Noninsulin Approaches to Managing Type 2 Diabetes

JUNE 23, 2016 Houston, Texas

Education Partner

AZ T2DM PriMed Cover Pages Houston R2.indd 1

3/21/16 11:11 AM

FACULTY

EILEEN

Egan, DNP, FNP-C, CDE Chief Nurse Practitioner Winthrop Center for Comprehensive Diabetes Care Winthrop Endocrine, Diabetes, & Metabolism Faculty Practice Mineola, New York Adjunct Faculty Department of Graduate Studies & Advanced Practice Nursing Stony Brook University Stony Brook, New York

RICHARD E. Pratley, MD

Samuel E. Crockett, MD, Chair in Diabetes Research Medical Director, Florida Hospital Diabetes Institute Senior Scientist, Translational Research Institute for Metabolism and Diabetes Adjunct Professor, Sanford Burnham Prebys Medical Discovery Institute Orlando, Florida

MARK W. Stolar, MD

Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

EDUCATIONAL OBJECTIVES • Individualize therapeutic goals for patients with T2DM based on disease severity, comorbidities, treatment-related risks, and psychosocial status • Discuss the clinical profiles of current and emerging fixed-dose combinations of antihyperglycemic medications • Intensify multidrug noninsulin regimens for various patient types to address poor glycemic control and other relevant clinical parameters • Engage patients in their antidiabetes management plans to motivate lifestyle changes and improve treatment adherence

AZ T2DM PriMed Cover Pages Houston R2.indd 2

FACULTY FINANCIAL DISCLOSURE STATEMENTS

CONFLICT OF INTEREST RESOLUTION STATEMENT

The presenting faculty reported the following: Eileen Egan, DNP, FNP-C, CDE, has nothing to disclose.

Richard E. Pratley, MD, is a member of the Speakers Bureau for AstraZeneca plc and Novo Nordisk Inc. He receives grant/research support from Eli Lilly & Company, Merck & Co., Inc., Novo Nordisk Inc., sanofi-aventis U.S. LLC., and Takeda Pharmaceuticals U.S.A., Inc. He receives honoraria from Novo Nordisk Inc. He is consultant to AstraZeneca plc, Boehringer Ingelheim, GlaxoSmithKline, Hanmi Pharmaceutical Co., Ltd., Janssen Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly & Company, Merck & Co., Inc., Novo Nordisk Inc., and Takeda Pharmaceuticals U.S.A., Inc. Mark W. Stolar, MD, is a member of the Speakers Bureau for AstraZeneca plc and Takeda Pharmaceuticals U.S.A, Inc.. He is a member of the Medical Advisory Board for AstraZeneca plc and sanofi-aventis U.S. LLC.

pmiCME requires all individuals in a position to influence educational content for pmiCME-certified CME activities to disclose relevant personal financial relationship(s) with commercial interests prior to contributing to the activity. pmiCME assesses disclosed relationships and follows a defined process to resolve real or implied conflicts to ensure, to the best of our ability, that all educational content is free of commercial bias. Financial disclosures are listed in this program and will also be announced prior to the start of each presentation and posted on www.pri-med.com.

EDUCATION PARTNER FINANCIAL DISCLOSURE STATEMENT The content collaborators at Integritas Communications have reported the following: Jim Kappler, PhD, has nothing to disclose.

PMICME CLINICAL STAFF AND TUFTS HEALTH CARE INSTITUTE EXPERT REVIEWER FINANCIAL DISCLOSURE As a continuing medical education provider accredited by the ACCME, it is the policy of pmiCME to require any individual in a position to influence educational content to disclose the existence of any financial interest or other personal relationship with the manufacturer(s) of any commercial product(s). pmiCME clinical staff and Tufts Health Care Institute expert content reviewers have provided financial disclosure and have no conflicts of interest to resolve for each of the sessions related to this activity.

OFF-LABEL/INVESTIGATIONAL DISCLOSURES During the course of their presentations, the faculty may mention uses of products that have not been approved in the United States for the indication(s) being discussed. All presenters are instructed to notify participants when they are discussing unapproved uses or investigational agents. In addition, specific slides will include notation of the off-label use or investigational agent being discussed. Views presented during this program related to unapproved uses of products are solely those of the presenter(s) and are not endorsed by pmiCME, DBC Pri-Med, LLC, or ACP.

ACCREDITATION STATEMENT pmiCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

ACKNOWLEDGMENT OF COMMERCIAL SUPPORT This activity is supported by an educational grant from AstraZeneca.

CLINICAL RESOURCE CENTER Access the program syllabus and additional resources by scanning the image on the left. If you do not have a QR Code Reader on your mobile device, visit getscanlife.com for a free download.

www.ExchangeCME.com/T2DM2015

3/21/16 11:11 AM

Achieving Treatment Goals Room for Improvement in T2DM

Patients Achieving Goal, %

100

1988-1994 2007-2010

90 80 70 60

a

a

a

50 40 30

a

20 10 0 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

aP<0.01.

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.

BP, blood pressure; LDL-C, low-density lipoprotein cholesterol.

Stark Casagrande S, et al. Diabetes Care. 2013;36(8):2271-2279.

Diabetes-Related Complications Rates in the United States

Events per 10,000 Adults With Diagnosed Diabetes

150

Acute MI

Stroke

125 100 75

Amputation

50

ESRD

25

Death from Hyperglycemic Crisis 4 2 0

1990

1995

2000

2005

2010

Data obtained from the National Health Interview Survey, the National Hospital Discharge Survey, the US Renal Data System, and the US National Vital Statistics System.

ESRD, end stage renal disease; MI, myocardial infarction.

