To Glycemia and Beyond: Managing Cardiovascular Risk in People With Type 2 Diabetes Using Incretin-Based Therapies

Co-Chairs, John B. Buse, MD, PhD, and Pam R. Taub, MD, FACC, FASPC, discuss type 2 diabetes in this CME/AAPA activity titled “To Glycemia and Beyond: Managing Cardiovascular Risk in People With Type 2 Diabetes Using Incretin-Based Therapies.” For the full presentation, downloadable Practice Aids, and complete CME/AAPA information, and to apply for credit, please visit us at https://bit.ly/4l9nro0. CME/AAPA credit will be available until October 29, 2026.

1. To Glycemia and Beyond
Managing Cardiovascular Risk in People With
Type 2 Diabetes Using Incretin-Based Therapies

E

John B. Buse, MD, PhD
Verne S. Caviness
Distinguished Professor
Director, Diabetes Center
Director, NC Translational and
Clinical Sciences Institute
Senior Associate Dean,
Clinical Research

University of North Carolina
School of Medicine

Chapel Hill, North Carolina

Pam R. Taub, MD, FACC, FASPC
Director of Preventive Cardiology
Director of Step Family Foundation
Cardiovascular Rehabilitation and
Wellness Center

Professor of Medicine

UC San Diego Health System

La Jolla, California

Go online to access full CME/AAPA information, including faculty disclosures.

Copyright © 2000-2025, PeerView

2. Our Goals for Today

Enhance your ability to identify people with type 2 diabetes
mellitus (PWT2DM) who are at high risk of cardiovascular
(CV) complications

Update your knowledge of current guidelines and recent
evidence for CV risk reduction of GLP-1-based therapies
in PwT2D

Equip you with strategies for putting these new guidelines
into practice to individualize and intensify therapy for PwT2D

2000-2025, PeerView

3. Show Me the Evidence

Spotlight on Cardiovascular Risks
Bridging the Gap in Early Identification in PwT2DM

to Align With Emerging Evidence and Guidelines

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4. Improvements Are Needed to Reduce the Prevalence
d Inequalities betes-Related Complications

CDC: Trends and Inequalities in Diabetes-Related
Complications Among US Adults, 2000-2020'

Inequality Trends
ace end ex
typerglycomtc crisis 20 nt
TT
EL 20
HE
8> Hear failure Lt =
25 150
sé
5s ı Tf
é
FR a0 m
58 A AAA ee L = =
et
| Esuprmidess JL 4
2000 2002 2004 2006 2008 2010 2012 20M 206 2016 220
Time, y
1. Suelos Ret al. Dibolos Care, 2025:48:1029, PeerView

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5. 7.4
n=512 T2DM

n=722

+ rom DELIVER Dapagitein Evasion Improve th Lives o Patents WihPresened
Ejecion Facten Heat Fahre) rmay outcome. HF hospaaizaton or GY dea PeerView
1 Ostomnak Wet al Am Cal Corto 2025111011505

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6. Syndrome: The American Heart Associati

Classification System!

Stage 1

Se Stage 2 Stage 3 Stage 4
Nodos al Metabolic risk Subclinical CVD in Clinical CVD in
Y = factors and CKD CKM syndrome CKM syndrome
adipose tissue
Y

a > a

+ Focus on primordial + Overweight/obesity - Hypertriglyceridemia - Subclinical ASCVD
prevention and + Abdominal obesity + Hypertension + Subelinical HF
preserving CV health + Impaired glucose {nonmstabolietiolgies) + Risk equivalents of

tolerance KON subclinical CVD:
+ Moderate to very high-risk CKD;
ED high predicted risk

Metabolic syndrome for CVD using risk
calculator

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1. Ndumele CE et al. Circulation 2023;148:1608.

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7. How Is Car

Synthesis of T2DM
Guidelines From
Around the World

NICE
ADA
Esc
AACE/ACE
ACC

Canadian
Cardiovascular
Society

Chinese Diabetes
Society .
Chinese Society of .
Endocrinology N
KDIGO .

