Early Combination Therapy in the Treatment

of Type 2 Diabetes

November 16, 2018 - 12:10pm–1:10pm

New Mexico Nurse Practitioner Council2018 Fall ConferenceEl Monte Sagrado317 Kit Carson Rd, Taos, NM 87571

Curtis Triplitt, PharmD, CDE Texas Diabetes Institute University Health System Associate Professor of Medicine Clinical /Div. of Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX

Content Chair and Faculty Speaker:

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute, University Health System Associate Professor of Medicine, Clinical /Div. of Diabetes University of Texas Health Science Center at San Antonio San Antonio, TX

Disclosures: Dr. Triplitt has served on a Speakers Bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and Janssen Pharmaceuticals.

External Reviewer:

Felice Caldarella, MD, FACE, FACP, CDE

Endocrinologist

Center for Endocrine Health

Hunterdon Medical Center

Clinton, NJ

Disclosures: Dr. Caldarella discloses no relevant financial relationships with an ACCME-defined commercial interest in the last 12 months.

Planning Committee & Non-faculty Contributors

Additional non-faculty contributors and others involved in the planning, development,

and editing/review of the content have no relevant financial relationships to disclose in the last 12 months.

Program Overview

This symposium will present nurse practitioners and physician assistants with the current guideline recommendations for the treatment of type 2 diabetes. The program will review the benefits and risks of various classes of antihyperglycemic agents including SGLT-2 inhibitors, discuss considerations for early combination therapy, and strategies for reducing clinical inertia.

Credit Designation

Horizon CME designates this live activity for amaximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the providership of Horizon CME. Horizon CME is accredited by the ACCME to provide continuing medical education for physicians.

Target Audience

This CME initiative will target nurse practitioners and physician assistants.

Learning Objectives

• Review current guideline recommendations forthe initiation and intensification of therapy inpatient with type 2 diabetes

• Discuss the benefits and risks of variousclasses of antihyperglycemic agents

• Discuss clinical considerations for earlycombination therapy

• Implement strategies to reduce clinical inertiain the treatment of patients with type 2diabetes

Receipt of Credit

• Read the learning objectives and facultydisclosures

• Complete the Pre-Test

• Participate in the activity

• Complete the Post-Test

• Complete Final Evaluation

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

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This activity is supported by an independent educational grant from Merck.

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The evaluation will be available on Friday, November 23, 2018.

Please note that the evaluation and course materials will only be available for 30 days following the activity. You will not be able to claim credit or receive your certificate if you attempt to complete the evaluation after this 30-day period.

Early Combination Therapy in the Treatment of Type 2 Diabetes

Curtis Triplitt, PharmD, CDE

Associate Professor of Medicine, Division of Diabetes

University of Texas Health at San Antonio

Associate Director of Diabetes Research Center

Texas Diabetes Institute

San Antonio, TX

Objectives

• Review current guidelines recommendation for the initiationand intensification of therapy in patients with type 2 diabetes

• Discuss the benefits and risk of various classes ofantihyperglycemic agents

• Discuss clinical consideration for early combination therapy

• Implement strategies to reduce clinical inertia in the treatmentof patients with type 2 diabetes

Patient Case: Newly Diagnosed Type 2 DM

• Peter is a 51 year-old Caucasian male. He had routine lab work and physical 2 weeks ago. FPG of 267 mg/dL was noted. Repeat lab ordered for today’s visit. He states that he hasn’t lost any weight nor have felt thirsty or been going to the restroom more frequently.

• Allergies: Sulfa- severe rash- hospitalized when 12 years old.

• PMH: 1. Dyslipidemia 2. HTN 3. Obesity

• Past Surgical History: Cholecystectomy 24 year ago and right ulna fracture with plate and screw at 17 years old.

