for dipeptidyl peptidase 4 inhibitor (dpp-4i) cardiovascular · 2019-04-15 · for dipeptidyl...

For dipeptidyl peptidase 4 inhibitor (DPP-4i) cardiovascular outcomes trials (CVOTs), all trials met the primary goal of demonstrating that there is no increased risk of cardiovascular disease (CVD).

A. True

B. False

3

For the sodium-glucose cotransporter 2 inhibitor (SGLT-2i) CVOTs, all trials met the primary goal of demonstrating that there is no increased risk of CVD.

A. True

B. False

4

SGLT-2i CVOTs included which of the following results:

A. Met the primary goal of demonstrating that there is no increased risk of CVD

B. Useful for evaluating other potentially beneficial effects of the drugs

C. More precise estimates of the risk of other rare events

D. All of the above

5

Lower rates of acute renal failure and kidney injury were reported in which of the following trials?

A. EMPA-REG (empagliflozin)

B. HARMONY (albiglutide)

C. DECLARE-TIMI (dapagliflozin)

D. ELIXA (lixisenatide)

6

In the glucagon-like peptide 1 (GLP-1) CVOTs, which of the following demonstrated a benefit on major adverse cardiovascular events (MACE) and mortality?

A. Lixisenatide and semaglutide

B. Liraglutide and exenatide

C. Lixisenatide and exenatide

D. Liraglutide, semaglutide, and albiglutide

7

Which class of medication is preferred in the American Diabetes Association/European Association for the Study of Diabetes(ADA/EASD) type 2 diabetes mellitus (T2DM) algorithm for patients with T2DM and heart failure (HF)?

A. Thiazolidinediones (TZDs)

B. GLP-1 receptor agonists

C. SGLT-2 inhibitors

D. DPP-4 inhibitors

8

A New Look at Current Clinical Guidelines, CVOTs, and Evidence-Based Treatment Options

Richard Pratley, MD AdventHealth

Samuel E. Crockett Chair in Diabetes Research,

Medical Director,

AdventHealth Diabetes Institute

Senior Investigator and Diabetes Program Lead,

Translational Research Institute for Metabolism

and Diabetes

Orlando, Florida

Disclosure: Richard Pratley, MD

Consulting fee

▪ AstraZeneca, GlaxoSmithKline, Glytec, Janssen, Ligand, Lilly, Merck, Mundipharma, Novo, Pfizer, and Sanofi

Speaker’s bureau

▪ Novo

Received grant funding

▪ Janssen, Lexicon, Ligand, Lilly, Merck, Novo, and Sanofi

All honoraria and fees from these activities are paid to AdventHealth, a non-profit organization.

Dr. Pratley does not receive any direct or indirect compensation.

Overview: The New Era of Diabetes Treatment

▪ Rationale for CVOTs in diabetes mellitus

▪ Cardiovascular safety of new diabetes drugs: evidence to date

▪ TZDs

▪ DPP-4is

▪ SGLT-2is

▪ GLP-1 receptor agonists (GLP-1RAs)

▪ Insulin

▪ Implications of CVOTs for clinical practice

AACE, ACP, and ADA: Recommended Glycemic Targets

▪ AACE: An A1C level of ≤6.5% (optimal, if achieved in a safe, affordable manner; higher targets may be appropriate for certain individuals and may change for a given individual over time)

▪ ADA: An A1C goal of <7% for nonpregnant adults

▪ More stringent A1C goals (eg, <6.5%) may be appropriate for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects

▪ Less stringent A1C goals (eg, <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, and advanced micro- or macrovascular complications

▪ ACP: An HbA1c level of 7% to 8% in most patients with T2DM

▪ Personalize glycemic control goals based on discussion of benefits/harms of pharmacotherapy; patients' preferences, general health, and life expectancy; treatment burden; and costs of care

▪ Consider deintensifying pharmacologic therapy in patients with T2DM who achieve HbA1c of <6.5%

AACE=American Association of Clinical Endocrinologists. ACP=American College of Physicians. ADA=American Diabetes Association .

American Diabetes Association. Diabetes Care. 2019;42(suppl 1):S1-S193.

Garber AJ, et al. Endocr Pract. 2019;25(1):69-100.

Qaseem A, et al. Ann Intern Med. 2018;168(8):569-576.

Complementary Mechanisms of Action of Current Diabetes Medications

TZDs

Bromocryptine

SGLT-2is

Metformin

GLP-1RA DPP-4is

InsulinSulfonylureasMeglitinides

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

Islet b-cell

Impaired insulin secretion

Neurotransmitter dysfunction

Decreased glucose uptake

Islet a -cell

Increased glucagonsecretion

Increased lipolysis

Increased glucosereabsorption

Increased HGP

Decreasedincretin effect

Hyperglycemia

GLP-1RA, DPP-4is

HGP=hepatic glucose production.

2008 FDA Guidance for Industry on Evaluating the CV Risk of New Antidiabetic Therapies

For completed studies prior to NDA

▪ Integrated meta-analysis of phase 2/3 trials to compare CV events in patients randomized to investigational drug vs control

▪ Demonstrate new therapy will not result in an unacceptable CV risk

▪ Evaluated by MACE

▪ Estimated risk ratio for upper bound of the 2-sided CI for the investigational drug should be <1.8

▪ If upper CI=1.3-1.8, postmarketing CV surveillance trial may be required

CV=cardiovascular. NDA=New Drug Application. CI=confidence interval.