Gregg EW, et al. N Engl J Med. 2014;370(16):1514-1523.

1

Jerry

Case Background • 59-year-old accountant

•Family history

– Married with 1 son at college – Wife attends appointment

– Father treated for T2DM and died of MI at 55 years of age

•T2DM diagnosis last week

• Dietary habits

– Complaints of increased thirst and urination – Dark patches of skin behind his neck and under his arms (acanthosis nigricans)

– Primarily pasta and red meat – Few fruits or vegetables – 1-3 alcoholic drinks/day

• Smokes 1-2 packs/week • Medical history – Hypertension diagnosis 5 years ago • Lisinopril 40 mg daily • Atenolol 50 mg daily • Forgets medications 1-2 times weekly

Jerry

Recent Lab Results • BMI, 31.0 kg/m2 (obese) • BP, 129/75 mm Hg • FPG, 202 mg/dL

• Lipids – – – – –

– Second test, 198 mg/dL

• A1c, 8.7% • eGFR, 84 mL/min/ 1.73 m2 • ACR, 2.4 mg/mmol

TC, 165 mg/dL TG, 150 mg/dL LDL-C, 95 mg/dL HDL-C, 40 mg/dL ApoB, 82 mg/dL

• Sensory and eye exams unremarkable

ACR, albumin/creatinine ratio; ApoB, apolipoprotein B; BMI, body mass index; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

2

ADA/EASD Position Statement Setting Glycemic Goals in T2DM

More Stringent

Factors

Less Stringent

Highly motivated, adherent, excellent self-care capacities

Patient attitude and expected treatment efforts

Less motivated, nonadherent, poor self-care capacities

Low

Risks potentially associated with hypoglycemia, other adverse events

High

Newly diagnosed

Disease duration

Long-standing

Long

Life expectancy

Short

Absent

Important comorbidities

Severe

Absent

Established vascular complications

Severe

Readily available

Resources, support system

Limited

ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes.

Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379; Ismail-Beigi F, et al. Ann Intern Med. 2011;154:554-559.

Reducing T2DM Complications Multidimensional Treatment Goals Comprehensive Diabetes Management BP

A1c

Lipidsa

<140/90 mm Hg

ADA <7.0%

LDL-C: <100 mg/dL

(<130/80 mm Hg for some people)

AACE ≤6.5%

BMI <25 kg/m2

(<70 mg/dL with CVD)

HDL-C: >40 mg/dL in men >50 mg/dL in women TG: <150 mg/dL

Lifestyle Modifications

Healthy Diet, Exercise, Smoking Cessation a2015 ADA/AHA guidelines: Treat patients 40-75 years old with T2DM and LDL-C levels between 70 and 189 mg/dL with moderateintensity statin therapy (lower LDL-C by 30%-50%); use high-intensity therapy (lower LDL-C by ≥50%) if 10-year ASCVD risk is ≥7.5%).

ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease.

ADA. Diabetes Care. 2015;38(suppl 1):S1-S94; Garber AJ, et al. Endocr Pract. 2015;21(4):438-447; Fox CS, et al. Diabetes Care. 2015;38(9):1777-1803.

3

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.

ADA Recommendations

Managing Hyperglycemia in T2DM Healthy Eating, Weight Control, Increased Physical Activity Metformin

Monotherapy Efficacy (A1c) Hypoglycemia Weight Side Effects Costs

High Low risk Neutral/Loss GI/Lactic acidosis Low If individualized A1c target not reached after ~3 months, proceed to 2-drug combination

Dual Therapya

Dual Therapya + SU Efficacy (A1c) Hypoglycemia Weight Major Side Effect(s) Costs

+ TZD

Metformin

+ DPP-4 Inhibitor

+ SGLT-2 Inhibitor

High High Intermediate Intermediate Moderate risk Low risk Low risk Low risk Gain Gain Neutral Loss Hypoglycemia Edema, HF, Fx Rare GU, Dehydration Low High High High

+ GLP-1 RA

+ Insulin (Basal)

High Low risk Loss GI High

Highest High risk Gain Hypoglycemia Variable

Consider starting at this stage when A1c ≥9%. starting at this stage when A1c ≥9%.

DPP-4, dipeptidyl peptidase-4; Fx, bone fracture; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; GU, genitourinary; HF, heart failure; SGLT-2, sodium glucose cotransporter-2; SU, sulfonylurea; TZD, thiazolidinedione.

ADA. Diabetes Care. 2015;38(suppl 1):S1-S94. aa Consider

4

AACE/ACE Algorithm

Glycemic Control and Early Dual Therapy Lifestyle Modification Entry A1c <7.5%

Entry A1c ≥7.5%

Entry A1c >9.0%

Monotherapya

Dual Therapya

Symptoms

METFORMIN

or other first-line agent

Metformin GLP-1 RA SGLT-2 inhibitor DPP-4 inhibitor TZD AG inhibitor SU/GLN

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

GLP-1 RA SGLT-2 inhibitor DPP-4 inhibitor TZD Basal Insulin Colesevelam Bromocriptine QR AG inhibitor SU/GLN

NO

YES

Dual Therapy OR Triple Therapy

± Other

Insulin

Agents

Add or Intensify Insulin

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

Possible benefits or few adverse events Use with caution

Order of medications listed are a hierarchy suggested hierarchy of usage. of medications listed are a suggested of usage.

aaOrder

ACE, American College of Endocrinology; AG, α-glucosidase; GLN, glinide; QR, quick release.

Garber AJ, et al. Endocr Pract. 2016;22(1):84-113.