Patient Case: Background

• Family History: T2DM – both parents, 1 brother, and 1 sister; CKD – mother, not on dialysis; Father – MI at age 52; all have HTN

• Social Hx: Married for 25 years, works as insurance adjuster, 2 children, ages 22 and 19 years old – both healthy

• Chews tobacco, has tried quitting “at least 20 times”

• Alcohol – 0-3 beers or glasses of wine only on a weekend, no drugs

• “I’m not a big fan of drugs, I was hospitalized when 12 years old due to a drug. Can I get control without?”

• Diet: Family eats very healthy thanks to wife – not high carbohydrates, rare sugar drinks, likes cheesecake. When “on the road” eats very unhealthy.

Patient Case: Medications and Labs

• Current medications

– Lisinopril 10 mg PO daily, amlodipine 5 mg PO daily, and atorvastatin 20 mg PO daily

• Physical exam: BMI 35 kg/m2 BP 132/80 mmHg HR 74 BPM

• Laboratory:

– A1C 8.8% FPG 206 mg/dL Random microalbumin/creatinine 12 mg/g

– UA-normal except for +3 urine CBC-WNL

– TC-201 mg/dL LDL-114 mg/dL HDL-39 mg/dL TG-242 mg/dL

– Scr 0.7 (eGFR = 123 mL/min/1.73m2)

Guideline Recommended Glycemic Goals*

a2-hour postprandial glucose concentration; bPeak postprandial capillary plasma glucose; FPG = fasting plasma glucose; PPG = postprandial glucose.1. Garber AJ, et al. Endocr Pract. 2018;24(1):91-120. 2. American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S55–S64. 3. Qaseem A, et al. Ann Intern Med. 2018;168(8):569-576.

AACE1 ADA2 ACP3

A1C (%)≤6.5 if no serious illness or low hypo risk>6.5 if with serious illness or hypo risk

<6.5% for select patients

<7% for most patients

<8% if previous severe hypoglycemia or multiple

comorbidities

7-8%

FPG <110 mg/dL 80-130 mg/dL

PPG <140 mg/dLa <180 mg/dLb

ACP recommendations are controversial and are a departure from all major guideline recommendations including Canadian, European, and NICE

Diabetic Complications Progress with Increasing A1C*

*Based on the Diabetes Control and Complications Trial (DCCT) data.Adapted from DCCT Research Group. N Engl J Med. 1993;329:977–986. Skyler J. Endocrinol Metab Clin North Am. 1996;25:243.

6 80R

elat

ive

risk

of

com

plic

atio

ns 15

10

7 12

Percentage of A1C level (%)10

5

119

Retinopathy

Nephropathy

Neuropathy

Intensive Glycemic Control in T2DM Reduces Risk of Complications (UKPDS)

*UKPDS 35: Prospective observational analysis of UKPDS patients (n = 4585, incidence analysis; n = 3642, RR analysis); median 10.0 years of follow-up.HbA1c = hemoglobin A1c; RRR = relative risk reduction; PVD = peripheral vascular disease; MI = myocardial infarction.Stratton IM, et al. BMJ. 2000;321(7258):405-412.

Risk Reduction with 1% Decline in A1C* (7.9% vs 7.0%)

45

30

0

RR

R

(%)

MicrovascularDisease

MI CataractExtraction

39

15

P<.0001

PVD Stroke HeartFailure

DeathRelated toDiabetes

37 43 14 16 2112 19

P = .35 P = .021 P<.0001 P<.0001

Glycemic Control & Vascular Complications in T2DM Across Major Trials

1. Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589. 3. Gerstein, et al. NEJM. 2008;358:2545-2559. 4. ACCORD Study Group. NEJM. 2010; 363:233-244. 5. Patel, et al. NEJM. 2008;358: 2560-2572. 6. Duckworth, et al, NEJM 2009;360:129-139.

Microvascular Macrovascular Mortality

UKPDS1,2

ACCORD3,4

ADVANCE5

VADT6

Observational Follow-up

Baseline Characteristics of the Landmark Trials in T2DM

CV = cardiovascular; T2DM = type 2 diabetes.

