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Emerging Challenges in Primary Care:

2018

The Progression of Type 2 Diabetes:

A Rational Approach for Long-term Disease Management

Faculty§ Rodolfo J. Galindo, MD

Assistant Professor of MedicineEmory University School of MedicinePrincipal Investigator, Center for Diabetes and Metabolism ResearchDivision of Endocrinology, Diabetes and MetabolismEmory University Hospital Midtown Medical Chair, Hospital Diabetes TaskforceEmory Healthcare System Atlanta, GA

§ Javier Morales, MD, FACP, FACEClinical Associate Professor of MedicineDonald and Barbara Zucker School of Medicine At Hofstra/Northwell UniversityVice PresidentAdvanced Internal Medicine Group, P.C.East Hills, NY

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Faculty§ Leann Olansky, MD, FACP, FACE

Department of Endocrinology, Diabetes and MetabolismEndocrinology & Metabolism InstituteCleveland ClinicCleveland, OH

§ Mark Stolar, MD Associate Professor of Clinical MedicineFeinberg School of Medicine Northwestern UniversityChicago, IL

§ Jeff Unger, MD, FAAFP, FACEAssistant Clinical Professor of Family Medicine UC Riverside School of MedicineDirector, Unger Concierge Primary Care Medical GroupRancho Cucamonga, CA

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Disclosures

§ Rodolfo J. Galindo, MD has no relevant financial relationships to disclose.

§ Javier Morales, MD, FACP, FACE serves on the speakers bureau and as a consultant for Lilly, Novo Nordisk, Janssen, and Abbott.

§ Leann Olansky, MD, FACP, FACE has no relevant financial relationships to disclose.

§ Mark Stolar, MD serves on the speakers bureau for Astra Zeneca.

§ Jeff Unger, MD, FAAFP, FACE serves as a consultant, researcher and advisory board member for Novo Nordisk, Janssen, and Abbott Diabetes.

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Learning Objectives

§ Recognize the pathogenesis of type 2 diabetes (T2D) as a progressive, multi-defect disorder

§ Discuss the strengths and limitations of current guidelines for diabetes management

§ Successfully use strategies for adherence to multiple medications to improve outcomes in diabetes

§ Examine data on current combination strategies to choose therapies that most effectively address a patient’s underlying pathophysiologic needs

PRE-TEST QUESTIONS

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Please rate your confidence in your ability to manage T2D as a multi-defect disorder with individualized combination therapy:

1. Not at all confident2. Slightly confident3. Moderately confident4. Pretty much confident5. Very confident

Pre-test ARS Question 1

Pre-test ARS Question 2How often do you select antidiabetic therapy based on its mechanism of action?

1. Never2. Rarely3. Sometimes4. Often 5. Always

Pre-test ARS Question 3Approximately how many patients with Diabetes do you see on a weekly basis, in any clinical setting?

1. None

2. 1-5

3. 6-10

4. 11-15

5. 16-20

6. 21-25

7. >25 9

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Severity of Glucose Intolerance

Normal GlucoseTolerance

Insulin Resistance

Insulin Secretion

β-Cell Function

DiagnosisImpaired GlucoseTolerance

FPGPPG

Time in Years

By diabetes onset, up to 80% of β-cell function may be lost1,2

Decreasing β-cell function partially driven by incretindefect

PPG=postprandial plasma glucose; FPG=fasting plasma glucose.1. Defronzo RA. Diabetes. 2009;58:773-795. 2. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. Figure adapted from Kendall DM, et al. Am J Med. 2009;122(6 Supp):S37-S50.

Progressive β-Cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2D

ARS Question 4

All of the following are pathophysiologic mechanisms of T2D, EXCEPT:

1. Increased lipolysis

2. Decreased incretin effect

3. Decreased glucagon secretion

4. Increased glucose reabsorption

Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773-795.

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ARS Question 5

According to current AACE and ADA guidelines, which therapy should be considered for a patient with symptoms of hyperglycemia at diagnosis of T2D?