Combination Regimens for T2DM Targeting Multiple Disease Mechanisms

Impaired Insulin Secretion

Decreased Incretin Effect Islet -cell

Increased Lipolysis

Islet -cell

Hyperglycemia Increased Glucagon Secretion

Increased Hepatic Glucose Production

Increased Glucose Reabsorption

Neurotransmitter Dysfunction

Defronzo RA. Diabetes. 2009;58(4):773-795.

5

Decreased Glucose Uptake

Hurdles to Intensive Therapy

Annualized Rate of Severe Hypoglycemiaa, %

Rates of Severe Hypoglycemia UKPDS1

ADVANCE2

ACCORD3

VADT4

P<0.001 vs CON

HR 1.86 (1.42-2.40) P<0.001

P<0.001

P=0.01

5.0

4.6 3.8

4.0 3.0 2.0 1.0 0

1.8

1.4

1.5

0.7

1.8

0.7

0.4

CON GLY INS

STD INTb

STD INTb

STD INTb

A1c= 7.9% 7.1% 7.2%

7.3% 6.5%

7.5% 6.4%

8.4% 6.9%

aHypoglycemia

requiring any assistance; bIntensive glycemic control was defined differently in these trials.

ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation; CON, conventional therapy; GLY, glibenclamide; HR, hazard ratio; INS, insulin; INT, intensive therapy; STD, standard therapy; UKPDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

1. UKPDS Group. Lancet. 1998;352(9131):837-853; 2. Patel A, et al; [ADVANCE]. N Engl J Med. 2008;358(24):2560-2572; 3. Gerstein HC, et al; [ACCORD]. N Engl J Med. 2008;358(24):2545-2559; 4. Duckworth W, et al. N Engl J Med. 2009;360(2):129-139.

ADVANCE

Patients With â&#x2030;¥1 Hypoglycemic Event(s), %

Severe Hypoglycemia vs Adverse Endpoints HR (95% CI): 3.27 (2.29-4.65)a

HR (95% CI): 3.53 (2.41-5.17)a HR (95% CI): 2.19 (1.40-3.45)a

b

HR (95% CI): HR (95% CI): 3.79 (2.36-6.08)a 2.80 (1.64-4.79)a

b

aAdjusted

for multiple baseline covariates; bPrimary endpoints.

Major macrovascular event=cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Major microvascular event=new or worsening nephropathy or retinopathy.

CI, confidence interval.

Zoungas S, et al. N Engl J Med. 2010;363(15):1410-1418.

6

Pathophysiologic Cardiovascular Consequences of Hypoglycemia  CRP

 Macrophage/ neutrophil activation  Platelet activation

 VEGF

 IL-6

Inflammation Blood coagulation abnormalities

 Factor VIII

Hypoglycemia

Endothelial dysfunction

Sympathoadrenal response  Noradrenaline Rhythm abnormalities

 Vasodilatation

Hemodynamic changes  Heart workload  Contractility  Output

Heart rate variability

CRP, C-reactive protein; IL-6, interleukin-6; VEGF, vascular endothelial growth factor.

Desouza CV, et al. Diabetes Care. 2010;33:1389-1394.

a

b

ΔFibrinogen, mg/mL

0.10 0.05 0.00 -0.05 -0.10 Baseline 400

End of Clamp b

200

Day 1 a

b

0

-400 End of Clamp

Day 1

Hypoglycemia Euglycemia

Day 7

0 -1 2

End of Clamp

Day 1

0 -1 -2 Baseline

End of Clamp

Day 1

Timepoint

bP<0.01

vs euglycemia; vs euglycemia apart (data are mean ± standard error of the mean).

N=10 patients with T2DM underwent paired hyperinsulinemic clamp stuides at least 4 weeks apart. hsCRP, high-sensitivity CRP. Chow EYK, et al. Diabetologia. 2013;56(suppl 1):S243.

7

Day 7 b

1

Timepoint aP<0.05

a

1

Baseline

-200 Baseline

3 2

Day 7

ΔhsCRP, mg/L

ΔClot Lysis Time, s

Maximum Absorbance, AU

Effects of Hypoglycemia on Thrombosis in T2DM

Day 7

Hypoglycemia

Risks of Cardiac Arrhythmias Risks of Events During Hypoglycemia vs Euglycemia in Insulin-Treated Patients

Day

Night

IRR

95% CI

P

IRR

95% CI

P

Bradycardia

NA

NA

NA

8.42

1.40-51.0

0.02

Atrial ectopic

1.35

0.92-1.98

0.13

3.98

1.10-14.40

0.04

VPB

1.31

1.10-1.57

<0.01

3.06

2.11-4.44

<0.01

Complex VPB

1.13

0.78-1.65

0.52

0.79

0.22-2.86

0.72

IRR, incident rate ratios; VPB, ventricular premature beats.

N=25 insulin-treated patients with T2DM and a history of CVD or â&#x2030;Ľ2 cardiovascular risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring.

Chow E, et al. Diabetes. 2014;63(5):1738-1747.

Hypoglycemia With Antidiabetes Therapies Estimated A1c Reduction, %

Hypoglycemia Incidence, %

Short-acting GLP-1 RA1,a

0.5-0.7

3.8-10.7*

Long-acting GLP-1 RA1,b

0.7-1.6

0-10.9*

inhibitors2,c

0.4-0.8

0.3-5*

SGLT-2 inhibitors3,b

0.7

0-6*

Sulfonylureas6

1-2

18-30

Drug Class

DPP-4

Pioglitazone6

0.5-1.4

0-3.7

Basal insulin6,d

1.5-3.5

29.9-61.2

*Hypoglycemia risks are higher when agents are combined with a sulfonylurea or insulin. aExenatide

twice daily; bIncludes liraglutide, exenatide once weekly, albiglutide, and dulaglutide; cIncludes saxagliptin, linagliptin, and sitagliptin; dIncludes canagliflozin, dapagliflozin, and empagliflozin; dIncludes neutral protamine Hagedorn insulin, insulin glargine, and insulin detemir.

1. Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/; 2. Boland CL, et al. Ann Pharmacother. 2013;47(4):490-505; 3. Nauck MA. Drug Des Devel Ther. 2014;8:1335-1380.

8

Jerry

Initial Treatment • Target A1c ≤6.5% • His PCP engages Jerry in discussion around lifestyle modifications, including smoking cessation and weight loss • Suggests a Certified Diabetes Educator – Patient education – Detailed dietary and exercise recommendations

• Provided medical nutrition therapy • Jerry and his PCP also review the possibility of initiating therapy with 2 antihyperglycemic agents

Noninsulin Antihyperglycemic Therapy Potential 2-Drug Combinations in the US

SU/GLNa (5 Agents) TZDb (2 Agents) DPP-4 Inhibitorc (4 Agents) SGLT-2 Inhibitord (3 Agents) GLP-1 Receptor Agoniste (5 Agents)

159 Possible Noninsulin Combinations in 2-Drug Regimens

10 4

10

8

20

8

6

15

6

12

10

25

10

Not recommended in combination

15

Metforminf (2 Agents)

SU/GLN (5 Agents)

TZD (2 Agents)

DPP-4 Inhibitor (4 Agents)

SGLT-2 Inhibitor (3 Agents)

20

Potential Combinations Not Recommended aPossible

SUs and GLNs include glimepiride, glipizide, glyburide, nateglinide, and repaglinide; bPossible TZDs include pioglitazone and rosiglitazone; cPossible DPP-4 inhibitors include alogliptin, sitagliptin, linagliptin, and saxagliptin; dPossible SGLT-2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin; ePossible GLP-1 RAs include exenatide twice daily, exenatide once weekly, liraglutide, dulaglutide, and albiglutide; fPossible metformin drugs include standard and extended release formulations.

ADA. Diabetes Care. 2015;38(suppl 1):S1-S94; Nauck M, et al. Diabetes. 2015;64(suppl 1):A3 [abstract 10-OR].

9

Noninsulin Dual Therapy

Avoiding Agents With High Hypoglycemia Risks SU/GLNa (5 Agents) TZDb (2 Agents) DPP-4 Inhibitorc (4 Agents) SGLT-2 Inhibitord (3 Agents) GLP-1 Receptor Agoniste (5 Agents)

10

79 Remaining Possible Noninsulin 2-Drug Regimens

4

10

8

20

8

6

15

6

12

10

25

10

Not recommended in combination

15

Metforminf (2 Agents)

SU/GLN (5 Agents)

TZD (2 Agents)

DPP-4 Inhibitor (4 Agents)

SGLT-2 Inhibitor (3 Agents)

Potential Combinations Not Recommended

20

Combinations With Agents Associated With High Hypoglycemia Risks

aPossible

SUs and GLNs include glimepiride, glipizide, glyburide, nateglinide, and repaglinide; bPossible TZDs include pioglitazone and rosiglitazone; cPossible DPP-4 inhibitors include alogliptin, sitagliptin, linagliptin, and saxagliptin; dPossible SGLT-2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin; ePossible GLP-1 RAs include exenatide twice daily, exenatide once weekly, liraglutide, dulaglutide, and albiglutide; fPossible metformin drugs include standard and extended-release formulations.

ADA. Diabetes Care. 2015;38(suppl 1):S1-S94; Nauck M, et al. Diabetes. 2015;64(suppl 1):A3 [abstract 10-OR].

Noninsulin Dual Therapy

Avoiding Agents With High Risks of Weight Gain or Hypoglycemia SU/GLNa (5 Agents) TZDb (2 Agents) DPP-4 Inhibitorc (4 Agents) SGLT-2 Inhibitord (3 Agents) GLP-1 Receptor Agoniste (5 Agents)

10

51 Remaining Possible Noninsulin 2-Drug Regimens

4

10

8

20

8

6

15

6

12

10

25

10

Not recommended in combination

15

Metforminf (2 Agents)

SU/GLN (5 Agents)

TZD (2 Agents)

DPP-4 Inhibitor (4 Agents)

SGLT-2 Inhibitor (3 Agents)

Potential Combinations Not Recommended

20

Combinations With Agents Associated With High Hypoglycemia or Weight Gain Risks

aPossible

SUs and GLNs include glimepiride, glipizide, glyburide, nateglinide, and repaglinide; bPossible TZDs include pioglitazone and rosiglitazone; cPossible DPP-4 inhibitors include alogliptin, sitagliptin, linagliptin, and saxagliptin; dPossible SGLT-2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin; ePossible GLP-1 RAs include exenatide twice daily, exenatide once weekly, liraglutide, dulaglutide, and albiglutide; fPossible metformin drugs include standard and extended-release formulations.

ADA. Diabetes Care. 2015;38(suppl 1):S1-S94; Nauck M, et al. Diabetes. 2015;64(suppl 1):A3 [abstract 10-OR].

