Combining a -like -1 Receptor Agonist with Basal : The Why and How

Jeffrey R. Unger, MD, ABFM, FACE Director Unger Primary Care Concierge Medical Group Rancho Cucamonga, CA Director Metabolic Studies Catalina Research Institute Chino, California Statements of Sponsorship and Support

This CME symposium is sponsored by:

This CME symposium is supported by an educational grant from Sanofi US. Register at: www.pcmg-us.org Faculty Disclosure

• Dr Unger discloses that he is on the advisory board for Abbott , Novo and Janssen and on the speaker’s bureau for Novo, Teva and Janssen.

• He does contracted research for Abbott Diabetes, Janssen, Novo, GSK, Merck, Dexcom, Lilly and Sanofi-Aventis. He has ownership interest in Novo and receives a royalty for Lippincott Publishing. CME Information

• This Live activity, Combining a Glucagon-like Peptide-1 Receptor Agonist with Basal Insulin: The Why and How, from 04/15/2016 - 04/15/2017, has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Learning Objectives

At the completion of this activity, the participant will be able to: • Describe the benefits of reducing postprandial • Identify the benefits and limitations of classes of medications for lowering postprandial glucose • Identify the benefits and limitations of available short- and long-acting glucagon-like peptide-1 receptor agonists. • Select a glucagon-like peptide-1 receptor agonist based on patient clinical and personal needs. Case Study- Mary

• 61 yo female diagnosed with T2DM 8y ago • Management • Initially- lifestyle + • Subsequent additions • → symptomatic • → fluid retention • Basal insulin added 1½ y ago • Now 52 units/d (0.62 units/kg) • Has experienced 3 episodes of mild hypoglycemia Case Study- Mary (cont)

• HbA1c has never been <7.0% (now 7.9%) • Over past month • FPG 103-136 mg/dL • PPG 164-213 mg/dL • Has gained 2.6 kg since starting basal insulin (BMI now 31 kg/m2) • BP 134/82 mmHg • Occasional tingling in feet • Grade 1 retinopathy • Current medications • Metformin 1000 mg BID • Basal insulin 52 units/d (0.62units/kg) • HCTZ 25 mg QD Case Study- Mary (cont)

Why is her HbA1c 7.9% despite her FPG being reasonably well controlled?

Why is she experiencing postprandial hyperglycemia? Fasting vs Postprandial Glucose Contribution to HbA1c

100%

80% 30% 50% 55% 60% 60% 70%

40% 70% 50% 20% 45% 40% Contribution to HbA1c to Contribution 30% 0% <7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2

HbA1c Range (%) Postprandial Plasma Glucose Fasting Plasma Glucose

American Diabetes Association Diabetes Care, American Diabetes Association, 2003. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. Monnier L, et al. Diabetes Care. 2003;26:881-885. Importance of Postprandial Glucose

Increasing 2-hour PPG is associated with an increasing risk of all-cause mortality, particularly for PPG ≥200 mg/dL 2 Upper Limit of Normal for PPG 1.5 Cause Mortality - 1

0.5 Relative Risk ofRelative All

Two-Hour Plasma Glucose (mg/dL)

Sorkin JD, et al. Diabetes Care 2005;28:2626-2632. 2-h Lunch PPG and HbA1c as Risk Factors

14-year follow-up San Luigi Gonzaga Diabetes Study P< P< 2.5 0.0001 P< 0.0001 P< 0.0001 2 0.0001 P= P= 0.019 0.008 1.5

1 Hazard Ratio Hazard

0.5

0 Cardiovascular Events All-cause Mortality FPG 2h after Breakfast 2h after Lunch Before Dinner A1c Blood glucose parameters were categorized independently according to achievement of ADA targets

Cavalot F, et al. Diabetes Care. 2011;34:2237-2243. Glycemic Effects of Glucose-Lowering Medications

Glycemic Effects Fasting Plasma Glucose Lowering

Neutral Mild Moderate Moderate/ Marked

Neutral •Basal Insulin

•Metformin • •Colesevelam Mild •SGLT-2i •TZD

•DPP-4i •AGi •SU Moderate •

Pramlintide Moderate/ •Rapid-/ Short- •

Postprandial GlucosePostprandial Lowering acting Insulin Marked •GLP-1R Agonista aFPG lowering: mild- , BID, ; moderate- , exenatide QW, Handelsman Y, et al. Endocr Pract. 2015;21(Suppl 1):1-87. Inzucchi SE, et al. Diabetes Care 2015;38(1):140-149. Garber AJ et al. Endocr Pract. 2013;19(Suppl 2):1-48. Optimization of Basal Insulin Therapy

Approximately 60% of patients with T2DM can achieve HbA1c ≤7.0% with basal insulin (+ oral agents) if taken CONSISTENTLY

Holman RR, et al. N Engl J Med. 2009;361:1736-1747. What is Meant by Optimized Basal Insulin?