1. Metformin monotherapy

2. Metformin plus 1 other antidiabetic drug

3. Metformin plus 2 other antidiabetic drugs

4. Basal insulin +/- other antidiabetic drugs

2018 ADA Standards of Care in Diabetes

DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione. ADA. Diabetes Care. 2018;41(Suppl. 1):S1–S159.

AACE: Glycemic Control Algorithm

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• Mechanism• Decreased hepatic glucose production. May not be sensitizer.• Decreased intestinal glucose absorption

• Advantages• No weight gain or hypoglycemia

• Disadvantages• Gastrointestinal side effects• Renal function monitoring• GFR<45ml/min/1.73m2è1000mg/day• GFR<30ml/min/1.73m2èdiscontinue

• Vitamin B12 deficiency

Biguanides: Metformin

http://care.diabetesjournals.org/content/34/6/1431.ful accessed July 2015

Discussion Points When Intensifying Pharmacotherapy

§ Tx intensification needed because diabetes is progressive, not because of patient “non-compliance.”

§ Maintaining A1C 6%-6.5% for 4-6 years after diagnosis induces metabolic memory and the legacy effect. Complications are reduced.

§ Tx options are based on disease duration. Longer duration = lower beta-cell mass and function.

§ Frequency, timing and route of administration should be clearly defined.

§ Discuss risks and benefits of all meds prescribed.

§ Excellent composite endpoint would be to achieve target A1C without weight gain or hypoglycemia.

Unger J. Diabetes Management In Primary Care. Lippincott. 2012

Factors to Guide Therapeutic Choices When A1C Not at Goal

Age If younger, durability of therapy/beta-cell impact importantIf older, safety essential

Comorbidity Risks of hypoglycemia Absolute risk of known side effect profile vs reported risk

Mechanism of action

What isn’t being treated currently? What is ineffective?

Clinical clues Acanthosis, low HDL, hypertriglyceridemia markers of insulin resistanceLeaner body weight = likelihood of beta cell dysfunction

SMBG PBG better guide than FBG when A1C <8.0%

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Consequences of Delayed Intervention

At 5.3 years, increased risks:- MI 67% (95% CI: 39%,101%)- Stroke 51% (95% CI: 25%, 83%)- HF 64% (95% CI: 40%, 91%)- Composite CVE 62% (95% CI:

46%, 80%)

8.5

8.0

7.5

7.0

6.5

6 12 54 6048

Months

A1C

%

Patients with A1C ≥7% not receiving IT within 1 year

Patients with A1C <7% who received IT before 1 year of diagnosis

Drives risk for complications

Bad glycemic“legacy”

CVE = cardiovascular endpoint; HF = heart failure; IT = treatment intensification; MI = myocardial infarctionPaul S et al. Cardiovasc Diabetol 2015;14:100 doi:10.1186/s12933-015-0260-x

Add-on Therapy: What Comes After Metformin?

§ Joe was diagnosed with diabetes 1 year ago

§ He was started on metformin when his A1C was 8.0%

§ Despite “trying his hardest” at weight loss and physical activity, his weight is the same and A1C remains 7.5%

§ What factors guide you as to next steps for therapy?

§ Should Joe have started combination therapy at diagnosis? If so, what combination?

Questions to Consider

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Sulfonylureas and GlitinidesAdvantages

§ Cheap

§ Oral

§ Effective for patients with MODY (Monogenetic Diabetes)

Disadvantages

§ Hypoglycemia risk § Elderly and CKD

§ Weight gain

§ Myocardial ischemic preconditioning, increases MI risk after PCI (glyburide)

§ Loss of durability in every clinical trial

§ Glitinides must be taken ½ hour before meals

Unger J. Diabetes Management In Primary Care. Lippincott. 2012

Thiazolidinediones (TZD):PioglitazoneAdvantages

§ No hypoglycemia§ Cheap§ Can prevent progression

of prediabetes to clinical diabetes

§ Durability of effect§ Favorable beta cell

function§ Only muscle and

adipocyte insulin sensitizer

§ May reduce NASH§ Favorable TG and HDL

effects

Disadvantages§ Weight gain

§ Edema

§ Cannot use in patients with HF

§ Bone fractures

§ ? Bladder cancer

DPP-4 InhibitorsAdvantages

• Enhance glucose-dependent insulin secretion

• Decrease inappropriate glucagon secretion**

• Oral, once daily• Very low side effect profile• Weight neutral• No apparent CV risk