Traditional CVOTs vs Diabetes CV Safety Trials

Traditional (eg, LDL-C) CV Outcome TrialsDesigned to Demonstrate CV Benefit

Diabetes CV Safety TrialsPrimarily Designed to Demonstrate CV Safety

Lower CV risk vs placebo or active comparator

Difference in LDL-C between treatment and placebo or active comparator

CV benefit of treatment demonstrated by significant reduction in CV outcomes

No adjustmentto maintain

LDL-C levels the same

in both groups

No increased CV risk vs placebo as part of standard care

Small or no difference in HbA1cbetween treatment and placebo

No increased CV risk (CV safety)of treatment demonstrated by noninferiority

Adjustmentto maintain

HbA1c levels the same in both groups

Initiation of blinded treatment or placebo or active comparator Initiation of blinded treatment or placebo

LDL-C=low-density lipoprotein cholesterol.

Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7-22. Collins R, et al; Heart Protection Study Collaborative Group. Lancet.

2003;361(9374):2005-2016. White WB, et al. N Engl J Med. 2013;369(14):1327-1335. Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. Green JB, et al.

Am Heart J. 2013;166(6):983-989.

–

Multiple Drug Classes Evaluated for T2DM With CV Risk

20192015 20202013 2014 2016 2017 2018 2021 2022

DEVOTE(Insulin degludec, insulin)

n=7637; duration ~2 years

Q2 2017–RESULTS

EMPA-REG OUTCOME(Empagliflozin, SGLT-2i)

n=7000; duration up to 5 years Q3 2015–RESULTS

CANVAS(Canagliflozin, SGLT-2i)

n=4418; duration 4+ years

Q2 2017–RESULTS

DECLARE-TIMI 58(Dapagliflozin, SGLT-2i)

n=17,276; duration ~6 years

Q3 2018–COMPLETED

CANVAS-R(Canagliflozin, SGLT-2i)


Q2 2017–RESULTS

CREDENCE (cardio-renal)(Canagliflozin, SGLT-2i)

n=4464; duration ~5.5 years Q3 2018–CANCELLED

(+ve efficacy)

EXAMINE(Alogliptin, DPP-4i)

n=5380; follow-up ~1.5 yearsQ3 2013–RESULTS

SAVOR-TIMI 53(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 years

Q2 2013–RESULTS

TECOS(Sitagliptin, DPP-4i)

n=14,671; duration ~3 years

Q4 2014–RESULTS

CARMELINA(Linagliptin, DPP-4i)

n=7003; duration ~4 years Q3 2018–RESULTS

ALECARDIO(Aleglitazar, PPAR-αγ) n=7226;

follow-up 2 yearsTermin. Q3 2013–RESULTS

ELIXA(Lixisenatide, GLP-1RA)

n=6068; follow-up ~2 years

Q1 2015–RESULTS

FREEDOM (ITCA 650, GLP-1RA

in DUROS®)n=4000; duration ~2 years

Q2 2016–TOPLINE RESULTS

EXSCEL(Exenatide ER, QW GLP-1RA)

n=14,752; follow-up ~3 years

Q3 2017–RESULTS

LEADER(Liraglutide, GLP-1RA)

n=9340; duration 3.5-5 yearsQ2 2016–RESULTS

HARMONY OUTCOMES(Albiglutide, QW GLP-1RA)n=9574; duration ~4 years

Q3 2018–RESULTS

SUSTAIN 6(Semaglutide, QW GLP-1RA)

n=3297; duration ~2.8 yearsQ3 2016–RESULTS

CAROLINA(Linagliptin, DPP-4i vs SU)n=6103; duration ~8 years

Completion Q1 2019

TOSCA IT(Pioglitazone, TZD)


Q4 2017†–RESULTS

ACE(Acarbose, AGI)


Q2 2017–RESULTS

REWIND(Dulaglutide,

QW GLP-1RA)n=9622;

duration ~6.5 yearsCompletion Q3 2018

PIONEER 6(Oral semaglutide, GLP-1RA)n=3176; duration ~1.5 years

Completion Q4 2018

AMPLITUDE-O(Efpeglenatide, QW GLP-1RA)

n=4000*; duration ~3 yearsCompletion Q2 2021

VERTIS CV(Ertugliflozin, SGLT-2i)


Completion Q3 2019

SCORED(Sotagliflozin, SGLT-1i,

and SGLT-2i)n=10,500*; duration ~4.5 years

Completion Q1 2022

SOLOIST-WHF (Sotagliflozin , SGLT-1i,

and SGLT-2i)n=4000; duration ~2.7 years

Completion Q1 2021

Insulin

SGLT-2i

GLP-1RA

DPP-4i

TZD

AGI

PPAR-αγ

ClinicalTrials.gov. Accessed 08 October 2018.

*Estimated enrolment. †Stopped early after a median follow-up of 57.4 months following futility analysis. Trials with filled boxes are completed. Trials with a white background are ongoing. AGI=alpha-glucosidase inhibitor. DUROS®=subcutaneous delivery system. ER=extended release. ITCA 650=continuous subcutaneous delivery of exenatide. PPAR-αγ=peroxisome proliferator‐activated receptors-α and γ. QW=once weekly. SU=sulphonylurea.

