Why GLP-1 Receptor Agonists & SGLT-2 Inhibitors? Making Sense of the Clinical Trial Data Vanita R. Aroda, MD Director, Diabetes Clinical Research Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School (UCLA, Class of 1994) The 9th Annual UCLA Diabetes Symposium Los Angeles, CA November 20, 2021
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Why GLP-1 Receptor Agonists & SGLT-2 Inhibitors? Making Sense of the Clinical Trial Data
Vanita R. Aroda, MDDirector, Diabetes Clinical ResearchBrigham and Women’s HospitalAssociate Professor of MedicineHarvard Medical School(UCLA, Class of 1994)
The 9th Annual UCLA Diabetes Symposium
Los Angeles, CA
November 20, 2021
Disclosures (12 months)
• Consultant: Applied Therapeutics, Duke, Fractyl, Novo Nordisk, Pfizer, Sanofi
• Employee (Spouse): Janssen
• Research (Clinical trials): Applied Therapeutics, Eli Lilly, Premier/Fractyl, Novo Nordisk, Sanofi
• Educational activities: American College of Cardiology, American Diabetes Association, Liberum, IMNE, PeerView, Pri-Med, MedScape, WebMD
• Member of the ADA Professional Practice Committee
Views are my own.
The Role of GLP-1 Receptor Agonists and SGLT2 Inhibitors in Mitigating Cardiorenal Metabolic Risk?
2. Clinical Evidence:
What is the clinical evidence surrounding SGLT2i and GLP-1 RA in
mitigating cardiorenal metabolic risk?
3. Physiologic/Mechanistic Insights:
How may GLP-1RA and SGLT2i mitigate cardiorenal metabolic risk?
4. Clinical Guidance:
What does current clinical guidance recommend?
5. BONUS: The patient-centered conversation
1. Scope:What is the scope and potential
impact of cardiorenal metabolic risk reduction?
Fox CS et al; Diabetes Care 31:1582–1584, 2008
WOMEN Participants without diabetes, aged 50-89
Participants with diabetes, aged 50-89
Lifetime Risk CVD (30-year risk)* 38.0% 67.1%
Stratified by BMI
-Normal weight 34.3% 54.8%
-Overweight 38.7% 69.3%
-Obese 46.7% 78.8%
MEN Participants without diabetes, aged 50-89
Participants with diabetes, aged 50-89
Lifetime Risk CVD (30-year risk)* 54.8% 78.0%
Stratified by BMI
-Normal weight 49.2% 78.6%
-Overweight 55.5% 74.0%
-Obese 66.8% 86.9%
Lifetime Risk of Cardiovascular Disease Among Individuals With and Without Diabetes Stratified by Obesity Status in the Framingham Heart Study
*Expressed as percent developing CVD, adjusted for the competing risk of death.
Shah AD et al; Lancet Diabetes and Endocrinology 2015; 3: 105–13
Distribution of initial presentations of cardiovascular diseases:-predominantly atherosclerotic, though multitude of etiologies
T2DM, CKD, and CVD: high albuminuriaand low eGFR are independent risk factors for cardiovascular and renal events in T2DM
And then came EMPA-REG (2015)...• The Question: What are the effects of empaglifozin (an SGLT-2 inhibitor), as compared with placebo
on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events who were receiving standard of care?
• Key Eligibility Criteria:– Adults with type 2 diabetes, BMI< 45 kg/m2, eGFR > 30 ml/min/1.73 m2– Established cardiovascular disease– A1c 7-9% (no therapy) or 7-10% (on stable therapy)
• Randomized Intervention:– Empagliflozin 10 mg or 25 mg or placebo (1:1:1; n=7,020), on a background of standard care
• Primary Outcome:– Composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke (3-point MACE)
• Years of Study Conduct: 2010-2015
• Follow up: median observation time 3.1 years
Zinman B et al. N Engl J Med 2015;373:2117-2128.
Zinman B et al. N Engl J Med 2015;373:2117-2128.
EMPA-REG: Reduction in Cardiovascular Outcomes, Death, and Hospitalization for Heart Failure
• The Question: What are the long-term effects of liraglutide on cardiovascular outcomes and other clinically important events when added to standard care in patients with type 2 diabetes?