1. ACCORD, Gerstein HC, et al. NEJM. 2008;358:2545-2559. 2. ADVANCE Collaborative Group, Patel A, et al. NEJM. 2008;358:2560-2572. 3. Duckworth, et al. NEJM. 2009;360:129-139 4. Adapted from UKPDS Group. Lancet. 1998;352:837-853.

ACCORD1 ADVANCE2 VADT3 UKPDS4

Number of subjects 10,251 11,140 1,791 4,209

Gender (% males) 62 58 97 61

Age (yrs) 62 66 60 53

Diabetes duration (yrs) 10 8 11.5 0

Baseline A1C (%) 8.1 7.5 9.4 7.1

CV events (%) ~35 ~32 ~40 unknown

Insulin use (%) ~35 ~1.5 ~50 0

Approach to the Management of Hyperglycemia

American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135.

6.0% 8.0%7.0%

Long Short

Absent Few / Mild Severe

Absent Few / Mild Severe

Newly diagnosed Long-standing

Highly motivated, excellent self-care capabilities

Low High

Readily available

Less motivated, poor self-care capabilities

Limited

Us

ua

lly no

t mo

difia

ble

Po

ten

tially m

od

ifiab

le

More stringent A1C 7% Less stringentPatient / Disease Features

Risks potentially associated with hypoglycemia and other drug adverse effects

Disease duration

Life expectancy

Important comorbidities

Established vascular complications

Patient attitude and expected treatment efforts

Resources and support system

• Intensification approach should be individualized

=Recommended for our patient RA

2018 ADA Guideline Recommendations

American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.

At diagnosis, initiate lifestyle management, set A1C target, and initiate therapy based on A1C

!

MET + 2 additional agents

Add 3rd agent based on drug-specific effects and patient factors

MET + additional agent

ASCVD?If YES, add agent with CV benefitIf NO, add agent with consideration for drug-specific effects and patient factors

If not at goal in 3 months*, proceed to Triple Therapy

Entry A1C ≥ 9%

If not at goal in 3 months*, proceed to Combination Injectables

If not at goal in 3 months*, proceed to Dual Therapy

Metformin

A1C < 9%

Refer to Insulin Algorithm

Consider Dual Therapy Triple Therapy Combination Injectables

Insulin + other agents

Other agents: GLP-1 RAs

A1C ≥ 10%, BG ≥300 mg/dL, or symptoms

Consider Monotherapy

2018 AACE/ACE Guideline Recommendations

Garber AJ, et al. Endocr Pract. 2018;24(1):91-120.

!

Entry A1C > 9.0%

No Yes

METor other first-line agent + second-line agent

+

GLP-1 RA

SGLT-2 i

TZD

Basil Insulin

DPP-4 i

Colesevelam

Bromocriptine QR

AGI

SU/GLN

!

!

!

METor other first-line agent

+

GLP-1 RA

SGLT-2 i

DPP-4 i

TZD

Basil Insulin

Colesevelam

Bromocriptine QR

AGI

SU/GLN

If not at goal in 3 months, proceed to Triple Therapy

Progression of Disease

Entry A1C ≥ 7.5%

If not at goal in 3 months, proceed to or intensify insulin therapy

If not at goal in 3 months, proceed to Dual Therapy

Dual

Therapy

MET

GLP-1 RA

SGLT-2 i

DDP-4 i

AGI

TZD

SU/GLN

Monotherapy*

Entry A1C < 7.5%

Triple

Therapy

OR

Insulin±

Other Agents

ADD or Intensify InsulinRefer to Insulin Algorithm

Few adverse events or possible benefits

Use with caution

Dual Therapy*

Triple Therapy*

Symptoms

!

!

!

!

!

!

Lifestyle Modification(including Medically Assisted Weight Loss)

ADA and AACE/ACE Recommendations for Peter

1. American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85. 2. Garber AJ, et al. Endocr Pract. 2018;24(1):91-120.