(saxagliptin, alogliptin, sitagliptin)

Disadvantages

• Cost• Efficacy• Pancreatitis warning• Durability?• ? Heart failure

(saxagliptin,alogliptin)• Same mechanism but

significantly less efficacy than GLP-1 RA

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GLP-1 Receptor AgonistsAdvantages

• Enhance glucose dependent insulin secretion

• Decrease inappropriate glucagon secretion

• Low risk of hypoglycemia

• Single dose effect on beta cell function

• Superior efficacy compared to orals

• Weight loss

• CVD safety / benefit

Disadvantages• Cost• Injection/injection site

issues• Nausea

• Pancreatitis warning (no longer for liraglutide and dulaglutide)

• MTC warning

GLP-1 RA Pharmacologic Activity Higher with GLP-1 RAs than DPP-4

DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10):2943-2952.

N=61 metformin-treated, evaluable patients

AddedGLP-1 RA

Activity

715

6475

50

25

02-H

our P

ostp

rand

ial P

lasm

a G

LP-1

Con

cent

ratio

n(p

M)

Baseline Sitagliptin once daily

Exenatidetwice daily

EndogenousGLP-1 Activity

2-Hour Plasm

a Exenatide C

oncentration (pM)

0

25

50

75

Plasma GLP-1 Plasma Exenatide

Incretin Therapies to Treat T2DM

Add GLP-1 analogues with longer half-life:

Incretin effect is impaired in T2DNatural GLP-1/GIP have extremely short half-lives

Injectables

Block DPP-4, the enzyme that degrades GLP-1:• Sitagliptin• Saxagliptin• Linagliptin• Alogliptin

Oral agents

Drucker. Curr Pharm Des. 2001;7(14):1399-1412. Drucker. Mol Endocrinol. 2003;17(2):161-171.

Exendin-4 Based:• Exenatide• Exenatide QW• Lixisenatide

Human GLP-1:• Liraglutide• Semaglutide• Dulagutide

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Only About One-third of Patients Are Adherent to GLP-1 RAs

Claims database study of 1321 patients with T2D treated with liraglutide qdAdherence defined as PDC ≥0.8

POORLY ADHERENT ADHERENT

34%Adherent with GLP-1 RA QD over 1 year of treatment

Buysman EK, et al. Adv Ther. 2015;32:341-355.

SGLT 2 InhibitorsAgents Canagliflozin

DapagliflozinEmpagliflozinErtugliflozin

Advantages Effectiveness independent of insulin Low risk for hypoglycemia Small amount of weight lossModest reduction in blood pressurePossible favorable CV/renal outcomes

Disadvantages Adequate renal function/monitoring requiredAmputation risk increasedEuglycemic DKACost

Glucoretic Based Therapies

Diabetes Care 2014;37: S14-79.

Normal Glucose Homeostasis

•Brain ~125 g/d•Rest of the body ~125 g/d

Glucose uptake ~250 g/day:

−

•Dietary intake ~180 g/d•Glucose production ~70 g/d• Gluconeogenesis• Glycogenolysis

+

Net balance ~ 0 g/day

Glucose input ~250 g/day:

Kidney filters circulating glucose

Glucose filtered~180 g/day

Glucose reabsorbed~180 g/day

Kidney reabsorbs

and recirculates glucose

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SGLT-2 Inhibitors: Mechanism of Action (cont)

Juxtoglomerular Complex

Proximal Convoluted

Tubules Loop of Henle

Free Filtration of Solute

Active Reabsorption

Glucose

SGLT-2SGLT-1Glucose

Type 2 Diabetes

EMPA-REG Trial

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.

