why glp-1 receptor agonists & sglt-2 inhibitors? making
TRANSCRIPT
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
https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-Kidney-Disease-Fact-Sheet.pdf
Ninomiya T et al; J Am Soc Nephrol. 2009 Aug;20(8):1813-21.
\
Gregg EW et al NEJM 2014; 370:1514-23Gregg EW, Hora I, Benoit SR. JAMA 2019; 321(19):1867-1868
Virani SS et al; Circulation. 2021;143:e254–e743..
What is the potential scope & impact of prevention?
No. of Cases 1990
No. of Cases 2010
Absolute Change, 1990-2010
Stroke
No. of cases 127,016 186,719 +59,703
No./10,000 persons 111.8 52.9 -58.9
Amputation
No. of cases 50,364 73,067 +22,703
No./10,000 persons 58.4 28.4 -30.0
End-stage renal disease
No. of cases 17,763 50,197 +32,434
No./10,000 persons 27.9 20.0 -7.9
Virani SS et al; Circulation. 2021;143:e254–e743.
Leading Global Causes of Years of Life Lost to Premature Mortality: #1 = Ischemic Heart Disease (IHD)
Leading Global Risk Factors for Years of Life Lived with Disability or Injury#1 & 2 = Glucose and BMI
Leading Risk Factors for Years of Life Lived with Disability or Injury in the US:#1 & 2 = BMI and Glucose
“Healthspan” (Healthy Lifespan)
“Lifespan”
Summary #1: Scope & Impact of Cardiometabolic Risk in T2DM• The lifetime risk of CVD in patients with T2DM is high, higher
with obesity, and reflects a multitude of etiologies.• The burden of complications is increasing, driven by prevalent
diabetes and the changing demographic of diabetes. • We now live in a ‘cardiometabolic’ world, which impacts both
lifespan and healthspan.
2. Clinical Evidence
• Cefalu W; Diabetes Care 2018; 41:14-31
The DM/CVOT Era (2013-2020)
Major Adverse Cardiovascular Outcomes with DPP-4i: Neutral
Scirica BM et al; NEJM 2013; 369: 1317-1326
White WB et al; NEJM 2013; 369:1327-1335
Green JB et al; NEJM 2015; 373:232-242
Rosenstock J et al; JAMA 2019; 321(1):69-79
Primary composite endpoint:SAVOR-TIMI (saxagliptin): 3-Point MACE: (time to CV death, non-fatal MI, non-fatal stroke)EXAMINE (alogliptin): 3-P MACE TECOS (sitagliptin): 4-P MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable anginaCARMELINA (linagliptin): 3-P MACE
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.
GLP-1 RA:Major Adverse Cardiovascular Events:HR 0.86, 14% reduction
CV death:HR 0.87, 13% reduction
Fatal or non-fatal Myocardial Infarction:HR 0.90, 10% reduction
Fatal or non-fatal Stroke:HF 0.83, 17% reduction
Sattar N et al; Lancet Diabetes Endocrinol 2021; 9: 653-62
GLP-1 RA:All-Cause Mortality: HR 0.88, 12% reduction
Hospital admission for heart failure:HR 0.89, 11% reduction
Composite kidney outcome including macro-albuminuria:HR 0.79, 21% reduction
Worsening of kidney function:HR 0.86, 14% reduction
Sattar N et al; Lancet Diabetes Endocrinol 2021; 9: 653-62
SGLT2i:Major Adverse Cardiovascular Events:HR 0.90, 10% reduction
CV death:HR 0.85, 15% reduction
Myocardial Infarction:HR 0.91, 9% reduction
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”
Hormone (Greek hormoa): arouse to activity
GIP: glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like peptide
In Patients with T2DM, the Incretin Effect is Impaired.GLP-1 agonism potentiates glucose-mediated (dependent) responses.