1. Agarwal A el al BMY. 2025:300:2082071

Poor glycemic control
Hypertension
Dyslipidemia
‘Smoking or tobacco use

vascular Risk Defined in T2DM
International Expert Panel Recommendations

and!
or

Higher
risk of
complications

Moderate

CV risk factors include but are not limited to
Harmful alcohol use or other substance use
Sedentary lifestyle

Family history of premature CVD or CKD

Obesity

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8. Guidelines Across Medical Specialties Increa

GLP-1-Based Therapies

Organization and Guideline Recommendation(s) for GL

First-line for PwT2DM and ASCVD, high CV risk, CKD, weight
o ol cere management, glucose lowering

AHA/ASA Updates in Stroke Prevention? Class 1 recommendation in PwT2DM

AHA/ACCIAANP/AAPA/ABC/ACCP/ACPM Class 2b recommendation for weight management in adults with
JAGSIAMA/ASPCINMA/PCNA/SGIM hypertension and BMI 227 kg/m?; may be effective as an adjunct
Guideline on High Blood Pressure in Adults? to reduce BP

ACC Scientific Statement on Obesity
Management in Heart Failure! For weight loss in HF (semaglutide or tirzepatide)
KDIGO/ADA Joint Consensus Statement on In addition to an SGLT2i if needed to achieve individualized
the Medical Treatment of PwT2DM in CKD® glycemic target

1. ADA Professional Pracice Commitee, Diabetes Care. 2025:48(Supp! 1) 5181-5206. 2. Raza AC et al. ACC Adv. 2025:4:101724,
3. Jones OW et al. Crcuianon, 2025 Aug 14. [Epub ahead of pin] 4. Ktbeson MM et al J Am Call Cardiol 2025 Jun 13 (Epub ahead of pen, PeerView
5. de Boer IHet al. Diabetes Care. 2022:45:3075-3090. e

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9. PeerView.com/ZSR827

GLP-1, GIP, and the Cardiovascular System!

Digestion Clinical Benefits
. Stroke risk |
y Ronen Eb Neuroprotection
Perfusion 7 Cardiac ischemia |
Contractility 7 Heart failure |
Heart rate } MACE rate |
Perfusion + Preservation of eGFR
Natriuresis } Kidney events |
Perfusion 7 an Rn
en Ea] Insulin resistance |
Perfusion ?
Vasculo-metabolic Metabolic optimization
coupling
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1.Avoguro A Fach GP. Lancet Diabetes Endocrine 202513790.802.

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10. GLP-1 RA Meta-Analysis: CV and Non-CV Outcomes in PwT2DM'

Parameter Hazard Rat NNT Reduction in
Trials (95% Cl) (95% Cl) Event, %
+ LEADER Three-point MACE 0.86 (0.81, 0.90) 63 (48, 97) 14
SUSTAINS: CV death 0.86 (0.79, 0.93) 139(95, 289) 14
+ EXSCEL
+ Harmony Outcomes Fatal or non-fatal MI 0.86 (0.79, 0.95) 141 (91, 357) 14
+ REWIND Fatal or non-fatal stroke 0.86 (0.79, 0.94) 234 (156, 525) 14
SIRIONFERS Hospital admission for HF 0.86 (0.79, 0.93) 199 (134, 421) 14
+ AMPLITUDE-O
Composite kidney outcome
+ FREEDOM-CVO dun ma onde 0.83(0.75,0.92) 170 (113, 380) 17
+ Fl
cou Worsening of kidney function 0.78 (0.69, 0.88) 134 (96, 243) 22
All-cause mortality 0.88 (0.82, 0.93) 102 (72, 185) 12
1. Lee MY tal. Diabetes Care. 2025:48:246-850 PeerView

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11. Fast Facts on STEP-HFpEF DM

Semaglutide in Adults With T2

Phase 3 Trial of Injectable
and Obesity-Related HFpEF

STEP-HFPEF DM Participants Had
Obesity-Related HFpEF and T2DM

Baseline Treatment
and HF History

83% used ß blocker

82% used ACEI, ARB, or ARNI

61% used loop diuretic

N=616
44% female; 69 years old (median)
pesen 85% had HTN
2 E
en = ES ool 39% had AF
64% had ?
BMI235 kofm? 24% had CAD
33% used SGLTA
Median =
- Median LVEF
None || Medienaic 30%
Median CRP 68% NYHA Class II
3.5 mg/L 71%

1.Kosiborod MN et al. N Engl JMed.2024,390:1394-1407.