DPP-4 Inhibitors

Median Duration of Follow-Up

Randomization Year 3Year 2Year 1

SAVOR-TIMI 53Primary Endpoint

CV death,

nonfatal MI, or nonfatal stroke

Saxagliptin

Placebo

CVD or CRF

A1C 6.5–12.0%

n=16,492

1.00 (95% CI

0.89, 1.12)

P=.99

Median

follow-up2.1 years

EXAMINE

CV death,


Alogliptin

Placebo

ACS

A1C 6.5–11.0%

n=5380

Median

follow-up1.5 years

0.96(upper boundary of 1-sided

repeated CI 1.16)

P=.315

TECOS

CV death,

nonfatal MI, or nonfatal stroke, or UA requiring

hospitalization

Sitagliptin

Placebo

CVD

A1C 6.5–8.0%

n=14,735

Median

follow-up3 years

0.98(95% CI 0.88, 1.09)

P=.645

for superiority

0.99(95% CI 0.89, 1.10)

P=.84for superiority

CV death,


CVOTs for DPP-4is

CRF=chronic renal failure. ACS=acute coronary syndrome.

Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. White W, et al. N Engl J Med. 2013;369(14):1327-1335. Green JB, et al. N Engl J Med.

2015;373(3):232-242.

CARMELINA Trial of Linagliptin: Impact on CV Safety and Kidney Outcomes

12.4%

9.4%

6.0%

12.1%

8.8%

6.5%

CV Death, Nonfatal MI, Nonfatal Stroke Decline in Kidney Function Hospitalization for HF

Patients (%) With CV Events, Decline in Kidney Function, or Hospitalization for HF–Linagliptin Compared to Placebo Added to Standard of Care. N=6980 Patients Randomized 1:1.

Linagliptin

Placebo

Data demonstrate no impact on CV, HF, or renal events, even in those who already

have kidney disease, when linagliptin is added to standard-of-care therapy. MI=myocardial infarction.

Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T,

George JT, von Eynatten M, McGuire DK; CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular

and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019 Jan 1;321(1):69-79. doi:10.1001/jama.2018.18269. PubMed PMID: 30418475

CAROLINA Trial of Linagliptin and Glimepiride

▪ The largest head-to-head comparison of an SU and a DPP-4i

▪ Randomized 6041 patients with relatively early T2DM and increased CV risk or with established CV complications to once-daily therapy with either linagliptin 5 mg or glimepiride 1-4 mg, in addition to standard of care

▪ Met its primary endpoint, defined as non-inferiority for linagliptin versus glimepiride in time to first occurrence of CV death, non-fatal MI or non-fatal stroke (3P-MACE)

Santamarina M and Carlson C. BMC Cardiovasc Disord. 2019;19(1):60.

SGLT2 Inhibitors

EMPA-REG Trial of Empagliflozin, an SGLT-2i: Main Results

Pa

tie

nts

With

Eve

nt, %

Empagliflozin

P=.04 for superiority

HR, 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

Pa

tie

nts

With

Eve

nt, %

Empagliflozin

P<.001

HR, 0.62 (95% CI, 0.49-0.77)

9

3

6

00 126 18 24 30 36 42 48

Cumulative Incidence of Death From CV Causes

Pa

tie

nts

With

Eve

nt, %

Empagliflozin

P=.002

HR, 0.65 (95% CI, 0.50-0.85)

Placebo76

45

00 126 18 24 30 36 42 48

Month

Hospitalization for Heart Failure

321

aCumulative incidence of death from CV causes, nonfatal MI, or nonfatal stroke.

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

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

Placebo

Empagliflozin

Placebo

Empagliflozin Placebo HR (95% CI) P Value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* .0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <.0001

Nonfatal MI 213/4687 121/2333 0.87 (0.70, 1.09) .2189

Nonfatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) .1638

EMPA-REG Trial of Empagliflozin, an SGLT-2i: CV Death, MI, and Stroke

Favors empagliflozin Favors placebo

0.25 0.50 1.00 2.00

Patients With Event/Analyzed

-

*95.02% CI. Cox regression analysis.

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

EMPA-REG Trial of Empagliflozin, an SGLT-2i: Renal Outcomes

▪ Lower rates of acute renal failure and kidney injury (5.2% vs 6.6% and 1.0% vs 1.6%, respectively; P<.05 vs placebo)

▪ A1C reduction of -0.52% to -0.68% vs placebo in CKD stages 2-3 (eGFR ≥30 to <90 mL/min/1.73 m2; P<.0001)

▪ Equivalent adverse event rates as placebo in patients in CKD stages 2-3

CANVAS Trial of Canagliflozin: Primary MACE Outcome

Neal B, et al. N Engl J Med. 2017 Jun 12.

20

18

16

14

12

10

8

6

4

2

00 1 2 3 4 5 6

Pa

tie

nts

With a

n E

ve

nt

(%)

Years Since Randomization

HR=0.86

95% CI (0.75-0.97)

P<0.0001 for noninferiority

P<0.0158 for superiority

Number of Patients

Placebo 4347 4153 2942 1240 1187 1120 789

Canagliflozin 5795 5566 4343 2555 2460 2363 1661

Placebo

Canagliflozin

CANVAS Trial of Canagliflozin: MACE Components and HF

HR (95% CI)

0.5 1.0 2.0

Primary CV outcome 0.86 (0.75-0.97)

CV death 0.87 (0.72-1.06)

Nonfatal MI 0.85 (0.69-1.05)

Nonfatal stroke 0.90 (0.71-1.15)

HHF 0.67 (0.52-0.87)

CV death or HHF 0.78 (0.67-0.91)

All-cause mortality 0.87 (0.75-1.01)

Favors canagliflozin Favors placebo

HHF=hospitalization for heart failure.