• Key Eligibility Criteria (established ASCVD/high risk ASCVD):– adults with type 2 diabetes (A1c > 7%) and high cardiovascular risk:
• Age >50 years with at least one cardiovascular condition (CHD, cerebrovascular disease, PVD, CKD stage 3 or greater, chronic heart failure II or III)
• Age > 60 years with at least one cardiovascular risk factor (e.g. microalbuminuria, proteinuria, HTN and LVH, LV systolic or diastolic dysfunction, ABI < 0.9).
• Randomized Intervention: Liraglutide 1.8 mg (or maximally tolerated dose) SC once daily vs placebo (1:1, n=9,340)
• Primary Outcome: First occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke
• Years of Study Conduct: 2010-2015
• Follow up: median 3.8 years Marso SP et al; NEJM 2016; 375: 311-322
LEADER: Liraglutide (GLP-1 RA) and CV Outcomes in T2DM
LEADER: Liraglutide (GLP-1 RA) and CV Outcomes in T2DM
Marso SP et al; NEJM 2016; 375: 311-322
Marso SP et al; NEJM 2016; 375: 311-322
Buse JB et al; 2020; Diabetes Care;43(7):1546-1552
EMPA-REG (SGLT2i) LEADER (GLP-1RA)
Primary Outcome HR 0.86 (95% CI 0.74-0.99)
HR 0.87 (95% CI 0.78-0.97)
CV Death 0.62 (0.49–0.77) 0.78 (0.66–0.93)
Nonfatal MI 0.87 (0.70–1.09) 0.88 (0.75–1.03)
Nonfatal Stroke 1.18 (0.89–1.56) 0.89 (0.72–1.11)
Hospitalization for Heart Failure
0.65 (0.50–0.85) 0.87 (0.73–1.05)
Mediation Analyses *Changes in hemoglobin (51.8%) and hematocrit (48.9%)
*HbA1c (41-83%)*Urine albumin/creatinine (29-33%)
Zinman B et al. N Engl J Med 2015;373:2117-2128Inzucchi SE et al; Diabetes Care 2018; 41:356-363.
McGuire DK et al; JAMA Cardiology 2021 6(2):148-158
Hospitalization for Heart Failure:HR 0.68, 32% reduction
-No major effect on outcome of Stroke
SGLT2i:
Stroke
McGuire DK et al; JAMA Cardiology 2021 6(2):148-158
Gerstein HC et al; Lancet Diabetes and Endocrinology 2020; 8:106-14.
Fatal or non-fatal stroke (HR 0.76)
Disabling stroke (HR 0.74)
Non-fatal stroke (HR
0.76)
Fatal stroke
Ischemic stroke, HR
0.75
Hemorrhagic stroke
Aroda VR; Lancet Diabetes and Endocrinology 2020; 8(2):90-92
“With the limited number of therapies…and the substantial attendant disability…the study … meaningfully supports the consideration of GLP-1 RA for stroke prevention in people with T2DM at increased CV risk.”
Comparison of GLP-1 RA and SGLT2i on Renal Outcomes in T2DM
Zelniker TA et al ; Circulation 2019; 139:2022-2031
A. Effects on broad kidney end point (new-onset macroalbuminuria, sustained doubling of serum creatinine or 40% decline in eGFR, ESKD, death of renal cause):
Benefits seen with both classes (GLP-1 RA and SGLT-2i )
B. Effects on kidney outcomes excluding macroalbuminuria
Benefits with SGLT-2i
Summary #2: Role of GLP-1 RA and SGLT2i in mitigating cardiorenal risk: Clinical Profile from CVOTs
*Numerical decrease in HHF also seen in meta-analysis, evolving area of study; †For GLP-1 RAs,the relative risk reduction of the kidney composite appeared to be mainly driven by a reduction in macroalbuminuria, excluding which, there was a nonsignificant effect of GLP-1 RA on the risk of doubling serum creatinine; ‡Worsening eGFR, end-stage kidney disease, or renal deathCV, cardiovascular; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular event;MI, myocardial infarction; SGLT2i, sodium-glucose cotransporter-2 inhibitorsZelniker et al. Circulation 2019; 139:2022–31
Demonstrated as a primary outcome
Demonstrated as part of secondary outcomes
GLP-1 RA* SGLT2i
StrokeHHF
Hard renal
endpoints‡
GLP-1
RA or
SGLT2i
• MACE
• MI
• CV death
• Broad
composite
renal
endpoints†
1
°
2
°
“A variety of risk factors converge on the artery topromote atherogenesis in
individuals with type 2 diabetes.”
