gregg EW, et al. JAMA. 2012;308:2489-2496.

4

0

≥1

≥2

≥3

4

Years of Continuous Remission (Partial or Complete)

Alice Overview •

46-year-old Latina woman with an unhealthy lifestyle

•

Lipids –

LDL-C, 121 mg/dL

•

BMI, 30.6 kg/m2 (obese)

–

HDL-C, 41 mg/dL

•

BP, 141/92 mm Hg

–

TG, 180 mg/dL

•

A1C, 8.5%

–

TC, 198 mg/dL

–

Target A1C, ≤6.5%

•

Father had T2DM

•

Medical history

•

FPG, 225 mg/dL

•

eGFR, 88 mL/min/1.73 m2

•

ACR, 2.5 mg/mmol

•

Lisinopril and atenolol

•

Normal sensory and fundoscopic exams

•

Often forgets medications

–

Hypertension

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

AACE/ACE Algorithm for Glycemic Control Lifestyle Modification Entry A1C ≥7.5%

Entry A1C >9.0%

Monotherapya

Dual therapya

Symptoms

If not at goal in 3 months, proceed to dual therapy aMedications

METFORMIN

Metformin GLP-1 RA SGLT2 inhibitor DPP-4 inhibitor AG inhibitor TZD SU/GLN

or other first-line agent

Entry A1C <7.5%

GLP-1 RA SGLT2 inhibitor DPP-4 inhibitor TZD Basal insulin Colesevelam Bromocriptine QR AG inhibitor SU/GLN

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

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.

NO

YES

Dual therapy OR triple therapy

Insulin ± other agents

Add or intensify insulin Possible benefits or few adverse events Use with caution

Alice Treatment 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

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

PPG = postprandial glucose.

Effects of Incretin Hormones

Insulin, mU/L

15

Oral glucose load (50 g)

10

Intravenous glucose infusion

Incretin Effect 5

0 –10

–5

60

Time, min

120

180

• 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.

GLP-1 RAs Effects on Human Physiology Pancreas1-4 Insulin secretion (glucose-dependent) and β-cell sensitivity Insulin synthesis Glucagon secretion (glucose-dependent)

Stomach1,4 Gastric emptying

Brain5-7 Body weight Satiety Energy intake

CV System8 Systolic BP

Liver4 Hepatic glucose output

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).

FDA-Approved GLP-1 RAs Daily Formulations Dosage Forms

Exenatide twice daily1

• 5 μg/dose in 1.2-mL prefilled pen • 10 μg/dose in 2.4-mL prefilled pen

Liraglutide2

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

Long Acting

Short Acting

Medication

aTreatment-emergent

Adverse Eventsa Nausea, vomiting, dyspepsia

Dosing 1. Start at 5 μg twice daily (1 hour before morning and evening meals) 2. Increase to 10 μg twice daily after 1 month

Nausea, 1. Initiate at 0.6 mg once diarrhea, daily, regardless of meals vomiting, 2. After 1 week, increase constipation, dose to 1.2 mg headache 3. If glycemic control is not acceptable, dose can be increased to 1.8 mg

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.

FDA-Approved GLP-1 RAs Weekly Formulations

Long Acting

Medication

Dosage Forms

Adverse Eventsa

Exenatide once weekly1

• Single-dose tray with 2-mg vial • Single-dose 2-mg prefilled pen

Albiglutide2

• 30-mg or 50-mg lyophilized Upper respiratory tract powder in single-dose pen infection, diarrhea, for reconstitution 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 increase to 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

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

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

Dosing

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

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

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.

Exenatide Twice Daily Glucose Control and Weight Loss Î&#x201D;A1C,% Background Therapyc

aP

1

2

3

Î&#x201D;Weight, kg 4

5

1

<.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.

2

3

4

5

Liraglutide Glucose Control and Weight Loss Î&#x201D;A1C,% Background Therapyd

1

2

3

Î&#x201D;Weight, kg 4

Liraglutide 1.8 mg aP

1

5

Placebo

2

3

Sulfonylurea

<.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.