American Diabetes Association1

Recommendations if:

• A1C <9.0%

• Monotherapy

• A1C ≥9.0%

• Dual therapy

• A1C ≥10%, blood glucose blood glucose ≥300 mg/dL, or patient is symptomatic

• Combination injectable therapy

AACE/ACE2

Recommendations if:

• A1C ≥7.5%

• Dual therapy

• A1C >9.0% and No Symptoms

– Dual or Triple Therapy

• A1C >9.0% + Symptomatic

– Insulin (± other drugs)

Patient Case: Continued

• You discuss the treatment options with Peter and decided to start him on metformin 500 mg BID and titrate to 1000 mg BID.

• At 3 month checkup his A1C was 7.5%. You discussed with him about possibly adding another drug. He asked for more time so that he can try exercising more and improve his diet to see if it would help. You agree.

• He had missed an appointment and returns for a follow-up visit 9 months later and his A1C was 7.4%. Since his A1C improved with his exercise and diet, a decision was made for him to continue it.

• He returns 6 months later for another checkup and his A1C was 7.7%.

Clinical Inertia Common in Real-World Treatment of Type 2 Diabetes

OADs = oral antidiabetic drugs.

Khunti K, et al. Diabetes Care. 2013;36(11):3411-3417.

# of OADs A1CMedian Time to Intensification

1 ≥7.0% 2.9 years

2 ≥7.0% >7.2 years

# of OADsA1C at

Insulin InitiationMedian Time to

Intensification with Insulin

1 8.7% 7.1 years

2 9.1% 6.1 years

Retrospective cohort study of 81,573 T2DM patients in the United Kingdom using the Clinical Practice Research Datalink database between January 2004 and December 2006, with follow-up until April 2011

Common Causes of Clinical Inertia• Provider

– Clear goals not specified

– Intervention not prescribed or implemented

– Initiate ineffective intervention

– Patient “sidetracks” visit

– Ineffective communication with patient

• Patient

– Denial having disease or that it is serious

– Low health-literacy

– Cost

– Burden of therapy (too many medications)

– Lifestyle issues and unwilling to highly prioritize health

– Absence of issues with disease makes themless likely to act

– Depression

• System

– Lack of decision planning

– No follow-up decision support

– No active outreach to patients

– No team-based approach to care

• Medications

– Impossible to get to goal with chosen therapy

– Side effects

– Cost

– Ease-of-use

• Communication

• Misunderstanding that T2DM is a progressive disease, which will require combination therapy

Provider Clinical Inertia

• Primary reasons providers fail to intensify treatment

– Overestimation of care provided

• i.e., providers overestimate their adherence to guidelines and the care they provide

– Citing “soft” reasons to avoid intensification of treatment

• i.e., perception that the overall care of their patient is improving, nonadherence among patients, and concerns about results from recent large CV trials

– Lack of training

Khunti K, et al. Br J Diabetes Vasc Dis. 2015;15:65-69.

Clinical Impact of Clinical Inertia

• Retrospective cohort study using UK Clinical Practice Research Datalink

• 105,477 newly diagnosed type 2 diabetes from 1990 with follow-up data available until 2012

• Mean A1C 8.1% at diagnosis, 11% had history of cardiovascular disease, and 7.1% experienced at least one CV event during 5.3 years of median follow-up

• One year delay in receiving intensified therapy (goal A1C < 7.0%) was associated with significantly increased risk of MI by 67%, stroke by 51%, HF by 64%, and composite CVE by 62%

MI = myocardial infarction; CV = cardiovascular

Paul SK, et al. Cardiovasc Diabetol. 2015;14:100.

Drawbacks of the Stepwise Treatment

• Even short periods of hyperglycemia increase risk of complications1–3

• A proactive approach is required to get patients to achieve their glycemic goals sooner

• May lead to clinical inertia

1. JAMA 2003; 290:2159–2167. 2. EDIC Group. JAMA 2002; 287:2563–2569. 3. Nathan DM, et al. N Engl J Med 2003; 348:2294–2303.