Neal B, et al. N Engl J Med. 2017;377(7):664-657.

DECLARE-TIMI 58 Trial of Dapagliflozin: Primary Outcomes

0 180 360 540 720 900

6%

4%

2%

0%1080 1260 1440

4.9% vs 5.8%

HR 0.83 (0.73-0.95)

P=0.005 for superiority

Pro

bab

ility

of e

ve

nt

CVD/HHF

Analysis time (days)

Dapagliflozin

0 180 360 540 720 900

6%

4%

2%

0%1080 1260 1440

10%

8.8% vs 9.4%

HR 0.93 (0.84-1.03)



Pro

bab

ility

of e

ve

nt

MACE

Analysis time (days)

Primary Endpoints

Placebo

DECLARE-TIMI 58 Trial of Dapagliflozin: CVD and HHF

Effect on CVD/HHF in Key Subgroups

P-

60-<90 mL/min/1.73m2

Favors dapaglif lozin Favors placebo

HR (95% CI)

ASCVD=atherosclerotic cardiovascular disease. MRF=multiple risk factors

CVD-REAL Study: SGLT-2 Inhibition Lowers the Risk of HF and Death in Real-World Analyses

oGLD=other glucose-lowering drug.

Kosiborod M, et al. Circulation. 2017;136(3):249-259.

Hazard Ratio

P-Value for SGLT-2i vs oGLD Comparison: <0.001P-Value for Heterogeneity: 0.169

Favors SGLT-2i Favors oGLD

0.05 0.10 0.25 0.50 1.00 2.00

US Truven Market ScanN=233,798; # of events=298 0.55 (0.44, 0.69)

Norway National RegistersN=25,050; # of events=278

0.62 (0.49, 0.79)

Denmark National RegistersN=18,468; # of events=167

0.77 (0.59, 1.01)

Sweden National RegistersN=18,378: # of events=191

0.61 (0.45, 0.82)

UK CPRD/THINN=10,462; # of events=16

0.36 (0.12, 1.13)

Germany DPVN=2900; # of events=11

0.14 (0.03, 0.68)

Total 0.61 (0.51, 0.73)

Hospitalization for HF

CVD-REAL Study: SGLT-2 Inhibition Lowers the Risk of HF and Death in Real-World Analyses (cont.)

Kosiborod M, et al. Circulation. 2017;136(3):249-259.

Hazard Ratio

P-Value for SGLT-2i vs oGLD Comparison: <0.001P-Value for Heterogeneity: 0.089

Favors SGLT-2i Favors oGLD

0.25 0.50 1.00 2.00

US Truven Market ScanN=143,264; # of events=250 0.38 (0.29, 0.50)

Norway National RegistersN=25,050; # of events=364

0.55 (0.44, 0.68)

Denmark National RegistersN=18,468; # of events=323

0.46 (0.37, 0.57)

Sweden National RegistersN=18,378: # of events=317

0.47 (0.37, 0.60)

UK CPRD/THINN=10,462; # of events=80

0.73 (0.47, 1.15)

Total 0.49 (0.41, 0.57)

All-Cause Death

GLP-1 Receptor Agonist

Time to First Occurrence of the Primary CV Event: CV Death,Nonfatal MI, Nonfatal Stroke or Hospitalization for UA

ELIXA Study of Lixisenatide: Primary Composite EndpointP

atie

nts

With E

ve

nt (%

)

0

5

10

15

20

0 12 24 36

Lixisenatide: 406/3034=13.4%

Placebo: 399/3034=13.2%

HR=1.02 (0.89, 1.17)

Months

30343034

27592785

15661558

476484

Number at riskPlacebo

Lixisenatide

32

UA=unstable angina.

1. Clinicaltrials.gov. Available at clinicaltrials.gov/ct2/show/NCT01147250. Accessed May 2015. 2. Pfeffer MA, et al. The Evaluation of Lixisenatide in Acute Coronary Syndrome — The Results of ELIXA. Session 3-CT-SY28 Presented at: American Diabetes Association (ADA) 75th Scientif ic Sessions; June 5-9, 2015; Boston.

ELIXA Study of Lixisenatide: Primary Outcome

OutcomeLixisenatide

n=3034Placebo n=3034

HR (95% CI)

Primary outcome (CV death, nonfatal MI, nonfatal stroke, or hospitalization for UA)

13.4% 13.2%1.02

(0.89-1.17)

Primary outcome plus HHF 15% 15.5%0.97

(0.85-1.10)

HHF 4.0% 4.2%0.96

(0.75-1.23)

All-cause mortality — —0.94

(0.78-1.13)

Patients followed for a mean of 2.1 years.

Pfeffer MA, et al. The Evaluation of Lixisenatide in Acute Coronary Syndrome — The Results of ELIXA. Presented at: American Diabetes Association (ADA) 75th Scientif ic Sessions; Session 3-CT-SY28. June 5-9, 2015; Boston, MA.

LEADER Trial of Liraglutide: Primary and Secondary Outcomes

0 6 12 18 24 30 36

Patie

nts

With E

ve

nt (%

)

Months Since Randomization

HR=0.87

95% CI (0.78-0.97)P<0.001 for noninferiorityP=0.01 for superiority

Placebo

Liraglutide

42 48

20

15

10

5

054 0 6 12 18 24 30 36

HR=0.78

95% CI (0.66-0.93)P=0.007

42 48

20

15

10

5

054 0 6 12 18 24 30 36

HR=0.85

95% CI (0.74-0.97)P=0.02

42 48

20

15

10

5

054

*Composite of death from CV causes, nonfatal MI, or nonfatal stroke.N=9340 patients with T2DM and high CV risk.

