Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals GLP-1 Physiology and Evolving Clinical Data on GLP-1 Receptor Agonists for the Management of Type 2 Diabetes Presented as a Live Webinar Tuesday, May 19, 2020 12:00 p.m. – 1:00 p.m. ET On-demand Activity Recording of live webinar Available after May 23, 2020 This webinar is not accredited for continuing education. FACULTY Curtis L. Triplitt, Pharm.D., CDCES Clinical Associate Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio Associate Director, Diabetes Research Texas Diabetes Institute, University Health System San Antonio, Texas View faculty bio at https://www.ashpadvantage.com/t2d/glp1/ WEBINAR INFORMATION Visit https://www.ashpadvantage.com/t2d/glp1/ to find • Webinar registration link • Group viewing information and technical requirements Any referenced figures, tables and graphs are copyrighted works of their respective owners; used with permission.
25
Embed
GLP-1 Physiology and Evolving Clinical Data on GLP-1 Receptor … · 2020-05-18 · GLP‐1 Physiology and Evolving Clinical Data on GLP‐1 Receptor Agonists for the Management of
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals
GLP-1 Physiology and Evolving Clinical Data on GLP-1 Receptor Agonists for the Management of Type 2 Diabetes
Presented as a Live Webinar Tuesday, May 19, 2020 12:00 p.m. – 1:00 p.m. ET
On-demand Activity Recording of live webinar Available after May 23, 2020
This webinar is not accredited for continuing education.
FACULTY Curtis L. Triplitt, Pharm.D., CDCES Clinical Associate Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio Associate Director, Diabetes Research Texas Diabetes Institute, University Health System San Antonio, Texas
View faculty bio at https://www.ashpadvantage.com/t2d/glp1/
WEBINAR INFORMATION Visit https://www.ashpadvantage.com/t2d/glp1/ to find
• Webinar registration link• Group viewing information and technical requirements
Any referenced figures, tables and graphs are copyrighted works of their respective owners; used with permission.
ASHP Financial Relationship Disclosure Statement Planners, presenters, reviewers, ASHP staff, and others with an opportunity to control CE content are required to disclose relevant financial relationships with ACCME-defined commercial interests. All actual conflicts of interest have been resolved prior to the continuing education activity taking place. ASHP will disclose financial relationship information prior to the beginning of the activity. A relevant financial relationship is a defined as a financial relationship between an individual (or spouse/partner) in control of content and a commercial interest, in any amount, in the past 12 months, and products and/or services of the commercial interest (with which they have the financial relationship) are related to the continuing education activity. An ACCME-defined commercial interest is any entity producing, marketing re-selling, or distributing healthcare goods or services consumed by, or used on, patients. The ACCME does not consider providers of clinical serve directly to patients to be commercial interests—unless the provider of clinical service is owned, or controlled by, an ACCME-defined commercial interest.
GLP‐1 Physiology and Evolving Clinical Data on GLP‐1 Receptor Agonists for the Management of Type 2 Diabetes
Curtis L. Triplitt, Pharm.D., CDCES
University of Texas Health Science Center at San AntonioTexas Diabetes Institute, University Health System
San Antonio, TexasProvided by ASHP Sponsored by AstraZeneca Pharmaceuticals
Curtis L. Triplitt ‐ Speakers bureau: AstraZeneca Pharmaceuticals; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk Inc.
All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant to this activity.
At the conclusion of this educational activity, participants should be able to• Identify glucose homeostasis actions of GLP‐1 in T2D• Discuss potential CVD and renal benefits of GLP‐1 RAs fromCVOTs
• Differentiate recommended placement of GLP‐1 RA therapybased on comorbidities identified in national guidelines
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Years
0
-15 -10 -5 0 5 10 15 20 25 30
200
150
100
50
250
Insulin resistance
Insulin levelR
ela
tive
Am
ou
nt
β-cell function
Incretin effect
Diagnoseddiabetes
Diabetes Onset
350
300
250
200
150
100
Postmeal glucose
Fasting glucose
Glu
co
se
(m
g/d
L)
50
Diabetes Is a Chronic and Progressive Disease1,2
*By the time diabetes is clinically diagnosed, β‐cell function may be reduced by ≥50%; subjects in the upper tertile of impaired glucose tolerance (IGT) are near‐maximally insulin resistant and have lost more than 80% of their β‐cell function1‐3Representative depiction of the natural progression of type 2 diabetes (time course and function)11. Adapted with permission (pending) from Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Defronzo RA Diabetes. 2009; 58:773‐95;3. Holman RR. Diab Res Clin Prac. 1998;40(suppl):S21‐S25.