Myocardial infarction

Microvascular complications

Inci

den

ce p

er10

00 p

atie

nt-

year

s

Updated mean HbA1c (%)

20

40

60

80

6 7 8 9 10 11

0

0

NormalA1C

levels

5

T2DM Patients Experience Progressive Deterioration in Glycemic Control Over Time

UKPDS Group. Lancet. 1998;352:837–853. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21–S25.

IntensiveConventional

Time from randomization (y)

Med

ian

A1c

(%

)

UKPDS: A1C Level

9

8

7

60

30 96 1512

Years from diagnosis

β-c

ell

fun

ctio

n (

%)

β-Cell Function

100

60

40

20

0−10 −2−6 62

80

−4−8 40−12

Requirement for Multiple Therapies in T2DM to Maintain Glycemic Control

*Based on UKPDS data.Turner RC, et al. JAMA. 1999;281:2005–2012.

0Year 3

(%)

20

100

60 50

7580

40

Time from randomization (years)

Year 9

Percentage of patients needing >1 drug to achieve glycemic control*

Initial Triple Therapy with Metformin, Pioglitazone, and Exenatide BID vs. Conventional Stepwise Therapy

*Triple therapy = MET/TZD/GLP-1RA; Conventional Stepwise Therapy = Treatment with metformin with sequential addition of an SU and then basal insulin

Abdul-Ghani MA, Puckett C, Triplitt CL et al. Diabetes Obes Metab. 2015;17:268-275.

• 221 T2DM patients were randomized in an open-label study to receive intensive triple therapy or conventional stepwise triple therapy*

Initial Triple

Therapy

9

8

7

6

0 6 12 18 24Time (Months)

A1C

(%

)

Conventional Stepwise Therapy

* * * * * *6.50%

5.95%

P<0.001

Initial Triple Therapy vs. Conventional

• By 6 months, achieved an A1C <6.0% and maintained these levels over a 2-year period

• 7.5 fold lower risk of any hypoglycemia

• Weight loss: -1.2 kg vs. +4.1kg (p<0.01)

BL1

Advantages and Disadvantages of Antihyperlgycemic Agents

Sulfonylureas

• Glyburide, glipizide, glimepiride

• Advantages

– High efficacy; low cost

• Disadvantages

– High hypoglycemia risk; weight gain

– Glyburide not recommended in patients with renal disease

American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.

DPP-4 inhibitors

• Alogliptin, linagliptin, saxagliptin, sitagliptin

• Advantages

– No hypoglycemia risk; no weightgain; well tolerated

• Disadvantages

– Intermediate efficacy; may worsen heart failure (alogliptin, saxagliptin);reduce dose in renal disease (alogliptin, saxagliptin, sitagliptin)

SAVOR-TIMI 53, EXAMINE, and TECOS:Hospitalization for Heart Failure

*Statistically significant increase in hospitalizations for heart failure associated with saxagliptin use in SAVOR-TIMI.1. Scirica BM, et al. N Engl J Med. 2013;369:1317–1326. 2. White WB, et al. N Engl J Med. 2013;369:1327–1335. 3. Green JB, et al. N Engl JMed. 2015;373(3):232–242.

SAVOR-TIMI(saxagliptin vs placebo)

EXAMINE(alogliptin vs placebo)

TECOS(sitagliptin vs placebo)

289/8280(3.5%)

106/2701(3.9%)

228/7332(3.1%)

Study Drugn/N (%)

228/8212(2.8%)

89/2679(3.3%)

229/7339(3.1%)

Placebon/N (%)

1.27

1.19

1.00

HazardRatio

1.07, 1.51

0.89, 1.58

0.83, 1.20

95%CI

0.009*

0.238

0.983

p-Value

0 1 2

Favors Treatment Favors Placebo

In patient with CHF, recommend sitagliptin

Advantages and Disadvantages of Antihyperlgycemic Agents (Continued)

SGLT-2 inhibitors

• Canagliflozin, dapagliflozin, empagliflozin,ertugliflozin,

• Advantages

– No hypoglycemia risk; weight loss, proven CV, CHF, and renal benefit (canagliflozin, empagliflozin)

• Disadvantages

– Intermediate efficacy; GU infections; contraindicated in renal dysfunction

– Risk of amputations & bone fractures(canagliflozin); risk of DKA

American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.