10

GLP-1 Signaling

Effects Related to Glucose Control Pancreas1

Brain5-7

Insulin secretion (glucose-dependent) and β-cell sensitivity2,3 Insulin synthesis4 Glucagon secretion3 (glucose-dependent)

Satiety Energy intake Body weight

Cardiovascular System8 Systolic BP

Liver 4

Stomach1,4

Hepatic glucose output

Gastric emptying

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

DPP-4 Inhibitors vs Sulfonylureas Added to Metformin

P=0.01 (2 years)

Noninferior vs SU (2 years)

Noninferiority vs SU demonstrated at 52 weeks5

Agent

0.0

ΔA1c From Baseline, %

Δ Weight, kg DPP-4 inhibitor

SU

DPP-4 inhibitor

SU

ALO1,a

−0.9a

+1.0

1

23

LINA2,b

−1.4a

+1.3

7a

36

SAXA3,c

−1.5

+1.3

3

38

SITA4,d

−1.6

+0.7

5

34

-0.1 -0.2

−0.16

-0.3 -0.4

−0.36

-0.5 -0.6 -0.7 -0.8

Hypoglycemia % of patients

−0.59 −0.72

−0.35 −0.41 −0.51 −0.54

ALO (25 mg)1,b

GLIP

LINA (5 mg)2,c

GLIM

-0.9

SAXA (5 mg)3,d

-1.0

SITA (100 mg)4,e

aP<0.001

vs SU; 104-week trial of alogliptin; baseline A1c, 7.6%; cLINA: 104-week trial of linagliptin; baseline A1c, 7.7%; 104-week trial of saxagliptin; baseline A1c, 7.7%; eSITA: 104-week trial of sitaglptin; baseline A1c, 7.3%.

1. Del Prato S, et al. Diabetes Obes Metab. 2014;16:1239-1246; 2. Gallwitz B, et al. Lancet. 2012;380:475-483; 3. Göke B, et al. Int J Clin Pract. 2013;67:307-316; 4. Seck T, et al. Int J Clin Pract. 2010;64:562-576; 5. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. bALO:

dSAXA:

11

GLP-1 RAs vs DPP-4 Inhibitors Added to Metformin

P<0.001

ΔA1c From Baseline, %

0.5

P<0.0001

Δ Weight, kg

P<0.001

P<0.0001

Agent

P<0.001

0.08 0.0 -0.5

−0.39

-1.0 −0.78

−0.9

-0.52 -0.83

−0.9 −1.1

-1.5 -2.0 -2.5

Hypoglycemia, % of patients

GLP-1 RA

DPP-4i

GLP-1 RA

DPP-4i

−2.8

NA

5

NA

−2.3b

−0.8

1d

3 5

EXEN BID1,d EXEN QW2,e LIRA3,f

−3.4a

-1.0

5d

DULA4,g

−3.0b

−1.5

10d

5

ALBI5,h

−0.8c

-0.2

24d,j

16j

−1.5 −1.5 EXEN BID (10 μg)1,e

DULA (1.5 mg)4,h

EXEN QW (2 mg)2,f

ALBI (30 or 50 mg)5,i

LIRA (1.8 mg)3,g

Placebo

SITA

aP<0.0001

vs DPP-4 inhibitor; bP<0.001 vs DPP-4 inhibitor; cP<0.05 vs DPP-4 inhibitor; dNo statistical analysis performed; BID: 30-week study of exenatide twice daily; baseline A1C, 8.2%; fEXEN QW: 26-week trial of exenatide once weekly; baseline A1c, 8.4%; gLIRA: 26-week trial with liraglutide; baseline A1c, 8.5%; hDULA: 52-week trial; baseline A1c, 8.1%; iALBI: 26-week trial of albiglutide; baseline A1c, 8.2%; jAlmost all patients experiencing hypoglycemia were also taking a sulfonylurea.

1. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100; 2. Bergenstal RM, et al. Lancet. 2010;376:431-439; 3. Pratley RE, et al. Lancet. 2010;375(9724):1447-1456; 4. Nauck M, et al. Diabetes Care. 2014;37(8):2149-2158; 5. Leiter LA, et al. Diabetes Care. 2014;37(10):2723-2730. eEXEN

LEADER

Liraglutide in T2DM With High Cardiovascular Risk Primary Outcomea Hazard ratio, 0.87 20 (95% CI, 0.78–0.97) P<0.001 for noninferiority P=0.01 for superiority

Patients With Event, %

20

15

CardiovascularRelated Death

15

Placebo

10

Liraglutide

5

10

Death From Any Cause

20

15

Hazard ratio, 0.78 (95% CI, 0.66–0.93) P=0.007

Placebo

5

Hazard ratio, 0.85 (95% CI, 0.74–0.97) P=0.02

10

Placebo

5

Liraglutide

Liraglutide 0

0 6 12 18 24 30 36 42 48 54

0

0 6 12 18 24 30 36 42 48 54

0

0 6 12 18 24 30 36 42 48 54

Months Since Randomization aComposite

of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

N=9340 patients with T2DM and high cardiovascular risk.

Marso SP, et al. N Engl J Med. 2016 June 13 [Epub ahead of print].

12

Safety With Incretin-Based Agents Acute Pancreatitis

• Precautions1-5

• Recommendations1-5

– Cases have been reported – Unknown if pancreatitis history increases risk with DPP-4 inhibitors – Consider treatments other than GLP-1 RAs in patients with history of pancreatitis

– Ask about pancreatitis history – Educate patients about signs and symptoms of pancreatitis – Discontinue if pancreatitis symptoms occur – Report cases of pancreatitis to www.fda.gov/medwatch

Pancreatitis risk is 1.5- to 3-fold higher in individuals with diabetes6-8 1. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf); 2. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf); 3. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf); 4. Albiglutide prescribing information. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MGIFU-COMBINED.PDF; 5. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf; 6. Girman CJ, et al. Diabetes Obes Metab. 2010;12(9):766-771; 7. Garg R, et al. Diabetes Care. 2010;33(11):2349-2354; 8. Yang L, et al. Eur J Gastroenterol Hepatol. 2013;25(2):225-231

Safety of Incretin Therapy 2014 FDA and EMA Analysis

• FDA and EMA conducted parallel, independent safety assessments of incretin-based drugs following postmarketing reports of pancreatitis or pancreatic cancer in treated individuals “Assertions of a causal association are not consistent with current data” “Product information and labeling reflect current understanding of risk” • Both agencies continue to investigate safety signals and data from ongoing trials EMA, European Medicines Association.