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had HF hospitalization within 1 year

Median KCCQ-CSS: 59.4 points

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12. STEP-HFpEF DM: Injectable Semaglutide Effectively

Obesity-Related HFpEF in People With T2DM'

Change in KCCQ-CSS At 1 year, SC semaglutide led to larger
FE SC semaglutido reductions in dual primary endpoints in patients
2 with obesity-related HFpEF and T2DM
2 Estimated dference,
3 73 points
a RC 4.1404)
A ar
E Change in Bodyweight
2 o
3 2
E un
‘Time Since Randomization, wk 3 185%C1.7.5%-52)
N arian El Ps ot
maga 0 2 m m so <=
Load = ims a ul 5 SC semaglutide
maglutide reduced A1C, despite well- a
controlled glycemia at baseline, without an S
increase in clinically significant hypoglycemia cee ee à a oa a
e Time Since Randomization, wk
rene rene aa cepa 0 ay aaa mw aR
ed on anys of cvatance ne nan somoa eng dae, pe) om mma m am m m « PeerView

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13. MMI

Fast Facts

Phase 3 Trial of Tirz

With Obesity and HFpEF

El

SUMMIT Pa
Obesity and HFpEF

¡pants Had

Baseline Treatment
and HF History

N=731 80% used ACEI, ARB, or ARNI
54% female; 65 years old (mean)
74% used diuretic,
48% had T2DM
eu Eu ya aed 25% had AF 63% used $ blocker
te 30% had CAD
47% had HF hospitalization} within 1 year
Median
Mean LVEF
NT-proBNP
196 pgmLe || MeanesFR 60.8% 35% used MRA
Median hsCRP | | mL/min/1.73m* | | NYHA Class I
5.8 mg/L 72.5% used SGLT2i
Mean KCCQ-CSS: 53.5 points
2 in traepatide am.

1. Packer Metal. N Engl J Med, 2025:392:427-437.

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14. Tirzepatide Improves Outcomes in HFpEF: SUMMIT‘

Primary Outcome

Death From CV Causes or Worsening HF Event

HR 0.62 (95%, 041-095)
P= 02

Tu

‘Cumulative Incidence, %

izepaide

Time Since Randomization, wk

‘causes: 8 tirzepatide, 5 placebo; HR 1.58 (0.52 to 4.83)

other HFPEF trials, counted deat
jeaths

se death: 19 tirzepatide, 15 placebo; HR 1

om undetermined

line, %

1. Packer Metal. N Engl J Med, 2025:392:427-437.

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Change in KCCQ-CSS Change in 6MWD
E
as E sie
ws $3
jar dq
58%
¿de
eng so
Ben Bae
[2 E] 2 “raiment © €
Time, wk regimen Time, wk

esimans

Change in Weight

Placebo

Tiaepatce
31
u

à =

Le PeerView

Change From Baseline
in Body Weight, %
Bae à

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15. Fast Facts on

in Adults With

FLOW Participants Had T2DM and
Pre-Existing CKD

Baseline Treatment

and HF History

N = 3,533

30% female; 66.6 years old (mean)

83% used SGLT2i

80.2% used lipid-lowering drug

23.9% Asian | | Baseline SBP
Median BMI E 61.4% used insul
32 kglm? 45% Black || gasoline DBP uses sul)
157% Latinx | | 76.2 mmHg
= = Median eGFR
revious MI or 47. 50.4% used diuretic
troke 4 Gey mLmin/1.73 m? aes
22.9% z UACR
566 malg

SC semaglutide is approved to reduce the risk of sustained eGFR decline, ESKD,
and CV death in adults with T2DM and CKD?

1. Parone Veta Engl Med 2026391:108 121.2, Ozempe (mag) PresrbingInomnanon. ip un costa Jovi ges, docs ae IB ZOTAC

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16. Effect of Injectable Semaglutide
Key Findings From FLOW!