Patie

nts

With

Ev

ent,

%

EmpagliflozinP=0.04 for superiorityHazard ratio, 0.86 (95.02% CI, 0.74–0.99)

Placebo20

15

5

10

00 126 18 24 30 36 42 48

Cumulative Incidence of the Primary Outcomea

Patie

nts

With

Ev

ent,

%

Empagliflozin

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

Placebo9

3

6

00 126 18 24 30 36 42 48

Cumulative Incidence of Death From CV Causes

Patie

nts

With

Ev

ent,

%

Empagliflozin

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

Placebo76

45

00 126 18 24 30 36 42 48

Month

Hospitalization for Heart Failure

321

38% risk reduction

14% risk reduction

35% risk reduction

Death from a CV event, non-fatal MI, or stroke

Empa 10, 25 mg or standard of care

Empa-Reg Renal Data

Warner C, et al. NEJM. DOI: 10.1056/NEJMoa1515920

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Why Not Use Insulin as Add-on Therapy?

§ Effective means of insulin-providing therapy

§ Most potent A1C reductions

§ Indicated as add-on to monotherapy when A1C above 8.5%

§ Hypoglycemia and weight gain are barriers but insulin itself does not cause weight gain metabolically

§ Bedtime NPH, basal insulin or ultralong-acting basal insulins provide varying cost options as add-on therapy, with differences in hypoglycemia and weight gain

Barriers to Multimolecular Therapy

§ Adherence

§ Hypoglycemia

§ Underutilization of combination meds

Medication Adherence in T2D

§ Medication adherence rates are ~45% among diabetics

§ ~1/3 of all initial prescriptions for glucose-lowering agents go unfilled

§ Non-adherence increases likelihood of long-term complications / negative glycemic legacy and risk of hospitalization

§ Hospitalization risk is 30% at the lowest quintile of adherence vs. 13% in highest quintile

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Improving Patient Adherence§ Discussion between patients and clinicians related to

risk:benefit ratio is critical

§ Choose therapies that reduce risk of hypoglycemia and weight gain § Hypoglycemia risk increases with duration of disease

and age§ Hypoglycemia increases risk of mortality

§ Consider use of drugs that may improve CV outcomes (death from MI, nonfatal MI, stroke, CHF) and/or renal disease progression

§ Decisions that are “patient-centered” are likely to improve clinical outcomes

Garcia-Perez et al. Diabetes Ther. 2013;4:175–194

Meet Edward: A 45 y/o Man with T2D

§ 45 y/o Hispanic male with 2-year history of T2D

§ Currently on metformin 1000 mg BID

§ A1C 7.3% 1 year ago, 7.6% 3 months ago, and 8.0% today

§ Obese (BMI 33.7 kg/m2), sedentary, diet very high in carbohydrates§ Says he is unlikely to modify his lifestyle soon

§ PE: Normal except for acanthosis nigricans

§ SMBG shows average FBG 140mg/d but PBG >200mg/dL

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ARS QuestionWhat Is Happening Physiologically with

Edward?1. Beta-cell function is declining

2. Metformin is not providing adequate insulin sensitivity

3. Lifestyle nonadherence is main reason for his increasing blood glucose

4. Impact on weight is more important than durability of action in choosing next therapy for this patient

5. 1 and 2

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ARS Question: What Would You Add Next?

1. Basal insulin

2. Combination oral agent

3. DPP-4 inhibitor

4. GLP-1 RA

5. Pioglitazone

6. Secretagogue

7. SGLT-2 inhibitor

Andy: 54 y/o with CAD and T2D§ 54 y/o man with 3-year history of T2D

§ Controlled on metformin 850 bid and glimepiride 1 mg

§ A1C has ranged from 7.1% to 7.3%

§ Last year, hospitalized for NSTEMI; found to have grade 1 diastolic dysfunction and grade 1 right carotid bruit that did not require intervention

§ At a recent office visit, A1C had risen to 7.8% with no changes in diet, activity, or weight

§ Reports 2 episodes of hypoglycemia while on the golf course but attributed them to missing lunch

Considerations in Intensifying Therapy in Patients with CAD

§ Impact of hypoglycemia risk on CV risk

§ Impact on cardiometabolic risk factors

§ Impact on CV outcomes (liraglutide, empagliflozin)

§ Impact on CNS/Stroke outcomes (semaglutide, pioglitazone)

§ What’s the best change in therapy for Andy?