Egan AG, et al. N Engl J Med. 2014;370(9):794-797.

13

DPP-4 Inhibitors

Safety: Additional Considerations • Most common adverse effects1 – – – – –

Nasopharyngitis Headache Nausea Hypersensitivity Skin reactions

• FDA warnings – There is a risk for joint pain that can be severe and disabling2 – For saxagliptin and alogliptin, consider benefits vs risks in patients at risk for heart failure, and consider discontinuing if heart failure develops3 • SAVOR-TIMI 53 analysis showed that patients at highest risk of heart failure– related hospitalization had previous heart failure or chronic kidney disease4

• Reduce dose of alogliptin, saxagliptin, and sitagliptin in patients with moderate/severe renal impairment, or ESRD (CrCl ≤50 mL/min)1 CrCl, creatinine clearance.

1. Grunberger G. J Diabetes. 2013;5:241-253; 2. US FDA: Available at www.fda.gov/Drugs/DrugSafety/ucm459579.htm; Accessed September 4, 2015; 3. See Drugs@FDA: Available at www.accessdata.fda.gov/scripts/cder/drugsatfda/; 4. Scirica BM, et al. Circulation. 2015;132(15):e198.

Nausea/Vomiting With GLP-1 RAs

Pooled Results From Placebo-Controlled Trials Medication

Nausea Incidence, %

Vomiting Incidence, %

Albiglutide1

11%

4%

Dulaglutide2

12%-21%

6%-13%

Exenatide BID3

8%-44%

4%-18%

QW4

11%-27%

11%

8%-35%

6%-17%

Exenatide

Liraglutide5

• Potential approaches to reduce risks for nausea and vomiting3,6 – Educate on meal size, eating pace, and dose timing relative to meals – Prescribe short-term antiemetic therapy for select patients 1. Albiglutide prescribing information. https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/ Prescribing_Information/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF; 2. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf; 3. Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021773s029s030lbl.pdf); 4. Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022200s008lbl.pdf); 5. Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf); 6. Ellero C, et al. Diabet Med. 2010;27(10):1168-1173.

14

GLP-1 RAs

Safety: Additional Considerations • Use caution in patients with renal impairment or renal transplantation, especially initiating or escalating doses1-6 – Hypovolemia due to nausea/vomiting may worsen renal function – Do not use exenatide formulations in patients with severe renal impairment (CrCl <30 mL/min) or ESRD

• All long-acting GLP-1 RAs should not be used in patients with MEN2 or a personal/family history of MTC2-5 – Counsel regarding MTC risk and symptoms of thyroid tumors – Report MTC to state cancer registry, regardless of treatment http://www.naaccr.org/Membership/MembershipDirectory.aspx MEN2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma.

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

6. Idorn T, et al. Diabetes Care. 2016;39(2):206-213.

SGLT-2 Inhibition

Insulin-Independent Reversal of Glucotoxicity Tubular Lumen

Proximal Tubule

Insulin sensitivity in muscle and liver1,2

3Na+ ATP 2K+

SGLT-2

GLUT-2

Na+/ Glucose

3Na+ ATP 2K+ GLUT-1

Glucose

Glucose

Reduced BP and body weight3,4 Gluconeogenesis2,5

SGLT-1

Improved β-cell function6,7

Na+

Glucose GLUT-2, glucose transporter 2.

1. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14; 2. Merovci A, et al. J Clin Invest. 2014;124(2):509-514; 3. Baker WL, et al. J Am Soc Hypertens. 2014;8(4):262-275.e9; 4. Desouza CV, et al. Clin Ther. 2015;37(6):1178-1194; 5. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883; 6. Ferrannini E, et al. J Clin Invest. 2014;124(2):499-508; 7. Polidori D, et al. Diabetologia. 2014;57(5):891-901.

15

SGLT-2 Inhibitors vs Sulfonylureas Added to Metformin

Noninferior vs SU ΔA1c From Baseline, %

0.0 -0.1

Δ Weight, kg

Agent

-0.2

SGLT-2 Inhibitor

SU

SGLT-2 Inhibitor

SU

CANA1,b

−4.0a

+0.7

5a

34

DAPA2,c

−3.2a

+1.4

3a

41

EMPA3,d

−3.2a

+1.6

2a

24

-0.3 -0.4 -0.5 −0.52 −0.52

-0.6 -0.7

−0.66 −0.73

-0.8

−0.81

-0.9

CANA (300

-1.0

GLIP

mg)1,b

GLIM

DAPA (2.5-10 mg)2,c

−0.93

EMPA (25

Hypoglycemia, % of patients

mg)3,d

aP<0.0001

vs SU. bCANA: 52-week trial of canagliflozin (baseline A1c, 7.8%); cDAPA: 52-week trial of dapagliflozin (baseline A1c, 7.7%), 87% of patients received the 10-mg dose; d EMPA:104-week trial of empagliflozin (baseline A1c, 7.9%).