Marso SP, et al. N Engl J Med. 2016;375(4):311-322.

Primary Outcome a CV-Related Death Death from Any Cause

LEADER Trial of Liraglutide: Time to First Renal Event

46684672

46354643

45614540

44924428

Number at riskLiraglutide

Placebo44004316

43044196

42104094

41143990

16321613

454433

0 6 12 18 24 30 36 42 48

10

6

4

2

054

8

Patie

nts

With E

ve

nt (%

)

Placebo

Liraglutide

HR 0.78

95% CI (0.67-0.92)P=0.003

Macroalbuminuria, Doubling of Serum Creatinine, ESRD, Renal Death

Time Since Randomization (Months)

Mann J. Microvascular outcomes, in Buse J, et al. Results of the liraglutide effect and action in diabetes - evaluation of cardiovascular outcome results (LEADER) trial. Presented at the American Diabetes Association 76th Scientif ic Sessions, Session 3-CT-SY24. June 13, 2016, New Orleans, LA.

The cumulative incidences were estimated with the use of the Kaplan-Meier method, and the HRs with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. ESRD=end-stage renal disease.

SUSTAIN 6 Trial of Semaglutide: Primary Outcomes

Marso SP, et al. N Engl J Med. 2016;375:1834-1844.

Pa

tie

nts

With E

vent

(%)

0 8 16 24 40 56 72 88 104

100

60

40

20

0

80

32 48 64 80 96 109

0 8 16 24 40 56 72 88 104

10

6

4

2

0

8

32 48 64 80 96 109

Weeks Since Randomization

16491648

16161619


Semaglutide15861601

15671584

15341568

15081543

14791524

HR 0.74; 95% CI (0.58-0.95)P<0.001 for noninferiority


Primary Outcome

Placebo

Semaglutide

SUSTAIN 6 Trial of Semaglutide: Secondary Outcomes

Marso SP, et al. N Engl J Med. 2016;375:1834-1844.

Pa

tie

nts

With E

vent

(%)

0 8 16 24 40 56 72 88 104

100

60

40

20

0

80

32 48 64 80 96 109

0 8 16 24 40 56 72 88 104

5

3

2

1

0

4

32 48 64 80 96 109


16491648

16241623


Semaglutide15981609

15871595

15621582

15421560

15161543

HR 0.74; 95% CI (0.51-1.08)P=0.12

Nonfatal MIP

atie

nts

With E

vent

(%)

0 8 16 24 40 56 72 88 104

100

60

40

20

0

80

32 48 64 80 96 109

0 8 16 24 40 56 72 88 104

5

3

2

1

0

4

32 48 64 80 96 109


16491648

16291630


Semaglutide16111619

15971606

15711593

15481572

15281558

HR 0.61; 95% CI (0.38-0.99)P=0.04

Nonfatal Stroke Pa

tie

nts

With E

vent

(%)

0 8 16 24 40 56 72 88 104

100

60

40

20

0

80

32 48 64 80 96 109

0 8 16 24 40 56 72 88 104

5

3

2

1

0

4

32 48 64 80 96 109


16491648

16371634


Semaglutide16231627

16171617

16001607

15841589

15661579

HR 0.98; 95% CI (0.65-1.48)P=0.92

Death From CV Causes

Placebo

Semaglutide

EXSCEL Trial of Exenatide QW: Primary Outcomes

0 1 2 3 4 5

18

16

12

6

0

9

3

HR 0.91; 95% CI (0.83-1.00)



Pa

tie

nts

With E

vent

(%)

Primary Outcome (3-Point MACE)

Time Since Randomization (Years) Placebo

Exenatide QW

Holman RR, et al. N Engl J Med. 2017;377(13):1228-1239.

EXSCEL Trial of Exenatide QW: Secondary Outcomes

Holman RR, et al. N Engl J Med. 2017;377:1228-1239.

0 1 2 3 4 5

18

16

12

6

0

9

3

HR 0.86; 95% CI (0.77-0.97)

Pa

tie

nts

With E

vent

(%)

Death From Any Cause

Time Since Randomization (Years)

Pa

tie

nts

With E

vent

(%)

0 1 2 3 4 5

18

16

12

6

0

9

3

HR 0.88; 95% CI (0.76-1.02)


Death From CV Causes

0 1 2 3 4 5

18

16

12

6

0

9

3

HR 0.94; 95% CI (0.78-1.13)

Pa

tie

nts

With E

vent

(%)


HHF

Placebo

Exenatide QW

HARMONY Trial of Albiglutide: Primary Outcome

HR 0.78; 95% CI (0.68-0.90)

Event rate per 100 person-years: albiglutide 4.57; placebo 5.87



Time to First Occurrence of CV Death,

Nonfatal MI, or Nonfatal Stroke

Time From Randomization (Years)

0 4 8 12 16 20 24

10

16

14

12

0

8

6

4

2

28

Number at risk

Albiglutide

Placebo

4731 4503 3148 1064

4732 4460 3074 1030

4613

4603

4239

4208

2142

2077

—

—

Randomization(1:1)

Placebo QW + standard of care

Albiglutide 30 mg* QW+ standard of care

End of Treatment

Safety follow-up

Safety follow-up

Treatment period: Assessed every 4 months (clinic visit)†

5 weeks

Study Design and Inclusion Criteria

9463 patients

▪ T2DM, ≥40 years old with HbA1c >7.0%

▪ Established CVD

Primary endpoint

▪ Time from randomization to first occurrence

of a MACE, defined as CV death, nonfatal MI,

or nonfatal stroke

Hernandez AF, et al. Lancet. 2018; 392(10157):1519-1529.