Libby P, Plutzky J. Circulation 2002. 106:2760-2763.DeBoer MD; Nutrition 2013; 29: 379-386Libby P. Nature 2021; 592(7855):524-533
3. Physiologic/Mechanistic Insights
GLP-1RA: History of the Incretin Concept
• Rehfeld JF. Frontiers in Endocrinology 2018; 9: 1-7
19051889
1964
1902
1983
Pancreas as the site of diabetes
A gut hormone may stimulate the endocrine
pancreas
Invention of the radioimmunoassay
1932
1973
1960
1987
Demonstration of a glucose-dependent incretin mechanism
Evidence of an insulinotropicgut hormone
1971
Coining the word incretin
1930
Discovery of secretin; the first hormone
1966
Gut glucagon-like immunoreactivity Identification of GIP
GIP as an incretin
Identification of GLP-1
Truncated GLP-1 as an incretin
Incretin: “any gut hormone, which under physiological circumstances stimulates the secretion of pancreatic hormones.”; Latin increscere: “to increase”
21% reduction in primary cardiovascular outcomes & 24% reduction in secondary composite outcomes
in those achieving > 10% body weight in 1st year
Aroda VR et al; Lancet Diabetes Endocrinol 2017;5: 355–66
Graphic from Libby P, Plutzky J. Circulation 2002. 106:2760-2763
Semaglutide (GLP-1RA) reduced hs-CRP and PAI-1, along with lipid profiles moreso than comparator treatment
Consistent mechanistic insight (reduction of hs-CRP with
GLP-1RA) from more routine diabetes therapeutic studies
Trial product estimand data presented (treatment effect of medication without confounding influence of rescue medication use and treatment discontinuations)
Aroda VR et al; Diabetes Care 2019; 42: 1724-1732Rodbard HW et al; Diabetes Care 2019; 42:2272-2281
Illustration from Libby P, Plutzky J. Circulation 2002. 106:2760-2763
C-REACTIVE PROTEIN: oral semaglutide vs empagliflozin
Heerspink HJ et al; N Engl J Med 2020;383:1436-46.
-Adults with or without T2DM (~67% with T2DM)-eGFR 25-75 ml/min/1.73 m2
and urinary albumin-to-creatinine ratio 200-5000 mg/g, on stable ACE inhibitor or ARB if tolerated
Primary outcome: worsening heart failure or CV death
Epub 2019 Sep 19NEJM Nov 2019FDA updated indication: Oct 2019
Anker SD et al; N Engl J Med. 2021 Aug 27
N=5988; Class II-IV HF, EF > 40%Empagliflozin 10 mg daily vs placebo, + usual therapy
Summary #3: Mechanistic Insights
GLP-1 RA and SGLT2i appear to have complementary, non-overlapping physiologic/mechanistic benefits toward mitigating Cardio-Renal Metabolic Risk.
->While mechanisms are still being elucidated, we have a clearer picture of GLP-1 RA addressing atherosclerotic & inflammatory cardiovascular pathways, with
SGLT2-i addressing myocardial energetics and cardio-renal pathways.
Graphics from Tuttle KR et al; Amer Journal of Kidney Diseases 2021; 77:94-109 andLibby P, Plutzky J. Circulation 2002. 106:2760-2763
Walk through the ADA Recommendations (2009->2021)
4. Clinical Guidance
UKPDS 35
Every 1% lower HbA1c is associated with decreased risk of the following:
Benefit of early glycemic management for T2D
12%
Stroke
19%
Cataract extraction
16%
Heart failure
14%
Myocardial infarction
43%
Lower extremity amputation or fatal peripheral vascular
disease
37%
Microvascular disease
14%
All-cause mortality
21%
Death related to diabetes
p<0.05 for all data depictedHbA1c, glycated haemoglobin; UKPDS, UK Prospective Diabetes Study; T2D, type 2 diabetesStratton et al. Brit Med J. 2000;321:405–12.