1. Cefalu WT, et al. Lancet. 2013;382(9896):941-950; 2. Nauck MA, et al. Diabetes Care. 2011;34(9):2015-2022; 3. Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2(9):691-700.

Patients With Event, %

20

Patients With Patients With Event, % Event, %

EMPA-REG Trial

9

Cumulative Incidence of the Primary Outcomea P=0.04 for superiority Hazard ratio, 0.86 (95.02% CI, 0.74–0.99)

15 10

Empagliflozin

5 0

0

6

12

18

24

30

36

42

P<0.001 Hazard ratio, 0.62 (95% CI, 0.49–0.77)

Empagliflozin

3

7 6 5 4 3 2 1 0

48

Cumulative Incidence of Death From CV Causes Placebo

6

0

Placebo

0

6

12

18

24

30

36

Hospitalization for Heart Failure

42

48

Placebo

P=0.002 Hazard ratio, 0.65 (95% CI, 0.50–0.85)

Empagliflozin 0

6

12

18

24

Month

30

36

aCumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

N=7020 patients with T2DM at high risk of cardiovascular events.

Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.

16

42

48

Safety Issues With SGLT-2 Inhibitors Genital Mycotic Infections and UTIs

FDA Warnings • Increased risk of bone

• Evaluate and

fractures with canagliflozin

treat promptly

Risks of  eGFR and  Serum Creatinine

• FDA assessing risk of leg/

SGLT-2 INHIBITOR SAFETY

foot amputations (mostly toes) with canagliflozin

Volume Depletion May Cause Hypotension

• Evaluate renal function

before and during therapy

• Assess and correct volume

• Recent FDA warning: consider

predisposition for acute kidney injury before starting canagliflozin or dapagliflozin • Avoid dapagliflozin if eGFR <60 mL/min/1.73 m2 • Avoid canagliflozin or empagliflozin if eGFR <45 mL/min/1.73 m2 – Limit canagliflozin to 100 mg if eGFR is 45–59 mL/min/1.73 m2

status before therapy

• Risk factors – Loop diuretics – Older age – Low systolic BP – eGFR <60 mL/min/1.73 m2

UTI, urinary tract infection.

Abdul-Ghani MA, Defronzo RA. J Intern Med. 2014;276(4):352-363; List JF, et al. Diabetes Care. 2009;32(4):650-657; See Drugs@FDA (www.accessdata.fda.gov/scripts/cder/drugsatfda/).

SGLT-2 Inhibitors and Diabetic Ketoacidosis • Concerns

Potential Mechanisms

– 20 cases of DKA in T2DM reported to the FDA Adverse Events Reporting System (3/2013 to 6/2014) • Euglycemic DKA in T1DM (9 published cases) or T2DM (4 published cases) • Mostly women and/or linked to reduced insulin doses • Possible links to increased activity, recent illness, alcohol, and decreased food intake • Cases responded to IV rehydration + insulin

– Recent AACE statement • DKA occurs infrequently; risk-benefit ratio favors continued use of SGLT-2 inhibitors • Patients taking SGLT-2 inhibitors should avoid excess alcohol and very-low carbohydrate/ketogenic diets

– Consider lower doses in T1DM studies

SGLT-2 Inhibition Increases glucose renal clearance Decreases renal clearance of ketone bodies Endogenous and/or exogenous insulin levels reduced + Dehydration or increased activity level + Increased α-cell secretion of glucagon (mediated by SGLT-2) Increased lipolysis “Eudiabetic Ketoacidosis”

DKA, diabetic ketoacidosis; IV, intravenous.

Handelsman Y, et al. Endocr Pract. 2016 Jun 1. [Epub ahead of print]; Taylor SI, et al. J Clini Enocrinol Metab. 2015;100(8):2849-2852; Peters AL, et al. Diabetes Care. 2015;38(9):1687-1693.

17

SGLT-2 Inhibitor Plus Incretin-Based Therapy

Targeting Multiple Disease Mechanisms Impaired Insulin Secretion

Decreased Incretin Effect

Increased Lipolysis

Islet -cell

Islet -cell

Hyperglycemia Increased Glucagon Secretion

Increased Glucose Reabsorption

Increased Hepatic Glucose Production

Neurotransmitter Dysfunction

Decreased Glucose Uptake

Defronzo RA. Diabetes. 2009;58(4):773-795.

Empagliflozin/Linagliptin Combination Mean Baseline, 64 mmol/mol

Mean Baseline

7.99 % 8.04% 7.99% 8.05% 8.05% (n=134) (n=135) (n=133) (n=132) (n=133)

87.9 87.3 86.7 87.8 89.5 (n=134) (n=135) (n=133) (n=132) (n=133)

0.0 -0.5 -1.0 -1.5 -2.0

-0.14 (-0.33, 0.06) P=0.179 -0.41 (-0.61, -0.21) P<0.001

Change From Baseline in Body Weight, kg

Change From Baseline in A1c, %

24-Week Data in T2DM

-0.57 (-0.76, -0.21) P<0.001

0.0 -1.0 -2.0 -3.0 -4.0

-0.41 (-0.61, -0.21) P<0.001

Empagliflozin 25 mg/Linagliptin 5 mg Empagliflozin 10 mg/Linagliptin 5 mg

Empagliflozin 25 mg Empagliflozin 10 mg

N=674 individuals with T2DM who had not received diabetes therapy for ≥12 weeks (week 24 data).

Lewin A, et al. Diabetes Care. 2015;38(3):394-402.