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

Hypoglycemia and Cardiovascular Risk

CV Outcomes Trials for GLP-1 RAs

1. Marso SP. N Engl J Med. 2016 Sep 16; 375:311-322 2. PfefferM. N Engl J Med. 2015 Dec 3;373(23):2247-57

Trial Agent Complete

FREEDOM-CVO

Exenatide ICTA650 2016

REWINDNCT01394952 Dulaglutide 2019

EXSCELNCT01144338 Exenatide QW 2017

LEADER1NCT01179048 Liraglutide 2016

ELIXA2NCT01147250 Lixisenatide 2014

SUSTAIN-63NCT01720446 Semaglutide 2016

No increased risk for CV death, heart attack, stroke, unstable angina, or heart failure in people with T2DM and recent acute coronary syndrome with lixisenatide

13 % reduction in first occurrence of death from CV causes, death from any causes, nonfatal MI, or nonfatal stroke with liraglutide

26 % reduction in CV death, nonfatal MI, or nonfatal stroke was significantly lower among patients (at high CV risk) with semaglutide versus placebo

Phase 3 safety trial meets primary & secondary endpoints demonstrating non-inferiority for cardiovascular (CV) safety with exenatide qw / micropump

Shavante: 39 y/o on Multiple Meds§ 39 y/o with 4-year history T2D

§ Had gestational diabetes with last 2 pregnancies but was diabetes-free for 4 years

§ Initially treated with metformin 1000 mg bid, then added glimepiride 4 mg, and finally sitagliptin 100 mg

§ Only has time to exercise 1 day/week; diet is affected by what her kids will eat

§ At last 2 visits, A1C 8.4% and weight stable at 238 lbs

§ Average FBG 130 mg/dL

§ Doesn’t check later in the day because those numbers were too high when she did check

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ARS Question 6 What might be an appropriate next step for Shavante?

1. Add pioglitazone and/or SGLT-2 inhibitor

2. Discontinue all oral agents and initiate basal-bolus insulin

3. Discontinue glimepiride and sitagliptin and start 2 alternative oral antidiabetic agents

4. Enhance adherence by initiating once weekly GLP-1 RA or daily combined basal insulin/GLP-1 RA

1. Buse JB, et al. Diabetes Obes Metab. 2015;17(2):145-151. 2. Holst JJ, Vilsbøll T. Diabetes Obes Metab. 2013;15(1):3-14. 3. Vora J, et al. Diabetes Metab. 2013;39(1):6-15.

Insulin degludec/liraglutide (DEG-LIRA), insulin glargine/lixisenatide (GLAR-LIXI) combinations FDA-approved

GLP-1 RA + Basal Insulin

•Simple to initiate•Can control FPG and PPG•Do not impair α-cell response to hypoglycemia (reduce severe hypoglycemia)

•Reduce weight•Achieve A1C target in ~60%a

•Simple to initiate•Control nocturnal hyperglycemia •Control FPG•Less hypoglycemia risk vs NPH•Can cause weight gain•Achieve A1C target in ~50%a

GLP-1 RAs

Basal insulin

analogs

Recommendations for GLP-1 RA with Basal Insulin

§ GLP-1 RA may be used in combination with basal insulin in patients who do not reach glycemic target with 2-3 glucose-lowering medications1-4

§ If taking a sulfonylurea (SU), consider discontinuing or reducing the dose of SU

§ If adding GLP-1RA to basal insulin, consider reducing basal insulin dose 20% if A1C ≤8.0%§ Thereafter, adjust basal insulin dose based on self-

monitoring of blood glucose especially in first six weeks post insulin dose reduction

§ Monitor for hypoglycemia

1. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. 2. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135. 3. Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87. 4. Garber AJ, et al. Endocr Pract. 2015;21:e1-e10.