Efficacy Safety/Tolerability • Minimize hypoglycemia • HbA at goal 1c • Severe • ≤7% for this patient • Nocturnal • FPG 80-130 mg/dL • Minimize weight gain

Patient Factors • Needs, interests, capabilities • Schedule/Lifestyle • SMBG

American Diabetes Association. Diabetes Care. 2016;39(Suppl 1):S1-S106. Philis-Tsimikas A. Am J Med 2013;126:S21-S27. Is More Basal Insulin Better? Increasing doses of basal insulin may lead to diminishing returns —Reduction in FPG and HbA1c plateau —Incidence of hypoglycemia rises over time

50 End of 4-week 250 run-in period 47 units Mean(mg/dL) FPG 40 (0.48 units/kg) 198 mg/dL Mean Glargine 200 30 Dose 25 units 20 149 mg/dL 150 10 FPG 117 mg/dL 10 units Total Daily Insulin Dose (U) Insulin Daily Total 0 100 0 2 4 6 8 24 Week of Treatment N=367 In combination with 1 or 2 oral agents

Riddle MC, et al. Diabetes Care. 2003;26(11):3080-3086. When Basal Insulin May Not Be Enough to Achieve Glycemic Control

 HbA1c >7.0%, despite FPG 80-130 mg/dL  And…  Total basal insulin dose exceeds 0.5-1 unit/kg/day1  Severe, nocturnal, or frequent symptomatic hypoglycemia  Difference between bedtime and AM (BeAM) blood glucose >55 mg/dL2

 Less likely to achieve HbA1c ≤7.0%  Increased risk of nocturnal hypoglycemia  Weight gain 1. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379. 2. Zisman A, et al. ADA Scientific Sessions 2011; Abstract 1121-P. Avoiding Overbasalization

• If the basal insulin dose is correct, the bedtime blood glucose should be about the same as the next morning’s FPG (assuming no prandial insulin at nighttime) • If the blood glucose decreases significantly overnight (ie, BeAM>55 mg/dL), the basal dose is too high • If the blood glucose increases significantly overnight, the basal dose is too low

BeAM, bedtime to pre-breakfast Intensifying Once-Daily Basal Insulin

Basal Insulin once daily (± Oral Agents) Options:

Basal Basal-Plus GLP-1 Basal-Bolus Premixed Insulin BID Bolus before Receptor BID-TID BID largest meal Agonist

Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. Garber AH, et al. Endocr Pract. 2013;19(Suppl 2):1-48. of GLP-1 Receptor Agonists Short-Acting Long-acting

Exenatide BID1 Exenatide QW2 t 2.4 hours Exendin-4 ½ Analogs Lixisenatide3

t½ 3 hours Albiglutide4

t½ 5 days Human GLP-1 Dulaglutide5

Analogs t½ 5 days Liraglutide6

t½ 13 hours

1. Byetta [package insert]. San Diego, CA: Pharmaceuticals, LLC; August 2014. 2. Bydureon [package insert]. San Diego, CA: Amylin Pharmaceuticals, LLC; May 2014. 3. Adlyxin [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; July 2016. 4. Tanzeum [package insert]. Research Triangle Park, NC: GlaxoSmithKline; May 2015. 5. Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Co.; October 2015. 6. Victoza [package insert]. Plainsboro, NJ: ; November 2015. GLP-1: Effects in Humans

That in turn… • Stimulates glucose- After food ingestion… dependent insulin secretion • Suppresses glucagon secretion • Improves insulin sensitivity • GLP-1 is secreted Slows gastric from L-cells of the emptying jejunum and ileum • Promotes satiety • Leads to a reduction of food intake