Healthy VolunteersType 2 Diabetes
Incretin Effect
Nauck MA, Meier JJ. Diabetes Obes Metab 2018; 20 (Suppl 1): 5-21.Nauck MA et al; Diabetologia 1993; 36:741-744
With GLP-1 infusion:
Glucagon Glucose
Insulin
Tsapas A, Avgerinos I, Karagiannis T et al; Ann Intern Med 2020; 173:278-286
Higher efficacy classes:-GLP-1 RA-Insulin
Treating earlier with 10 years of intensive therapy and mean A1c 7% followed by 10 years with mean 9% vs the vice versa would have:
33% reduction in CVD risk
52% reduction in reduced eGFR
Comparative efficacy of glucose-lowering medications on body weight
Tsapas A et al; Diabetes Obes Metab 2021; 1-9Drucker DJ, Nauck MA; Lancet 2006; 368: 1696–705
Primary outcome: Composite of-death from CV causes-nonfatal MI-nonfatal stroke-hospitalization for angina
Weight loss:1 year: 8.6% vs. 0.7% Study end: 6.0% vs. 3.5%
LOOK AHEAD Research Group; NEJM 2013; 369:145-54
Association of Magnitude of Weight Loss with CVD Incidence The LOOK AHEAD Study: Secondary Analysis
Look Ahead Study Group; Lancet Diabetes Endocrinol 2016;4:913-921
Weight Change Groups (% weight loss in 1st year)
Gain/Stable(<2% loss)
Small Loss (2-5%)
Medium Loss (5-10%)
Large Loss (> 10%) Test for Trend
Primary Outcome (composite of CVD death, myocardial infarction, stroke, or angina hospitalization)
Events/person years 289/17075 141/7870 154/8570 128/8942
Crude rate/100 person years
1.69 1.79 1.80 1.43
Unadusted HR (95% CI) 1.0 1.07 (0.88-1.31) 1.07 (0.88-1.31) 0.83 (0.67-1.02) 0.21
Adjusted HR (95% CI) 1.0 1.08 (0.88-1.33) 1.16 (0.95-1.42) 0.79 (0.64-0.98) 0.17
Secondary Outcome (Primary outcome plus CABG, CEA, percutaneous coronary intervention, hospitalization for CHF, PVD, total mortality)
Events/person years 422/16699 206/7657 203/8411 186/8792
Crude rate/100 person years
2.53 2.69 2.41 2.12
Unadjusted HR (95% CI) 1.0 1.08 (0.91-1.27) 0.96 (0.81-1.13) 0.83 (0.70-0.99) 0.04
Adjusted HR (95% CI) 1.0 1.05 (0.88-1.25) 0.97 (0.82-1.16) 0.76 (0.63-0.91) 0.006
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
Lopaschuk GD, Verma S; JACC: Basic to Translational Science 2020; 5: 632-44
SGLT2-i and the Kidney-Heart Connection for Organ Protection
Tuttle KR et al; Amer Journal of Kidney Diseases 2021; 77:94-109
SGLT2 inhibition and glomerular hemodynamics in diabetes
CREDENCE: Effects of Canagliflozin vs Standard of Care in a Primary Renal Outcomes Trial (Primary & Renal Outcomes)
• Perkovic V et al; NEJM 2019; 380:2295-306.
Primary Composite Outcome: End-stage kidney disease, doubling of serum creatinine level, renal or CV death
Renal-Specific Composite Outcome: End-stage kidney disease, doubling of serum creatinine level, or renal death
Trial Population:• T2D (HbA1c 6.5-12%)• Albuminuric kidney disease:
eGFR 30-<90 ml/min/1.73m2Albuminuria (UACR >300-5000)
• Treated with RAS blockade
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
Infl
uen
ce o
n d
rug
do
sage
s an
d c
ho
ices
; al
so a
sso
ciat
ed w
ith
ris
k o
f C
KD
p
rogr
essi
on
an
d a
dve
rse
ou
tco
mes
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
% f
un
ctio
n
Increased healthspan
Age
The concept of ‘healthy lifespan’
Considering the whole picture
Glucose
control
1
Weight
management
2
Disease
burden
4
Risk reduction
3
A broader, approach,
considering the whole picture is
needed to promote healthy
lifespan
Promoting “Ideal Cardiovascular Health”: Life’s Simple 7®
Health behaviours/risk factors
1.
Ogunmoroti et al. JAHA 2016; 5:e003954Ford et al. Circulation 2012;125:987–95https://www.heart.org/en/professional/workplace-health/lifes-simple-7; 2. https://playbook.heart.org/lifes-simple-7/
COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis; CKD, chronic kidney disease; PE, pulmonary embolism
Attainment of ≥3 of these health behaviours/risk factors translates into a
reduction in cardiovascular mortality
by greater than half
Cardiovascular disease Non-cardiovascular disease
Hip fractureDementiaCOPDDVT/PEPneumoniaCKDCancer
Inadequate Average Optimal
0
2
4
6
8
10
12
14
Even
t ra
te p
er 1
000
per
son
-yea
rs
HD
L
LD
L
7
Medication
Glucose Control
CardiovascularRisk Reduction
Overall burden
(disease, cost, etc)
Weight Management
Can Medications to Treat T2DM Support Interconnected Goals?
Davies MJ et al Diabetes Care 2018; 41:2669–2701