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Basal Insulin/GLP-1 RA Fixed-ratio Coformulations

*P<0.001 vs DEG-LIRA; †P<0.001 vs GLAR-LIXI.RCT=randomized controlled trial. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893. 2. Rosenstock J, et al. Diabetologia. 2014;57(suppl 1) [abstract 241]. 3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; Accessed August 23, 2017.

-1.9 -1.8-1.4 -1.6

-1.3-2

-1

0

Chan

ge in

A1

C, %

• ≤ 3 severe hypoglycemic episodes per group• Lower rate of hypoglycemia for LIRA vs DEG or DEG-LIRA (overall and

nocturnal)1

• Lower rate of hypoglycemia for GLAR-LIXI than for GLAR (overall)2,e

LIRADEG-LIRA GLARDEG GLAR-LIXIA1C < 7%, % 81 60* 65* 84 80

-0.5 -1.0

1.6 0.5

-3.0-5

0

5

Chan

ge in

Bo

dy W

eigh

t, kg

DEG-LIRA noninferior to DEG and superior to LIRA (26-week open-label, treat-to-target RCT;

N=1663 [insulin naïve]).1

GLAR-LIXI superior to GLAR (24-week open-label, treat-to-target

RCT; N=323 [insulin naïve]).2

*

*

†

Individual GLP-1 RAs should not be mixed with or injected adjacent

to insulin3

Principles of Multimolecular Therapy§ Metformin remains foundation of therapy but is not

universally effective in all patients, especially those who are insulin deficient

§ Look for untreated mechanistic targets and add accordingly

§ Remove any medications that are not providing expected therapeutic benefit

§ Reconsider pioglitazone for the insulin-resistant patient§ Metformin is NOT the sensitizer we once thought, though very

effective in lowering glucose overall

§ Look to GLP-1 RA and SGLT-2 in insulin-deficient patients and always look to add insulin earlier instead of additional oral agents

POST-TEST QUESTIONS

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After completing this activity, please rate your confidence now in your ability to manage T2D as a multi-defect disorder with individualized combination therapy:

1. Not at all confident2. Slightly confident3. Moderately confident4. Pretty much confident5. Very confident

Post-test ARS Question 1

Post-test ARS Question 2After completing this activity, how often do you intend to select antidiabetic therapy based on its mechanism of action?

1. Never2. Rarely3. Sometimes4. Often 5. Always

Post-test ARS Question 3

All of the following are pathophysiologic mechanisms of T2D, EXCEPT:

1. Increased lipolysis

2. Decreased incretin effect

3. Decreased glucagon secretion

4. Increased glucose reabsorption

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Post-test ARS Question 4

According to current AACE and ADA guidelines, which therapy should be considered for a patient with symptoms of hyperglycemia at diagnosis of T2D?

1. Metformin monotherapy

2. Metformin plus 1 other antidiabetic drug

3. Metformin plus 2 other antidiabetic drugs

4. Basal insulin +/- other antidiabetic drugs

Post-test ARS Question 5: Shavante§ 39 y/o with 4-year history T2D

§ Had gestational diabetes with last 2 pregnancies but was diabetes-free for 4 years

§ Initially treated with metformin 1000 mg bid, then added glimepiride 4 mg, and finally sitagliptin 100 mg

§ Only has time to exercise 1 day/week; diet is affected by what her kids will eat

§ At last 2 visits, A1C 8.4% and weight stable at 238 lbs

§ Average FBG 130 mg/dL

§ Doesn’t check later in the day because those numbers were too high when she did check

Post-test ARS Question 5…Cont’d What might be an appropriate next step for Shavante?

1. Add pioglitazone and/or SGLT-2 inhibitor

2. Discontinue all oral agents and initiate basal-bolus insulin

3. Discontinue glimepiride and sitagliptin and start 2 alternative oral antidiabetic agents

4. Enhance adherence by initiating once weekly GLP-1 RA or daily combined basal insulin/GLP-1 RA