18

0.1 (-0.9, 1.1) P=0.801 -0.5 (-1.5, 0.5) P=0.362 -2.0 (-3.0, -1.0) P<0.001 -1.2 (-2.2, -0.2) P=0.018

Linagliptin 5 mg

Saxagliptin and/or Dapagliflozin Add-on to Metformin SAXA+ DAPA+ MET (n=158)

45 SAXA+ MET (n=143)

DAPA+ MET (n=151)

0.0

-0.5

-1.0

Patients Achieving A1c Value <7.0%, %

Adjusted Mean (95% CI) Change From Baseline in HbA1c, %

24-Week Data in T2DM 35 30 25 20 15 10 5 0

-1.5

-2.0

40

SAXA+ DAPA+ MET (n=179)

-0.59% (-0.81%, -0.37%) P<0.00001

SAXA+ MET (n=176)

DAPA+ MET (n=179)

-0.27% (-0.48%, -0.05%) P=0.0166

N=534 patients with T2DM, A1c values between 8.0% and 12.0% (mean A1c, 8.9%), and an inadequate response to metformin.

Rosenstock J, et al. Diabetes Care. 2015;38(3):376-383.

GLP-1 RA + SGLT-2 Inhibitor

LS Mean % Change (±se) in Body Weight From Baseline

LS Mean Change (±se) in HbA1c From Baseline, %

Improved Glycemic Control and Weight Loss 0.4

0.17%

0.0

-1.00% (95% CI: -1.35, -0.65)

-0.4 Placebo CANA 100 mg CANA 300 mg

-0.8

-0.83% -0.89%

-1.06% (95% CI: -1.43, -0.69)

-1.2 12

0

18

1.0

-0.4% (-0.6 kg)

0.0 -1.0 -2.0

-3.0% (-3.3 kg) -3.7% (-3.9 kg)

Placebo CANA 100 mg CANA 300 mg

-3.0 -4.0 -5.0 0

6

12

18

Time Point, week

N=95 subjects with T2DM in CANVAS study who were taking GLP-1 receptor agonists.

Fulcher G, et al. Diabetes Obes Metab. 2016;18(1):82-91.

19

-2.5% (95% CI: -3.7, -1.4) (-2.7 kg [95% CI: -3.9, -1.4]) -3.2% (95% CI: -4.5, -2.0) (-3.3 kg [95% CI: -4.6, -1.9])

Jerry

Pharmacologic Treatment • Jerry and his PCP decide to start therapy with metformin BID and an SGLT-2 inhibitor – Jerry is educated on risks with both drugs – He is assessed for volume status – Both medications titrated up over next 2 weeks

• At a 3-month follow-up, Jerry’s A1c has fallen to 7.4% – Previous value, 8.7%

• Jerry often forgets which drugs he has taken each day – Frequently skips doses for T2DM or hypertension

• His weight is relatively unchanged – He reports continued bad eating habits during tax season

How can the PCP help improve Jerry’s adherence to lifestyle recommendations and his medications?

Simplify the Regimen Core Principles Adjust timing, frequency, amount, and dosage Match regimen to patient’s activities of daily living Recommend all medications are taken together Avoid medications with special requirements Avoid unnecessary side effects

Action • Prescribe once-daily medications • Dose to regular activities (eg, meals) • Consider combination formulations • Assess for drug-drug interactions and food absorption issues • Avoid medications that should not be taken with meals • Evaluate all potential side effects • May need to choose among side effects

Change the situation rather than change the patient!

American College of Preventative Medicine. Available at: www.acpm.org/resource/resmgr/timetools-files/ adherenceclinicalreference.pdf. Accessed September 3, 2015.

20

Decision Aids for T2DM Examples from the Mayo Clinic

• Decision aid cards provide information on T2DM medications • Card organized into 7 issues that may be of interest to the patient – – – – – – –

A1c reduction Daily routine Lower blood sugar Costs Daily sugar testing Other considerations Weight change

Available at http://shareddecisions.mayoclinic.org/decision-aid-information/ decision-aids-for-chronic-disease/diabetes-medication-management/.

Motivational interviewing is a collaborative conversation style for strengthening a person's own motivation and commitment to change by eliciting and exploring the persons own reasons for change Miller & Rollnick, 2013

21

Motivational Interviewing Stages of Change

1. Precontemplation Definition: Not yet considered or is unwilling or unable to change

6. Recurrence

2. Contemplation

Definition: Experienced a recurrence of the problems

Definition: Sees the possibility of change but is ambivalent and uncertain

5. Maintenance

3. Determination

Definition: Has achieved the goals and is working to maintain change

Definition: Committed to changing but still considering what to do

4. Action Definition: Taking steps toward change but hasnâ&#x20AC;&#x2122;t stabilized in the change process

22

Jerry

Key Points • Individualize treatment goals for patients with T2DM – Consider comorbidities – Address psychosocial factors – Take steps to reduce risk of hypoglycemia

• Ensure lifestyle modifications are the foundation of any treatment regimen for T2DM • Monitor multiple metabolic targets for comprehensive management and reduction of cardiovascular risk – A1c, lipids, BP

• When necessary, promptly intensify antihyperglycemic therapy – Consider early multidrug regimens that reflect the baseline degree of hyperglycemia and other clinical parameters – Minimize risks of hypoglycemia – Use combination formulations to address multiple pathologic mechanisms in T2DM and to simplify treatment regimens

Conclusions • Comprehensive T2DM management requires diligent monitoring of blood sugars, lipid profile, blood pressure, and body weight – Treatment is founded on lifestyle and behavioral modifications

• Hypoglycemic episodes are associated with serious adverse outcomes • Certain combinations of noninsulin agents can effectively reduce hyperglycemia with relatively low risks of hypoglycemia and potential for weight loss

23