TZDs

• Pioglitazone

• Advantages

– High efficacy; no hypoglycemia risk;low cost; potential CV benefit

• Disadvantages

– Weight gain; increase fracture risk;exacerbate heart failure; edema

EMPA-REG OUTCOME Study: Results

Zinman B, et al. N Engl J Med. 2015;373:2117-28.

Hazard ratio (95% CI) P value

Primary composite endpoint* 0.86 (0.74-0.99) 0.04

Death from any cause 0.68 (0.57-0.82) <0.001

CV death 0.62 (0.49-0.77) <0.001

Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23

Hospitalization for HF 0.65 (0.50-0.85) 0.002

Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001

*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR,hazard ratio; MI, myocardial infarction.

7,020 T2DM patients with established CVD were randomized to empagliflozin or placebo and followed over 3.1 years

CANVAS Study: Clinical Outcomes

*CV death, nonfatal MI, or nonfatal stroke. †Superiority.Neal B, et al. N Engl J Med. 2017;377:644-57.

Hazard ratio (95% CI) P value

Primary composite endpoint* 0.86 (0.75-0.97) 0.02†

CV death 0.87 (0.72-1.06)

Nonfatal MI 0.85 (0.69-1.05)

Nonfatal stroke 0.90 (0.71-1.15)

Fatal or nonfatal MI 0.89 (0.73-1.09)

Fatal or nonfatal stroke 0.87 (0.69-1.09)

HF hospitalization 0.67 (0.52-0.87)

CV death or HF hospitalization 0.78 (0.67-0.91)

All-cause death 0.87 (0.74-1.01)

Progression of albuminuria 0.73 (0.67-0.79)

40% reduction in eGFR, renal replacement therapy, or renal death

0.60 (0.47-0.77)

10,142 T2DM patients with established CVD were randomized to canagliflozin or placebo and followed for a median of 2.4 years

0.00 0.50 1.00 1.50

Favors canagliflozin

Increase risk of amputations were seen in the study, leading to Black Box Warning in label

Do Not Use Canagliflozin Patients with: Prior amputations, active diabetic foot ulcers, infections,

significant PAD, or significant neuropathy (undefined)

Advantages and Disadvantages of Antihyperlgycemic Agents (Continued)

GLP-1 RAs

• Dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide

• Advantages

– High efficacy; no hypoglycemia risk;weight loss; CV and renal benefit (liraglutide); proven CV safety (lixisenatide, exenatide ER)

• Disadvantages

– Injection; not recommended in patients with eGFR <30 mL/min; GI side effects common

American Diabetes Association. Diabetes Care. 2018;41(Suppl. 1):S73–S85.

Insulin

• Human insulin (i.e., NPH), analog insulin (i.e., glargine, detemir)

• Advantages

– Highest efficacy; can use in pregnancy and renal failure; proven CV safety (insulin glargine, degludec)

• Disadvantages

– Weight gain; increase hypoglycemia risk;

LEADER Study: Results

*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF.

Marso SP, et al. N Engl J Med. 2016:375:311-322.

Hazard ratio (95% CI)

P value

Primary composite endpoint* 0.87 (0.78-0.97) 0.01

Expanded composite endpoint† 0.88 (0.81-0.96) 0.005

Death from any cause 0.85 (0.74-0.97) 0.02

CV death 0.78 (0.66-0.93) 0.007

Fatal or nonfatal MI 0.86 (0.73-1.00) 0.046

Nephropathy 0.78 (0.67-0.92) 0.003

9,340 T2DM patients with established or at high CV risk were randomized to liraglutide or placebo and followed for a median of 3.5 years

0.00 0.50 1.00 1.50

Favors liraglutide

Patient Case: Continued

• After discussing the treatment options with Peter, you decided to add a DPP-4 inhibitor. Since he is already taking metformin, you suggested prescribing to him a single pill for the combination.