4

5

Exenatide Once Weekly Glucose Control and Weight Loss Î&#x201D;A1C,% Background Therapy

1,a

2,b

Î&#x201D;Weight, kg

3

Exenatide once weekly Pioglitazone

4

1,a

Exenatide twice daily

2,b

3

Sitagliptin

Insulin glargine

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.

4

Albiglutide Glucose Control and Weight Loss ΔA1C,% Background Therapy

1

2

ΔWeight, kg 3

Albiglutide 30 mg or 50 mg aP

4

1

Placebo

2

3

4

Insulin glargine

<.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.

Dulaglutide Glucose Control and Weight Loss

Background Therapyd

Î&#x201D;A1C,% 1

Dulaglutide 1.5 mg aP

2

3

Î&#x201D;Weight, kg 4

Exenatide twice daily

5,e

1

Insulin glargine

2

3

Metformin

4

5,e

Sitagliptin

<.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;37:21492158; 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.

Long-Term Efficacy and Safety 5-Year Data for Exenatide Once Weekly

8.5

50

8 7.5 7 6.5

6.8

6.8

6.9

7

6.5

6 0

1

Proportion of Patients, %

Mean A1C (SE), %

Open-Ended, Uncontrolled Extension of 30-Week DURATION-1 Baseline A1C, 8.1% 40

43.9 32.7

30 20 10 0

2

Year

3

4

5

≤6.5%

<7.0%

A1C Targets

• 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 weekly 2 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.

Weight Loss With GLP-1 RAs Not Driven by Gastrointestinal Adverse Events

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 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 Agent

Patients (N)

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

Trial

Duration Patient- Estimated (y) Years Completion

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

Safety Concerns With Antidiabetic Therapies Hypoglycemia Drug Exenatide twice daily1 Exenatide once weekly2 Liraglutide3 Albiglutide4 Dulaglutide5 DPP-4 inhibitors6,a SGLT2 inhibitors7,b Sulfonylureas6 Pioglitazone6 Basal Insulin6,c aIncludes

A1C Reduction, %

Hypoglycemia Incidence, %

0.5-0.7 1.6 0.8-1.1 0.8-1.0 0.7-0.8 0.4-0.8 0.7 1-2 0.5-1.4 1.5-3.5

3.8-10.7d 0-3.7d 3.7-10.9d 2-3d 2.6-5.6d 0.3-5 0-6d 18-30 0-3.7 29.9-61.2

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.

ADVANCE Severe Hypoglycemia vs Adverse End Points

Patients With â&#x2030;Ľ1 Hypoglycemic Event, %

Severe Hypoglycemia (n=231) 25

No Severe Hypoglycemia (n=10,909)

HR (95% CI): 3.27 (2.29-4.65)a HR (95% CI): 3.53 (2.41-5.17)a

20

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

15.9

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

15 10

10.2

11.5

10.1

9.0

10.0

9.5 4.8

5

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

4.3

0 Major Major Death From Any Macrovascular Microvascular Cause b b Event Event 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.

CV Disease

Non-CV Disease

Safe Prescribing With GLP-1 RAs Acute Pancreatitis Precautions1-5

Recommendations1-5

•

• •

•

Cases of pancreatitis have been reported Consider treatments other than GLP-1 RAs in patients with history of pancreatitis

• •

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 RAs Possible Thyroid and Endocrine Risk Contraindications1-5

Albiglutide Dulaglutide

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

•

X

Exenatide Exenatide Liraglutide Twice Daily Once Weekly

X

X

X

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

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 Use Possible Renal Impairment Risk Precautions

Renal issues1-5

•

Albiglutide

Use with caution

Dulaglutide

Use with caution

Exenatide Twice Daily

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

Exenatide Once Weekly

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

Liraglutide

Use with caution

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

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.