HARMONY Trial of Albiglutide: Secondary Outcomes

Albiglutide

(N=4731)

Placebo

(N=4732) HR (95% CI) P-Value†

3-point MACE (primary outcome)

338 428 0.78 (0.68-0.90)<0.0001, 0.0006

4-point MACE* 373 468 0.78 (0.69-0.90) 0.0005

CV death 122 130 0.93 (0.73-1.19) 0.578

Myocardial infarction 181 240 0.75 (0.61-0.90) 0.003

Stroke 94 108 0.86 (0.66-1.14) 0.300

CV death or HHF 188 218 0.85 (0.70-1.04) 0.113

All-cause death 196 205 0.95 (0.79-1.16) 0.644

Favors albiglutide

0.5 1.0 1.5 2.0

Favors placebo

*CV death, MI, stroke, and urgent revascularization for UA. †Data for the primary outcome are the P-value for noninferiority, P-value for superiority; all other P-values are nominal P-values for superiority.

Hernandez AF, et al. Lancet. 2018; 392(10157):1519-1529.

Putting the Mortality Rates From EMPA-REG and LEADER Trials Into Perspective

-40

-30

-20

-10

0

% D

ecre

ase

in M

ort

alit

y

ARB*

ACE

inhibitor†

Beta

blocker‡ MRA§

ARB +

neprilysin

inhibitor|| Empagliflozin¶ Liraglutide#

Study

duration (months)

38 41 10-12 21-24 27 36 46

ACE=acetylcholinesterase. ARB=angiotensin II receptor blocker. MRA=mineralocorticoid receptor antagonist.*SOLVD Treatment. †CHARM Alternative. ‡COPERNICUS and MERIT-HF. §RALES and EMPHASIS-HF. | |PARADIGM. ¶EMPA-REG OUTCOME. #LEADER.

Fitchett DH, et al. Eur J Heart Fail. 2016;19(1):43-53.

Established ASCVD or CKD

Glucose-Lowering Medication in T2DM: Overall Approach

First-line therapy is metformin and comprehensive lifestyle (including weight

management and physical activity); if HbA1c above target, proceed as below

To avoid clinical inertia, reassess and

modify treatment regularly

(3-6 months)

AS

CV

D

pre

do

min

ate

s GLP-1RA with proven CVD benefit*

SGLT-2i with proven CVD benefit*, if eGFR adequate†

EITHER/OR

If further intensification is required or patient is now unable to tolerate GLP-1RA and/or SGLT-2i, choose agents demonstrating CV safety

▪ Consider adding the other class (GLP-1RA or SGLT-2i) with provenCVD benefit*

▪ DPP-4i not on GLP-1RA

▪ Basal insulin‡

▪ TXD§

▪ SU||

HF

or

CK

D

pre

do

min

ate

s

▪ Avoid TZD in the setting of HF

Choose agents demonstrating CV safety

▪ Consider adding the other class with proven CVD benefit*

▪ DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1RA)

▪ Basal insulin‡

▪ SU‡

PREFERABLYSGLT-2i with evidence of reducing HF and/or CKD

progression in CVOTs if eGFR adequate||

ORIf SGLT-2i not tolerated or contraindicated or if eGFR less than adequate†, add GLP-1RA with proven CKD benefit*

if HbA1c above target


*Proven CVD benefit means it has label indication of reducing CVD events. For GLP-1RA strongest evidence for liraglutide > semaglutide > exenatide extended release. For SGLT-2i evidence modestly stronger for empaglif lozin > canaglif lozin. †Be aw are that SGLT-2is vary by region and individual agents w ith regard to indicated level of eGFR for initiation and continued care. | |Both empaglif lozin and canaglif lozin have show n reduction in HF and reduction in CKD progression in CVOTs. ‡Degludac or U100 glargine, have demonstrated CVD safety.§Low dose may be better tolerated, though less w ell-studied for CVD effects.

Glucose-Lowering Medication in T2DM: Overall Approach (cont.)C

om

pe

llin

g n

ee

d to

m

inim

ize

hy

po

gly

ce

mia

DPP-4i

GLP-1RA

SGLT-2i

TZD

SGLT-2i* OR TZD

SGLT-2i* ORDPP-4i ORGLP-1RA





SGLT-2i* OR TZD

GLP-1RA ORDPP-4i OR TZD


Consider the addition of SU4 OR basal insulin

▪ Choose later generation SU with lower risk of hypoglycemia

▪ Consider basal insulin with lower risk of hypoglycemia†


Continue with addition of

other agents as outlinedto the left

Without Established ASCVD or CKD





(3-6 months)

*Be aw are that SGLT-2is vary by region and individual agents w ith regard to indicated level of eGFR for initiation and continued care. †Degludac/glargine U300 <glargine U100/detemir <NPH insulin.

Glucose-Lowering Medication in T2DM: Overall Approach (cont.)