Drucker DJ. Curr Pharm Des. 2001;7:1399-1412. Drucker DJ. Mol Endocrinol. 2003;17(2):161-171. Pharmacodynamics of GLP-1 Receptor Agonists Effects Short-Acting Long-Acting Fasting blood glucose Modest reduction Strong reduction Postprandial blood Strong reduction Modest reduction glucose Fasting insulin secretion Modest stimulation Strong stimulation Glucagon secretion Reduction Reduction Hypoglycemia Modest Modest Gastric emptying rate Deceleration Transient effect Blood pressure Modest reduction Modest reduction Body weight 1-5 kg Reduction 1-5 kg Reduction Induction of nausea 20% to 50%; attenuates 20% to 40%; attenuates over weeks to many over 4 to 8 weeks months Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews. Endocrinology 8:728- 742, copyright 2012. Meier JJ. Nat Rev Endocrinol. 2012;8:728-742. Glycemic Efficacy of GLP-1 RAs in Head-to-Head Trials

Mono or Mono or Added to Added to Met Added to Met Added to Met Added to Added to Added to 4 Met ± SU 1 ± SU ± TZD 2 ± SU ± TZD 3 ± SU ± TZD Met ± TZD5 Met 6 Met7 0

-0.5 §

-0.8 -0.8 -0.79 -1 * -0.9 1.0 1.0 -0.96 -1.1 *† Change in HbA1c (%) HbA1c in Change * ‡ -1.3 * -1.5 -1.6 -1.5 -1.5 -1.4 -1.4

Exenatide 10 mcg BID Albiglutide 50 mg QW *P <0.05 between groups †Noninferiority vs liraglutide not met. Liraglutide 1.8 mg QD Dulaglutide 1.5 mg QW ‡Dulaglutide noninferior to liraglutide, Exenatide 2 mg QW Lixisenatide 20 mcg QD P < .0001 §Noninferior vs exenatide BID

1. Buse JB, et al. Lancet. 2009;374:39-47. 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310. 3. Buse JB, et al. Lancet. 2013;381:117-124. 4. Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2:289- 297. 5. Wysham C, et al. Diabetes Care. 2014;37:2159-2167. 6. Dungan K, et al. Lancet. 2014;384:1349- 1357. 7. Rosenstock J, et al. Diabetes Care. 2013;36:2945-2951. Changes in Non-Glycemic Endpoints With GLP-1 RAs Meta-analysis of 25 randomized clinical trials Patients with or without mellitus who received exenatide 10-20 mcg/day, exenatide 2 mg/week, or liraglutide 1.2-1.8 mg/day for ≥20 weeks

Endpoint Change 95% CI

Weight Loss -2.90 kg -3.59 to -2.22

Systolic BP -3.57 mmHg -5.49 to -1.66

Diastolic BP -1.38 mmHg -2.02 to -0.73

Total Cholesterol -3.9 mg/dL -6.19 to -1.55

Vilsbøll T, et al. BMJ. 2012;344:d7771. Tolerability of GLP-1 RAs

30 Nausea Vomiting Diarrhea Injection Site Reaction 25

20

15

10 Percent of of Patients Percent

5

NR NR NR 0 Exenatide Liraglutide Exenatide Albiglutide Dulaglutide Lixisenatide 10 mcg BID1 1.8 mg QD2 2 mg QW2 50 mg 1.5 mg QW4 20 mcg QD5 QW3 NR, not reported

1. Buse J, et al. Lancet. 2009;374:39-47. 2. Buse J, et al. Lancet. 2013;381:117-124. 3. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 4. Dungan KM, et al. Lancet. 2014;384:1349-1357. 5. Meier JJ, et al. Diabetes Care. 2015;38;1263-1273. Prandial Insulin vs GLP-1RA in Combination with Optimized Basal Insulin + Metformin

• Adults with T2DM

• HbA1c 7.0-10.0% • Receiving plus metformin

R Exenatide 10-20 mcg BID A (↓Basal Insulin ≥10%) 315 Glargine Those N optimization who D over 12 wks didn’t 30 weeks O 1:1 to achieve achieve M FPG HbA1c ≤100 mg/dL ≤7.0%... I 312 Z Lispro TID (↓Basal Insulin 33-50%) E

Diamant M, et al. Diabetes Care. 2014;37;2763-2773. Prandial Insulin vs GLP-1RA in Combination with Optimized Basal Insulin + Metformin (cont.)