Pre Diabetes
50%–80% loss of β-cell function at diagnosis*
The Incretin Effect • Oral glucoseadministration isassociated with a greaterincrease in plasma insulinlevels than a similaramount of glucose givenintravenously1
• This phenomenon hasbeen dubbed the incretineffect, and accounts forapproximately 50%–70%of the total insulinsecreted after oralglucose administration1
*P≤0.05 between the oral glucose load and IV glucose loadIR=immunoreactive; IV=intravenous1.Baggio LL et al. Gastroenterology. 2007;132:2131‐57; 2.Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492‐8.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Summary: GLP‐1 Physiology
• Type 2 diabetes is a progressive disease associated with worsening β‐celldysfunction, increases in insulin resistance, and resultant hyperglycemia1
• Research conducted in the 1980s demonstrated an impaired “incretineffect” in individuals with type 2 diabetes2
• The widespread physiologic actions of incretin hormones, GIP and GLP‐1,occur in the pancreas, stomach, brain, bone, adipose tissue, liver, muscle,cardiovascular system, and central nervous system3
• Though the basic physiology of GLP‐1 effects are known, there is muchmore to learn
1. Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Mudaliar S et al. Diabetologia. 2012;55:1865‐8;3. Baggio LL et al. Gastroenterology. 2007;132:2131‐57.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Continuously Infused GLP‐1 Nearly Normalized Blood Glucose in Patients With T2D
Healthy subjects, n = 6; patients with T2D, n = 7; mean data Rachman J et al. Diabetologia. 1997;40:205‐11.
0
100
200
300
SnackLunchBreakfast
Glu
cose
(m
g/d
L)
Continuous GLP-1 Infusion
T2D: Saline
Healthy subjects
T2D: Exogenous GLP-1
Time of Day (h)
12 AM 4 AM 8 AM 12 PM 4 PM
GLP‐1 Receptor Agonists for T2D
• GLP‐1 RAs are given subcutaneouslyor orally and bind to the nativeGLP‐1 receptor, and have similaractions as GLP‐1
• Indications:– In addition to diet/exercise to improve
glycemic control in patients with T2D1‐8
– To reduce MACE in patients with T2Dand established CVD (liraglutide5 andsemaglutide8) or in patients withmultiple cardiovascular risk factors(dulaglutide7)
MACE= major adverse cardiovascular events; MTC=medullary thyroid carcinoma1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
• These products differ in– Base molecule: exenatide or analog of
human GLP‐1– Half‐life of drug and frequency of dosing– Type of injection device
• Broadly speaking they can be groupedinto 2 groups– Intermittent GLP‐1 RAs1,4: No boxed
warning on MTC– Long‐acting GLP‐1 RAs2,3,5‐9: Boxed warning
on MTC in humans due to uncertainrelevance of preclinical findings
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Cautions
• Acute pancreatitis history– Not recommended– Weigh pros and cons
• Acute renal injury (ARI)– Careful attention to GI sideeffects in renal insufficiency
– Nausea/vomiting can putpatient at risk of ARI
• Gastroparesis– All GLP‐1 RAs can worsen– Not recommended
• Acute gallbladder– May contribute(cholecystitis or cholelithiasis)
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
WarningsRisk of Thyroid C‐Cell Tumors
• GLP‐1 RAs cause an increased incidence in thyroid C‐cell tumors at clinicallyrelevant exposures in rats and or mice compared to controls. It is unknownwhether GLP‐1 RAs cause thyroid C‐cell tumors, including medullary thyroidcarcinoma (MTC), in humans, as human relevance could not be determined byclinical or nonclinical studies.
• GLP‐1 RAs contraindications– Patients with a personal or family history of MTC– Patients with multiple endocrine neoplasia syndrome type 2 (MEN 2)
• Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain valuein patients treated with GLP‐1 Ras– Counsel patients regarding the risk and symptoms of thyroid tumors
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
GLP1 RA MACE Overview: Established CVD or Multiple Risk Factors
Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847.
LEADER ─
EXSCEL ─
REWIND ─
SUSTAIN 6 ─
PIONEER 6 ─
Overall ─
LEADER (lira)
EXSCEL (ExQW)
REWIND (dula)
SUSTAIN 6 (sema)
PIONEER 6 (oral sema)
Overall
0.94 (0.83, 1.07)
LEADER ─
EXSCEL ─
REWIND ─
SUSTAIN 6 ─
PIONEER 6 ─
Overall ─
Established CVD
Multiple Risk Factors
0.86 (0.80, 0.92)
Hazard Ratio (95% CI)
Favors GLP-1 RA Favors Placebo
0.4 0.8 1.4 2 2.60.5 1.21
GLP‐1 RA Renal Composite Overview:(new‐onset macroalbuminuria, sustained doubling of serum creatinine, or a 40% decline eGFR, end‐stage kidney disease, or death of renal cause)
Adapted from Zelniker TA et al. Circulation. 2019;139:2022–31.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
REWIND‐eGFR and Albuminuria Effects
Gerstain HC. Lancet. 2019;394:131‐8.