• He agrees and is looking forward to improving his glucose control.

Earlier Use of Combination Therapy May Improve Glycemic Control Compared With Conventional Therapy

Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345-1355. Campbell IW. Br J Cardiol. 2000;7:625-631.

Early combination approach---

Mean A1Cof patients

7

6

9

8

10

A1C

(%

)

OAD monotherapy

Diet andexercise

OAD combination

OAD uptitration

OAD + multiple daily

insulininjections

OAD + basal insulin

Duration of diabetesTime

Early Combination Instead of Step Therapy Initiation Improves Outcomes

• 1.4 times more likely to get to A1C goal <7%

• Significantly greater A1C reduction (-0.43%) with early combinationtherapy vs. monotherapy

• 1.56 fold higher risk of hypoglycemia if SU or insulin used as firstcombination

Phung OJ, et al. Diabetes Obes Metab. 2014;16(5):410-7. Adapted from Cahn A, Cefalu W, Diabetes Care. 2016;32(suppl 2):S137-S145

IncreasedHGPHyperg lycemiaDecreased GUptakImpa ired InsulinS ecretion Increased Li

HYPERGLYCEMIAHYPERGLYCEMIA

Decreased Incretin Effect

Decreased Insulin Secretion Increased

Lipolysis

Islet Cells – alpha cells

Increased Glucagon Secretion

Increased HGPNeurotransmitter

DysfunctionDecreased

Glucose Uptake

Increased Glucose

Reabsorption

Multiple Defects Contribute to the Pathophysiology of T2DM Necessitating Targeted Therapy

TZDs, GLP1 RASU, Insulin

GLP1 RA, DPP4i TZDs,

Insulin

SGLT2i

GLP1 RA

TZDs, MET, SU, GLP1 RA, Insulin GLP1 RA,

Bromocriptine

TZD, MET

Factors to Consider in Choosing Early Combination Therapy over Monotherapy

• Would clinical inertia be reduced?

• Is it pathophysiologically sound and is there complimentary mechanisms of action?

• Would patient be unlikely to get to goal with monotherapy?

• Would there be a possible delay in deterioration of glycemic control?

• Are the costs appropriate? Is there a cost advantage to the patient?

• Is the risk-to-benefit ratio acceptable?

• Would it improve unmet clinical needs, such as weight gain, hypoglycemia, CVD,and/or renal outcomes?

• Would adherence/compliance be improved?

Adapted from Cahn A, Cefalu W, Diabetes Care. 2016;32(suppl 2):S137-S145

Fixed-Dose Combination Therapy

• Complementary mechanisms of action

• Address multiple defects underlying T2DM

• Simplify administration and reduce medication burden

• May reduce costs

• Improve adherence

• Reduce clinical inertia

• Lower dose of individual components

Lavernia F, et al. Postgrad Med. 2015;127(8):808-17. Bianchi C, et al. Drugs. 2017;77(3):247-264.

Fixed-Dose Combinations for Treatment of T2DM

Class Combinations

Metformin/Sulfonylurea MET/glyburide; MET/glipizide; MET/glimepiride

Metformin/TZD MET/pioglitazone; MET/rosiglitazone

Metformin/DPP-4 inhibitor MET/alogliptin; MET/linagliptin; MET/saxagliptin; MET/sitagliptin;

Metformin/SGLT-2 inhibitorMET/canagliflozin; MET/empagliflozin; MET/ertugliflozin;

MET/dapagliflozin

Metformin/glinide MET/repaglinide

SGLT-2 inhibitor/DPP-4 inhibitor

Empagliflozin/linagliptin; Ertugliflozin/sitagliptin

TZD/Sulfonylurea Pioglitazone/glimepiride; Rosiglitazone/glimepiride

TZD/DPP-4 inhibitor Pioglitazone/alogliptin

Insulin/GLP-1 RA Insulin glargine/lixisenatide; Insulin degludec/liraglutide

Lavernia F, et al. Postgrad Med. 2015;127(8):808-17. Clinical Resource, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. July 2017.