Without Established ASCVD or CKD





(3-6 months)

If DPP-4i not tolerated if

contraindicated or patient already on

GLP-1RA, cautious addition of SU‡,

TZD‡, basal insulin

Co

st is

a m

ajo

r is

su

e**

††

Co

mp

ellin

g

ne

ed

to

m

inim

ize

w

eig

ht g

ain

o

r p

rom

ote

w

eig

ht lo

ss

GLP-1RA withgood efficacy for

weight loss*

SGLT-2i†

EITHER/OR

SGLT-2i†



If triple therapy required or SGLT-2i and/or GLP-1RA not tolerated or contraindicated, use regimen with lowest risk

of weight gainPREFERABLY

DPP-4i (if not on GLP-1RA) based on weight neutrality

GLP-1RA with good efficacy

for weight loss*


TZD§


Insulin therapy basal insulin with lowest acquisition cost

OR

Consider DPP-4i OR SGLT-2i with lowest acquisition cost§SU‡


SU‡

TZD§

* Semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide. †Be aw are that SGLT-2is vary by region and individual agents w ith regard to indicated level of eGFR for initiation and continued care. ‡Choose later generation SU to low er risk of hypoglycemia.§Consider country- and region-specif ic cost of drugs.

48

Summary

▪ Completed long-term CV safety trials have demonstrated no increased risk of CV events associated with newer anti-hyperglycemic agents

▪ DPP-4is not associated with an increased overall risk

▪ Potential for increased HF risk with some DPP-4is

▪ The LEADER trial (liraglutide), SUSTAIN-6 trial (semaglutide) and HARMONY trial (albiglutide) demonstrated CV benefit, whereas ELIXA (lixisenatide) EXSCEL and FREEDOM (exenatide) did not

▪ Label for liraglutide updated to reflect this

▪ The EMPA-REG Outcomes Trial (empagliflozin) and CANVAS (canagliflozin) demonstrated a CV benefit, decreased mortality (empagliflozin), and less HHF

▪ Label for empagliflozin recently updated to reflect this

▪ The DECLARE trial( Dapagliflozin) showed a benefit in its primary endpoint of decrease in Heart failure hospitalization as well as showing a decrease in progression of renal disease

▪ Guidelines are evolving rapidly to reflect the new evidence

www.tri-md.comwww.floridahospitaldiabetes.com

@FH_TRI_MD@RpratleyMD

Connect!

[email protected]

Please write your question on a question card and hand it to a staff member.

Cases in T2DM and Related Comorbidities

Neil Skolnik, MD Professor of Family and Community Medicine,Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphia, PennsylvaniaAssociate Director,Family Medicine Residency Program Abington Jefferson HealthJenkintown, Pennsylvania

Disclosure: Neil Skolnik, MD

Advisory board

▪ AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, Lilly, Mylan, and Teva

Speaker’s bureau

▪ AstraZeneca and Boehringer Ingelheim

Contracted research

▪ AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi

Case 1: Samantha

▪ 63-year-old woman with a 10-year history of T2DM who presents for routine follow-up and to go over labs

▪ Denies CP or SOB

▪ States that she has rare hypoglycemic episodes during which she feels her heart beating quickly and feels nauseated; when she checked her blood sugar it was 57

▪ Episodes resolve with eating a candy bar or drinking juice; occurring about once a month

▪ PMH: T2DM, HTN, hyperlipidemia

▪ Meds: metformin 1000 mg bid, glipizide 5 mg daily, lisinopril 10 mg daily, atorvastatin 20 mg daily, aspirin 81 mg daily

CP=chronic pancreatitis. HTN=hypertension. PMH=past medical history. SOB=shortness of breath.

Case 1: Samantha (cont.)

Physical exam

▪ General–alert, interactive

▪ Lungs–clear

▪ CV–RRR without murmurs

▪ Ext–no edema

▪ Feet–good pulses, sensation intact

Labs: CMP=WNL, Cr=1.2 (eGFR=60); A1C=6.8; LDL-C=92; urine Alb/Cr ratio=93 (normal 0-30)

Alb=albumin. CMP=comprehensive metabolic panel. Cr=creatinine. Ext=external. RRR=regular rate and rhythm. WNL=w ithin normal limits.

What Is Samantha’s A1C Goal?

A. Less than 8

B. Less than 7.5

C. Less than 7.0

D. Less than 6.5

What Do You Recommend Next?

A. Continue current medications

B. Add an SGLT-2i

C. Stop glipizide and add an SGLT-2i

D. Stop glipizide and add a GLP-1RA

Case 2: Raquel

▪ 58-year-old woman with T2DM returns for follow-up care

▪ Frustrated because she has been trying to diet without much success, and has lost and gained back 8 lbs over the last year

▪ Exercises by briskly walking for 20-30 minutes 3-5 times a week

▪ PMH: T2DM, HTN, hypercholesterolemia, coronary artery disease (s/p NSTEMI 2005 with placement of one stent)

▪ Meds: metformin 1000 mg bid, insulin glargine 25 u daily, HCTZ 12.5 mg daily, lisinopril 20 mg daily; rosuvastatin 20 mg daily, aspirin 81 mg daily

HCTZ=hydrochlorothiazide. NSTEMI=non-ST-elevation myocardial infarction. s/p=status post.

Case 2: Raquel (cont.)