0

Exenatide BID Lispro TID

-0.5 (%) 1c

-1 ∆HbA

P=NS

-1.5 0 6 12 18 24 30 Weeks Following Randomization American Diabetes Association Diabetes Care, American Diabetes Association, 2014. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. Diamant M, et al. Diabetes Care. 2014;37;2763-2773. Prandial Insulin vs GLP-1RA in Combination with Optimized Basal Insulin + Metformin (cont.) ∆Fasting Glucose* (mg/dL) Blood Glucose (mg/dL) # 15 Exenatide BID 200

10 Lispro TID *P=0.002 for all time points except 0 175 5

0 150

-5 # 125 -10 Dotted line: At randomization #P<.001 Solid line: Study end -15 100 0 6 12 18 24 30 Weeks Following Randomization

American Diabetes Association Diabetes Care, American Diabetes Association, 2014. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. Diamant M, et al. Diabetes Care. 2014;37;2763-2773. Albiglutide vs Prandial Insulin as Add-on to Insulin Glargine + Oral Agents

P= 0.2366 P= 0.0533

Albiglutide 30 or 50 mg QW; Prandial insulin TID American Diabetes Association Diabetes Care, American Diabetes Association, 2014. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. Rosenstock J, et al. Diabetes Care. 2014;37;2317-2325. Lixisenatide vs Liraglutide as Add-on to Insulin Glargine ± Metformin: Similar Reductions in the 24-h Plasma Glucose Profile

*P<0.05 for lixisenatide 20 mcg vs. liraglutide 1.2 mg; †P<0.05 for lixisenatide 20 mcg vs. liraglutide 1.8 mg; ‡P<0.05 for liraglutide 1.2 mg and 1.8 mg vs. lixisenatide 20 mcg; §P<0.05 for liraglutide 1.8 mg vs. lixisenatide 20 mcg.

American Diabetes Association Diabetes Care, American Diabetes Association, 2015. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. Meier JJ, et al. Diabetes Care. 2015;38:1263-1273. Lixisenatide vs Liraglutide as Add-on to Optimized Insulin Glargine ± Metformin

Responses at end of 28 weeks of therapy 3 2.3 Lixisenatide 20 mcg 2 1.8 Liraglutide 1.8 mg 1

0

-1 -0.6 -0.7

-2 -1.6

-3 -2.4

-4

Change from Baseline from Change -4 -5 -4.7

-6 HbA1c FPG Body Daily (%) (mg/dL) Weight Insulin Dose N=80 (kg) (units)

Meier JJ, et al. Diabetes Care. 2015;38:1263-1273. Insulin Detemir as Add-on Therapy to Metformin + Liraglutide1

• Adults with T2DM

• Treated with metformin (HbA1c 7.0-10.0%) or metformin + SU (HbA1c 7.0-8.5%)

R A Continue metformin + 12-wk run- If N liraglutide HbA1c D in: O ≥7.0% M Add insulin detemir 10 units I --SU DC’d Z evening/bedtime; titrate to 74- --Liraglutide E 108 mg/dL FPG initiated and If titrated to 1.8 HbA1c Continue metformin + mg/d <7.0% liraglutide (observational group) 26 weeks of treatment

DeVries JH, et al. Diabetes Care. 2012;35(7):1446-1454. Insulin Detemir as Add-on Therapy 1 to Metformin + Liraglutide (cont.)

Time (weeks) 0 12 24 0 Randomization

-0.5

-1 Change in (%) HbA1c Change

-1.5 1Weeks 0-26 Liraglutide + Detemir Liraglutide Liraglutide (obs)

American Diabetes Association Diabetes Care, American Diabetes Association, 2012. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. DeVries JH, et al. Diabetes Care. 2012;35(7):1446-1454. Insulin Detemir as Add-on Therapy to 1 Metformin + Liraglutide (cont.) 200 1Weeks 0-26 175

150 * # **

SMBG (mg/dL) 125

*P=.0003 **P=.0244 #P=.0141 100 Before 90 min after Pre-Lunch 90 min after Pre-Dinner 90 min after Bedtime Breakfast breakfast lunch dinner

Liraglutide + Detemir/Baseline Liraglutide + Detemir/26 wks Liraglutide/Baseline Liraglutide/26 wks

American Diabetes Association Diabetes Care, American Diabetes Association, 2012. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association. DeVries JH, et al. Diabetes Care. 2012;35(7):1446-1454. Efficacy Results from Observational Studies of Basal Insulin in Combination with a GLP-1RA HbA1c (%) Body Weight (kg) Insulin Dose (units/d)