Novel Combinations

• SGLT-2 inhibitor and DPP-4 inhibitor

– Complimentary MOA

– Low risk of hypoglycemia and weight gain

Efficacy of SGLT-2/DPP-4 Inhibitor Combination Therapy

1. Lewin A, et al. Diabetes Care. 2015;38:394-402. 2. Rosenstock J, et al. Diabetes Care. 2015;38:376-383.

TreatmentMean Change From Baseline

in A1C at Week 24, %P Value

Empa 25 mg/linagliptin 5 mg -1.08 <0.001 vs. Lina 5 mg

Empa 10 mg/linagliptin 5 mg -.124 <0.001 vs Empa 10 mg & Lina 5 mg

Empagliflozin 25 mg -0.95 -

Empagliflozin 10 mg -0.83 -

Empagliflozin 5 mg -0.67 -

Dapa 10 mg/saxagliptin 5 mg -1.47<0.0001 vs Saxa + MET0.0166 vs. Dapa + MET

Saxagliptin 5 mg + MET -0.88 -

Dapagliflozin 10 mg + MET -1.20 -

SGLT-2/DPP-4 Inhibitor Combination vs. Individual Agents in T2DM Patients Uncontrolled on Metformin

Pratley RE, et al. Diabetes Obes Metab. 2018;20(5):1111-1120.

LS

Mea

n C

han

ge

Fro

m B

asel

ine

±SE

Time

Combination therapy achieved significantly greater A1C reduction and greater percent of patients achieving A1C <7%• Ertugliflozin 5 mg – 26.4%• Ertugliflozin 15 mg – 31.9%• Sitagliptin 100 mg – 32.8%• Ertug 5 mg/Sita 100 mg – 52.3%• Ertug 15 mg/Sita 100 mg – 49.2%

-1.6

0.0

BL

-0.6

-1.2

W12W6 W52W39W26W18

-0.4

-1.0

-1.4

-0.2

-0.8

Ertugliflozin 5 mg +Sitagliptin 100 mg

Ertugliflozin 15 mg +Sitagliptin 100 mgSitagliptin 100 mg

Ertugliflozin 15 mg

Ertugliflozin 5 mg

Considerations for Add-on Medication Selection

Diabetes Canada Clinical Practice Guidelines Expert Committee, Lipscombe L, et al. Can J Diabetes. 2018;42(Suppl 1):S88–S103.

Add another agent best suited to the individual by prioritizing patient characteristics:

CLINICAL CONSIDERATIONS CHOICE OF AGENT

Antihyperglycemic agent withdemonstrated CV benefit (empa, lira, cana)

PRIORITYClinical cardiovascular disease

Other considerations: Degree of hyperglycemia

Risk of hypoglycemiaOverweight or obesity

CV disease or multiple risk factorsComorbidities (renal, CHF, hepatic)Preferences & access to treatment

Planning pregnancy

Consider relative A1C loweringRare hypoglycemia

Weight loss or weight neutralEffect on cardiovascular outcome

See therapeutic considerations; consider eGFR See cost column; consider access

No clinical cardiovascular disease

Avoidance of hypoglycemia and/or weight gain with adequate glycemic efficacy

DPP-4 inhibitor, GLP-1 receptor agonist or SGLT2 inhibitor

Key Takeaways

• A1C goals need to be individualized

– <7% for most patients and less stringent in patients with significant comorbidities or advanced age

• Clinical inertia is common in patients with T2DM

– Early combination therapy is proven to increase the number of patients who attain glycemic goal and reduce clinical inertia

• Individualize addition of diabetes medications based on glycemic goal and important clinical and patient considerations

– Comorbidities, ease-of-use, cost, etc…

– SGLT2 inhibitors or GLP-1 RA’s should be used in patients with established CAD or renal disease

Zinman B, et al. N Engl J Med. 2015;373(22):2117-28.

NOTES