▪ Labs: CMP=WNL, Cr=1.02; A1C=7.8; LDL-C=78; urine Alb/Cr ratio=20 (normal 0-30)

▪ Echocardiogram: normal ejection fraction, no valvular problems or wall motion abnormalities

What Is Raquel’s A1C Goal?

A. Less than 8

B. Less than 7.5

C. Less than 7.0

D. Less than 6.5


A. Slowly increase her basal insulin

B. Add pioglitazone

C. Add an SGLT-2i or GLP-1RA

D. Add rapid-acting insulin prior to her evening meal

Case 3: Matt

▪ 67-year-old male who presents for routine follow up and to go over studies that were ordered; at his last visit he was concerned that he had been having a small amount of swelling in his legs for about 6 months

▪ Denies CP or SOB

▪ No previous episodes of hypoglycemia

▪ PMH: T2DM, HTN, hyperlipidemia, coronary artery disease (stent x 1 in 2012)

▪ Meds: metformin 1000 mg bid, lisinopril 20 mg daily, HCTZ 12.5 mg daily, atorvastatin 40 mg daily, aspirin 81 mg daily

Case 3: Matt (cont.)

Physical exam

▪ General–NAD

▪ Lungs–clear

▪ CV–RRR with a II/VI systolic murmur, left upper sternal boarder

▪ Ext–trace edema bilateral

Labs: CMP=WNL, Cr=1.02; A1C=7.8; LDL-C=85; urine Alb/Cr ratio=20 (normal 0-30)

Echocardiogram: normal ejection fraction, grade 1 diastolic dysfunction

What Is Matt’s A1C Goal?

▪ Less than 8

▪ Less than 7.5

▪ Less than 7.0

▪ Less than 6.5


A. Continue current medications

B. Add an SGLT-2i

C. Add a GLP-1RA

D. Add pioglitazone

Decision Cycle for Patient-Centered Glycemic Management in T2DM

AGREE ON MANAGEMENT PLAN

SHARED DECISION-MAKING TO CREATE A MANAGEMENT PLAN

CONSIDER SPECIFIC FACTORS THAT IMPACT CHOICE OF TREATMENT

ASSESS KEY PATIENT CHARACTERISTCS

IMPLEMENT MANAGEMENT PLAN

GOALS OF CARE

▪ Prevent complications

▪ Optimize quality of life

▪ Current lifestyle▪ Comorbidities (ie, ASCVD, CKD, HF)▪ Clinical characteristics (ie, age, HbA1c, weight)▪ Issues such as motivations and depression▪ Cultural and socioeconomic context

▪ Individualized HbA1c target▪ Impact on weight and hypoglycemia▪ Side effect profile of medication▪ Complexity of regimen (ie, frequency,

mode of administration)▪ Choose regimen to optimize adherence

and persistence▪ Access, cost, and availability of medication

▪ Involves an educated and informed patient (and their family/caregiver)

▪ Seeks patient preferences▪ Effective consultation includes motivational

interviewing, goal-setting, and shared decision-making▪ Specify SMART goals (Specific, Measureable, Achievable, Realistic, Time limited)

▪ Patients not meeting goals generally should be seen at least every 3 months, as long as progress is being made; more frequent contact initially is often desirable for DSMES

ONGOING MONITORING AND SUPPORT, INCLUDING:

▪ Emotional well-being▪ Check tolerability of medication▪ Monitor glycemic status▪ Biofeedback including SMBG, weight,

step count, HbA1c, BP, lipids

REVIEW AND AGREE ON MANAGEMENT PLAN

▪ Review management plan▪ Mutual agreement on changes▪ Ensure agreement that therapy is implemented

in a timely fashion to avoid clinical inertia▪ Decision cycle undertaken regularly

(at least once/twice a year)

DSMES=diabetes self-management and support. SMBG=self-monitored blood glucose.

Please write your question on a question card and hand it to a staff member.

Conclusions

Large Group Discussion

For dipeptidyl peptidase 4 inhibitor (DPP-4i) cardiovascular outcomes trials (CVOTs), all trials met the primary goal of demonstrating that there is no increased risk of cardiovascular disease (CVD).

A. True

B. False

71

For the sodium-glucose cotransporter 2 inhibitor (SGLT-2i) CVOTs, all trials met the primary goal of demonstrating that there is no increased risk of CVD.

A. True

B. False

72

SGLT-2i CVOTs included which of the following results:

A. Met the primary goal of demonstrating that there is no increased risk of CVD

B. Useful for evaluating other potentially beneficial effects of the drugs

C. More precise estimates of the risk of other rare events

D. All of the above

73

Lower rates of acute renal failure and kidney injury were reported in which of the following trials?

A. EMPA-REG (empagliflozin)

B. HARMONY (albiglutide)

C. DECLARE-TIMI (dapagliflozin)

D. ELIXA (lixisenatide)

74

In the glucagon-like peptide 1 (GLP-1) CVOTs, which of the following demonstrated a benefit on major adverse cardiovascular events (MACE) and mortality?

A. Lixisenatide and semaglutide

B. Liraglutide and exenatide

C. Lixisenatide and exenatide

D. Liraglutide, semaglutide, and albiglutide

75

Which class of medication is preferred in the American Diabetes Association/European Association for the Study of Diabetes(ADA/EASD) type 2 diabetes mellitus (T2DM) algorithm for patients with T2DM and heart failure (HF)?

A. Thiazolidinediones (TZDs)

B. GLP-1 receptor agonists

C. SGLT-2 inhibitors

D. DPP-4 inhibitors

76

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