EstimatedGlomerular Filtration Rate
Urinary Albumin Creatinine Ratio(geometric mean)
Summary of MACE and Renal Composite Data in T2D1‐6
Long‐acting GLP‐1 RA class has demonstrated
• Reductions in MACE in patients with established CVD (~13%)• Reductions in renal composite endpoint (~18%)
– Mostly reduction in macroalbuminuria, (EXSCEL and REWIND demonstrated effects in reduction ofeGFR)
Liraglutide & Semaglutide are indicated to
• To reduce the risk of MACE in adults with type 2 diabetes and establishedcardiovascular disease
Dulaglutide
• To reduce the risk of MACE in adults with type 2 diabetes who have establishedcardiovascular disease or multiple cardiovascular risk factors
1. Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847; 2. Gerstein HC et al. Lancet. 2019;394(10193):121‐30; 3. ZelnikerTA et al. Circulation. 2019;139:2022–31; 4. Zelniker T et al. Lancet. 2019; 393(10166):31‐9; 5. Gerstein HC et al. Lancet. 2019;394(10193): 131‐8; 6. Bethel MA et al. Presented at: American Diabetes Association 78th Scientific Sessions; June 22‐26, 2018; Orlando, FL.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
First-Line Therapy is MET + Lifestyle Mod (inc. Weight Management + Physical Activity)
Indicators of High-Risk or Established ASCVD, CKD, or HF
Consider Independently of Baseline A1C or Individualized A1C Target
ASCVD Predominates Heart Failure or CKD Predominates
GLP-1 RA with proven CVD benefit*or
SGLT2-i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR adequate
SGLT2-i with proven CVD benefit* if eGFR adequate
GLP-1 RA with proven CVD benefit*if eGFR is less than adequate
(if SGLT2-i not tolerated)
If A1C above target If A1C above target
If intensification required or not tolerating GLP-1 RA and/or SGLT2-i, choose agents with CV safety:• Pts on GLP-1 RA, consider adding SGLT2-I*• DPP-4i if not on GLP-1 RA• Basal Insulin• TZD• SU
• Avoid TZD in setting of HFChoose agents demonstrating CV safety:• Pts on SGLT2-I, consider adding GLP1-RA*• DPP-4i (not saxa) in setting of HF (if not on a
GLP-1 RA)• Basal Insulin• SU
ADA 2020 Standards of Care
Antihyperglycemic Medication in T2D: Focus with ASCVD,
CKD, & HF
Adapted from ADA Standards of Care [web annotation]. Diabetes Care. 2020; 43(suppl 1):S1‐S212.*Label indication of reducing CVD events.
Without Established ASCVD, CKD, or Heart Failure
Need to Minimize HypoglycemiaCompelling Need to
Minimize Weight Gain or Promote Weight Loss
Cost is a Major Issue
SGLT2-i GLP-1 RA TZD DPP-4i SGLT2-iGLP-1 RA
(good efficacy for weight loss)
SU TZD
GLP-1 RA SGLT2-i SGLT2-i SGLT2-iGLP-1 RA
(good efficacy for weight loss)
SGLT2-i TZD SU
DPP-4i TZD DPP-4i TZD
TZD GLP-1 RA
If A1C is above target:Continue addition of agents as listed above
If A1C is still above target:Later gen SU or basal insulin (w/ low hypo risk)
If quadruple therapy required or SGLT2-i or GLP-1 RA not
tolerated then use regimen with lowest risk of weight gaina
Insulin therapy (basal insulin)
OrConsider DPP-4i or SGLT2-i
ADA 2020 Standards of Care
Antihyperglycemic Medication in T2D: Focus w/o ASCVD,
CKD or HF
Adapted from ADA Standards of Care [web annotation]. Diabetes Care. 2020; 43(suppl 1):S1‐S212. aDPP‐4I (if not on GLP‐1 RA based on weight neutrality; if DPP‐4I not tolerated or contraindicated or patient already on GLP‐1 RA, cautious addition of SU, TZD, or basal insulin.
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Summary• T2D is a progressive disease associated with worsening β‐cell dysfunction,
increases in insulin resistance, and resultant hyperglycemia1
• Patients with T2D are also characterized by an impaired “incretin effect”2
• The first GLP‐1 RA for the treatment of diabetes was approved in 20053– Today GLP‐1 RAs are formulated for daily or weekly SC administration, as well as daily oral
administration• CVOTs have shown that these agents reduce MACE in patients with T2D and
established CVD or multiple cardiovascular risk factors4,5,6
• GLP‐1 RAs markedly reduce body weight• GLP‐1 RAs have been studied for other effects beyond glycemia (Parkinson’s
disease and Alzheimer’s disease)7
Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Mudaliar S et al. Diabetologia. 2012;55:1865‐8; 3. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 4. Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847; 5. Sheahan KH et al. Postgrad Med J. 2019; doi: 10.1136/postgradmedj‐2019‐137186; 6.Dula [PI]. Indianapolis, IN; Lilly USA, LLC; 2020; 7. Athauda D. et al. Drug Discov Today. 2016;21:802‐18.
Key Takeaways
• GLP‐1 RAs– Have physiological actions that help patients with type 2diabetes improve glycemic control
– Consider for patients who need• Weight loss• Low risk of hypoglycemia
– Consider strongly in type 2 diabetes with• High risk of CVD or current diagnosis• Renal insufficiency with albuminuria