• Zaccardi F et al; https://doi.org/10.2337/dc20-2080
• American Diabetes Association. Standards of Medical Care in Diabetes – 2021. Diabetes Care 2021; 44(Suppl 1).
+ASCVD/Indicators of High Risk:• REWIND (dulaglutide) CV/risk
criteria:
-age > 50 years with established vascular disease
-age > 55 years with ischemia, stenosis >50%, LVH, eGFR <60 ml/min/1.73m2, or albuminuria
-age > 60 years, at least 2 risk factors (tobacco, dyslipidemia, htn, abdominal obesity)
Median follow-up 5.4 years
• DECLARE (dapagliflozin) CV/risk criteria:
-age > 40 years, established ASCVD
-men > 55 years, women > 60 years with 1 or more traditional risk factor (HTN, dyslipidemia, tobacco)
Median follow-up: 4.2 years
Gerstein HC et al; Lancet 2019; 394:121-130Wiviott SD et al; NEJM 2019; 380:347-57
Similar reductions in risk (HR) in those with established ASCVD and in those with risk factor criteria
Berg D et al; Circulation 2019; 140 (19): 1569-1577
+ASCVD/Indicators of High Risk
Classification of CKD, based on Cause, GFR, and Albuminuria
Degree of albuminuria is associated with risk of CVD, CKD progression, and mortality and may influence choice of antihypertensives and glucose-lowering agents
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American Diabetes Association; Diabetes Care 2021; 44 (Suppl 1)
Summary #4: Beyond glucose controlAmong patients with T2DM with established
ASCVD/high risk, established kidney disease, or heart failure, include evidence-supported
cardio/renal-protective agents in the regimen.
ADA Diabetes Care 2021; 44 (Suppl 1)
Nelson AJ et al; J Am Heart Assoc 2021; 10:e016835. DOI: 10.1161/JAHA.120.016835
• Anthem pharmacy & medical claims data, index date: April 18, 2018 (n=155,958)
• ASCVD + T2DM• High-intensity statin: 24.7% • ACE-I or ARB: 53.1% • SGLT2i or GLP-1RA: 9.9%• All 3 categories: 2.7%
• 12 months: 70.6% saw a cardiologist, 18% saw an endocrinologist
“Alarming gaps exist in the contemporary use of evidence-based therapies…These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.”
Conversations of the Heart: Think about Your Patient-Centered Conversations in Translating the
Evidence
Patient-Centered Physiology
• Diabetes increases the risk of heart and kidney disease, through multiple factors that converge on the cardiovascular system.
• Better control of diabetes and risk factors is associated with lower risk of heart and kidney disease.
Patient-Centered Care Goals
• Our care goals include reducing risk of heart & kidney disease to optimize long-term health.
• Specific medications that we choose to treat type 2 diabetes can help with these goals.
Patient-Centered Anticipatory Guidance
• (GLP-1 RAs): You may feel fuller, sooner, with better control of your appetite and weight – It is ok (& anticipated) that you may eat less than before. If you experience nausea, this will typically improve as you get used to the medicine.
• (SGLT2 inhibitors): Because these excrete (flush) glucose out in the urine, you may have increased urination. It is important to follow good genital and urinary hygiene & care.
Personal excerpt, illustrative, not intended as the complete or universal dialogue
Participant/Patient-Centered Conversations that Mutually Elevate & Advance
Why GLP-1 Receptor Agonists & SGLT-2 Inhibitors? Making Sense of the Clinical Trial Data
Age
% f
un
ctio
n Function(disease & disability)Healthspan
What matters to our patients?
*’Rectangularization’ is where any severe dysfunction is compressed to as short a period as possible as late in life as possible. In doing this, healthy function looks more like a rectangleSeals et al. J Physiol 2016;594:2001–24
Healthy lifespan: period of life free from major chronic clinical disease and disability; i.e. healthy aging
‘Rectangularization’* of function: increased healthspan, compression of morbidity