Conclusion: Combination therapy improved glycemic control without weight gain or an increased risk of hypoglycemia. From: Balena R, et al. Diabetes Obes Metab. 2013;15:485-502. 2013 Blackwell Publishing Ltd. All rights reserved Recommendations for GLP-1 RA Use in Combination With Basal Insulin • GLP-1 RA may be used in combination with basal insulin in patients who do not reach their glycemic target with 2-3 glucose-lowering medications1-4 • If taking a SU, consider discontinuing or reducing the dose of SU • If adding GLP-1RA to basal insulin, consider reducing basal insulin dose 10-20% if HbA1c ≤7.5% • Thereafter, adjust basal insulin dose based on SMBG • Monitor for hypoglycemia

1. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. 2. American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S1-S93. 3. Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. 4. Garber AJ, et al. Endocr Pract. 2015;21:e1-e10. Prandial Insulin vs GLP-1RA in Combination with Optimized Basal Insulin + Metformin (cont.) Study Results: Summary

HbA1c reduction Exenatide = Lispro

FPG reduction Exenatide > Lispro

PPG reduction Exenatide ≈ Lispro

Minor hypoglycemia Exenatide < Lispro

Nocturnal hypoglycemia Exenatide < Lispro

Weight change Exenatide ↓ Lispro ↑

Glargine dose Exenatide > Lispro

Treatment satisfaction Exenatide > Lispro

Diamant M, et al. Diabetes Care. 2014;37;2763-2773. Combination Products: IDegLira*

25 25 24 IDeg IDegLira 20

15

10

5 0 0 † -0.9 † -1.9 -5 -2.7 ∆HbA1c (%) ∆Weight (kg) Hypoglycemia Incidence (%) 26-week double-blind, randomized trial N=413 adults with type 2 diabetes treated with basal insulin + metformin ± SU/glinide †P<0.0001 *Investigational combination of insulin degludec and liraglutide Buse J, et al. Diabetes Care. 2014;37:2926-2933. Combination Products: LixiLan*

• 323 patients treated inadequately controlled with metformin (HbA1c Glargine LixiLan P 8.0-8.1%) U-100 (n=161) (n=162) • Randomized to • LixiLan 5 mcg/10 units ∆HbA1c -1.64% -1.82% 0.01 • Glargine U-100 HbA1c 78% 84% NS • Titrated to achieve FPG <7% 80-100 mg/dL • 24-week treatment ∆Weight 0.5 kg -1 kg 0.0001 period

*Investigational combination of insulin glargine 100 units/mL and lixisenatide

Rosenstock J, et al. Diabetes Care. 2016;doi:10.2337/dc16-0046. GLP-1 RAs in Combination with Insulin

Approved for Use in Combination with Glucagon-like Peptide-1 Receptor Agonist Basal Prandial Insulin Insulin Albiglutide QW1  Dulaglutide QW2  Exenatide BID3  Exenatide QW4 Liraglutide QD5  Lixisenatide QD6 

1. Tanzeum [package insert]. Research Triangle Park, NC: GlaxoSmithKline LLC; May 2015. 2. Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Company; October 2015. 3. Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; August 2014. 4. Bydureon [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; September 2015. 5. Victoza [package insert]. Princeton, NJ: Novo Nordisk; November 2015; 6. Adlyxin [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; July 2016. Case Study- Mary (cont)

Recall • HbA1c 7.9% • Over past month • FPG 103-136 mg/dL • PPG 164-213 mg/dL • Has gained 2.6 kg since starting basal insulin (BMI now 31 kg/m2) • BP 134/82 mmHg • Occasional tingling in feet • Grade 1 retinopathy • Current medications • Metformin 1000 mg BID • Basal insulin 52 units/d (0.62units/kg) • HCTZ 25 mg QD Case Study- Mary (cont)

• What changes would you make to her diabetes treatment plan? • Do her previous hypoglycemia episodes while on basal insulin affect your decision? • If you were to add a GLP-1RA, which would you choose? • What if she had fasting hyperglycemia as well? • Do her weight and blood pressure affect your choice? • How would medication adherence affect your choice? • What education would you provide to her about medication side effects? Questions and Answers Combining a Glucagon-like Peptide-1 Receptor Agonist with Basal Insulin: The Why and How Jeffrey R. Unger, MD, ABFM, FACE Director Unger Primary Care Concierge Medical Group Rancho Cucamonga, CA Director Metabolic Studies Catalina Research Institute Chino, California