Alice Treatment 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 RAs Shorter-Acting vs Longer-Acting Formulations

Compounds Half-life Effects • FPG reduction • Postprandial hyperglycemia reduction • Fasting insulin secretion stimulation • Glucagon secretion • Weight reduction • Potential for nausea

aNot

Shorter Acting

Longer Acting

Exenatide twice daily, lixisenatidea

Albiglutide, dulaglutide, exenatide once weekly, liraglutide, semaglutidea

2-5 hours

12 hours to several days

Modest Strong

Strong Modest

Modest Reduction Yes Yes

Strong Reduction Yes Yes

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.

Nausea and Vomiting Pooled Results From Placebo-Controlled Trials Medication

•

Nausea Incidence, %

Vomiting Incidence, %

Albiglutide1

11

4

Dulaglutide2

12-21

6-13

Exenatide twice daily3

8-44

4-18

Exenatide once weekly4

11-27

11

Liraglutide5

8-35

6-17

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.

GLP-1 RAs vs Basal Insulin Patient Quartiles Based on Baseline A1C 1st

Change in A1C From Baseline, %

0 -0.8

2nd

4th

1st 0

-0.6 -1.2

-1

3rd

-0.9

-0.9

-2

-2.3

-2.1

-3

-1.1

3rd

-0.9 -1.4

4th

-1.2 -1.8

-1.5

-2 -3

Exenatide QW Glargine

-4

Baseline A1C, % End of Trial A1C, % n

-0.5

-1

-1.3 -1.3

2nd

Liraglutide Glargine

-4

7.1

7.1

7.7

7.8

8.4

8.5

9.9

9.8

7.2

7.1

7.9

7.9

8.5

8.6

9.5

9.4

6.4

6.6

6.6

6.8

7.1

7.1

7.5

7.7

6.3

6.6

6.8

7.0

7.2

7.4

7.7

7.9

55

49

54

59

59

59

60

53

61

63

55

69

49

44

59

49

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.

Combining GLP-1 RA and Basal Insulin Complementary actions Basal insulin analogs

• Simple to initiate

• Simple to initiate • Control nocturnal hyperglycemia and FPG • Lower hypoglycemia risk than NPH • Can cause weight gain • Achieve A1C target in

GLP-1 RAs

~50%a

• 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

Additive effects Potential for better overall A1C control 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.

GLP-1 RAs Plus Basal Insulin Meta-Analysis of Randomized Controlled Trials Weighted Mean Difference (95% CI)

ΔA1C, % Buse et al (2011) DeVries et al (2012) Li et al (2012) Seino et al (L-Asia; 2012) Riddle et al (Duo-1; 2013) Riddle et al (L; 2013) Diamant et al (2014) Lane et al (2014) Mathieu et al (2014) Rosenstock et al (2014) Shao et al (2014) Wit et al (2014) Ahmann et al (2014) Rosenstock et al (LixiLan; 2014) Seino et al (LIRA-ADD2INSULIN; 2014)

–0.70 (–0.72 to –0.68) –0.43 (–0.68 to –0.18) –0.13 (–0.32 to 0.06) –0.88 (–0.93 to –0.83) –0.30 (–0.58 to –0.02) –0.30 (–0.58 to –0.02) –0.03 (–0.17 to 0.11) –0.26 (–0.52 to 0.00) –0.35 (–0.48 to –0.22) –0.16 (–0.33 to 0.01) –0.11 (–0.23 to 0.01) –0.78 (–1.10 to –0.46) –1.19 (–1.36 to –1.02) –0.20 (–0.40 to 0.00) –0.80 (–0.96 to –0.64)

Overall (I2 = 96.6%, P <.0001) Favors GLP-1 RA + Basal Insulin

–0.44 (–0.60 to –0.29) –1

–0.5

15 studies were eligible and included in the analysis (N = 4348 participants).

Eng C, et al. Lancet. 2014;384:2228-2234.

0

0.5

1

Favors Comparator

Alice Key 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