The GLP1-RA Class of Medications - syllabus.aace.comsyllabus.aace.com/2018/Chapters/Upper_New_York/slides/Astapova-Chavez... · Learning Objectives 1. Understand the physiological

Beyond A1CNon-glycemic Effects of GLP-1 Receptor Agonists

Olga Astapova MD, PhDLuis Chavez MDURMC Endocrinology Fellows

Disclosures

› No conflicts of interest.

Learning Objectives

1. Understand the physiological role of our gut hormones in glucagon inhibition, glucose dependent insulin secretion, appetite regulation and gastric motility.

2. Understand the effectiveness of this class of medication to reduce hyperglycemia and weight.

3. Learn about cardiovascular benefits of GLP1 receptor agonists.

4. Become familiar with adverse effects and cost of GLP1 receptor agonists.

Diabetes Treatment Goals

Avoiding imminent death

Alleviating symptoms of hyperglycemia

Preventing complications

1920s

Insulin

1950s

Tolbutamide

2000s

FraminghamDCCT / EDICUKPDS

FingerstickBG metersHemoglobin A1C

1970s

JAMA. 2015;314(1):52-60;2. World Heart Federation. Cardiovascular disease risk factors

Action to Control Cardiovascular Risk in Diabetes (ACCORD)

HbA1C 6.4%

HbA1C 7.5%

N Engl J Med 2008; 358:2545-2559

“Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials.”

GLP1 Receptor Agonists

Saraiva and Sposito Cardiovascular Diabetology 2014, 13:142

Albèr et al. Diabetes Obes Metab. 2017 Jul;19(7):915-925

Exenatide (Byetta)

Lixisenatide (Adlyxin)

Liraglutide (Victoza)

Albiglutide (Tanzeum)

Dulaglutide (Trulicity)

Semaglutide (Ozempic)Insulin ↑

Among patients with T2DM at increased risk for CV events, does daily liraglutide reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo?

LEA

DER

N Engl J Med 2016; 375:311-322

9340 patients

≥ 50 years old

Type 2 diabetes

Mean 12.8 years diabetes duration

Mean HbA1C 8.7%

High CV risk: > 70% had CV disease

Placebo

(plus standard care)

Liraglutide

(plus standard care)

Hemoglobin A1C and Weight ReductionLE

AD

ER

WEIGHT2.3 KG

N Engl J Med 2016; 375:311-322

LEA

DER

13.0%

14.9%

Primary Composite Outcome❑cardiovascular death❑nonfatal myocardial infarction❑nonfatal stroke

N Engl J Med 2016; 375:311-322

Renal BenefitLE

AD

ER

N Engl J Med 2016; 375:311-322

LEA

DER

Adverse Events

N Engl J Med 2016; 375:311-322

LEA

DER

Adverse Events

N Engl J Med 2016; 375:311-322

LEA

DER

Adverse Events

N Engl J Med 2016; 375:311-322

LEA

DER

Adverse Events

N Engl J Med 2016; 375:311-322

Among patients with T2DM at increased risk for CV events, does daily liraglutide reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo?

LEA

DER

YES

N Engl J Med 2016; 375:311-322

Albèr et al. Diabetes Obes Metab. 2017 Jul;19(7):915-925

Exenatide (Byetta)

Lixisenatide (Adlyxin)

Liraglutide (Victoza)

Albiglutide (Tanzeum)

Dulaglutide (Trulicity)

Semaglutide (Ozempic)

In patients with type 2 DM at high CV risk, is semaglutidenon-inferior to placebo in terms of CV safety?

SUST

AIN

-6

3297 patients

Mean age: 65

Type 2 diabetes

Mean 13.9 years diabetes duration

Mean HbA1C 8.7%

60% ischemic heart disease

93% hypertension

Placebo

(plus standard care)

Semaglutide

(plus standard care)

N Engl J Med 2016; 375:1834-1844

High CV risk

Hemoglobin A1C ReductionSU

STA

IN-6

N Engl J Med 2016; 375:1834-1844

Weight ReductionSU

STA

IN-6

N Engl J Med 2016; 375:1834-1844

Primary Composite Outcome

6.6%

8.9%

N Engl J Med 2016; 375:1834-1844

❑cardiovascular death❑nonfatal myocardial infarction❑nonfatal stroke

SUST

AIN

-6

Adverse EventsSU

STA

IN-6

N Engl J Med 2016; 375:1834-1844

In patients with type 2 DM at high CV risk, semaglutide is superior to placebo in terms of CV safety.

SUST

AIN

-6

Lancet Diabetes Endocrinol. 2018 Feb;6(2):105-113

GLP-1 Receptor Agonists: CV Outcomes Compared with Placebo

LixisenatideLiraglutide

SemaglutideExenatide

LixisenatideLiraglutide

SemaglutideExenatide

Ongoing Clinical Trials

Ther Adv Chronic Dis 2018, Vol. 9(1) 33–50

GLP1 Receptor Agonists Decision Making

PROS CONS

↓ HbA1C Nausea

↓ Weight Heart burn

↓ Cardiovascular events Gallstones

↓ Overall mortality Cost

Take Home Points

› Fundamental paradigm shift in T2D management.

› Several classes of glucose lowering medications improve CV outcomes in RCTs.

› These emerging data should shift focus of T2D Rx from A1C alone to comprehensive CV risk reduction.

We now have options to treat T2DM that have beneficial

outcomes beyond A1C reduction.

~ Your friendly neighborhood endocrinology fellows ~