First Major Kidney Disease Event First Kidney-Specitic Component Event Total eGFR Slope

3

HR = 0.75 95% 0.066088)
Dr

HR = 0,79 8% 0.066084)

» Ao, Bu Sc somaptin
#0 Se somagialdo # 3
‘he 12) > sumo Fe
io En ll Zo

» » E Placebo

» » = "| orwena name 118 mumen on

” ‘SC semaghtide ee

Tine Since Randomization, mo Tine Since Randomization, mo

Time Since Randomization, mo

Risk of primary outcome (major kidney disease events ie, a composite of onset of kidney failure, 250% reduction
eGFR from baseline, or death from kidney-related or CV causes) reduced 24% in SC semaglutide group. Risk of
MACE was 18% lower, and the risk of death (any cause) was 20% lower, in the SC semaglutide group vs
placebo. More serious AEs were reported with placebo (53.8%) vs SC semaglutide (49.6%)

1. Pethoie Vet a. New Eng J Med, 2028 391:100421. PeerView

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17. Fast Facts on SOUL: Phase 3 Trial of Oral Semaglutide

in Adults With T2DM, ASCVD, and/or CKD'

SOUL Participants Had
T2DM and ASCVD and/or CKD

Baseline Treatment

ASCVD Meds T2DM Meds
N = 9,650 89% LLT 76% metformin
29% female; 68 years ld (median)
5 = 79% ACEVARB/ARNI AE
| 23% Asian | | 56% had CVD 29%] sulfonylurea
en 3% Black | | 13% had CKD 77% antiplatelet tx
14% Hispanic | | 27% had both 27%] SGLT2i
J 61% B blocker
; 23%] DPP-4i
Median hs-CRP PP
2.0 mg/L Mena 022600 42% diuretic [] 43% 120
40% had MI
eGFR 8.0%
74 mL/min/1.73 m? Mozeihadeircke) 9.5% anticoagulant 3% all others"
AG DR am od Mason. PeerView

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18. Oral Semaglutide Reduced MACE, Limb Events, A1C, and Weig

in PwT2DM and ASCVD and/or CKD: Key Findings From SOUL‘

Major Adverse =
MACE Limb Events AIG Weight
1
# HA sem choose 2,5 HR.0.71 (86% CI 082-096) H EN zagmeı s0
2 ey: No. ofevents pa.
ge 12 Ina orevons Ce Bs
® |» Placebo, 668 2.0 |" Semagiutise, 579 ad
10 |" Semagiuse, 579 78
5 seit Le
3 8 ri 6 =
Ê Bas De Oral
6 Placebo 13 Oral semaglutide
2 oral a . 2
3 o semaglutide; 5 73 illa se 83.6 (95% Cl,
34 semaglutide 12 Ss 834838)
E = 7.298% C1, 2%
o 2 EB 7273)
o 00 a 1 0 Y 1
0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 013 52 104 156 208 013 62 104 166 208
Months Since Randomization i Weeks Since Baseline
m
1. Meute DK el 1 Eng J Med. 2025 3922001-2012. PeerView

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19. Injectable Semaglutide Reduces the Progression of PAD

in PwT2DM: Evidence From STRIDE"

Median Maximum Walking Distance Median Maximum Pain-Free Walking Distance
52-week double-blind, vs Baseline (Primary Endpoint) vs Baseline

mmulpesniee RCT 125 Median difference vs placebo: 26.4 m
Adults with T2DM and (95% Cl, 11.8-40.9)

PAD with intermittent
claudication, able to
walk >200 m

— 25% women

Median difference vs placebo: 13.8 m
(95% Cl, 4.1-23.5)
SC semaglutide

116

SC semaglutide

— 68 y median age
— 41% BMI 230

Randomized to

semaglutide SC 1.0 mg " a o
or placebo + SC semaglutide resulted in clinically meaningful improvements in function,

symptoms, and QoL in PwT2DM and PAD!

Time Since Randomization, wk Time Since Randomization, wk

N 762) + MWD and PFWD were consistently and significantly improved regardiess of baseline
T2DM characteristics (eg, T2DM duration, BMI, AIC, or SGLT2i use)?
+ AEs similar to other clinical trials of SC semaglutide, with higher rates of GI AEs in
PwT2DM and BMI <30 kg/m? "
1. BanacaMP al Lact 2254051580196, 2. Run Weta Diels Care. 2025 ne 2 [pu ted ec PeerView

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20. Fast Facts on SURPASS-CVOT: Phase 3 Trial of Tirzepatide vs

Dulaglutide in PwT2DM and ASCV
First CVOT for a GIP/GLP-1 RA and first active-controlled CVOT for a GLP-1-based therapy
Baseline Treatment
DM and ASCVD for T2DM
N= 13,299 81% metformin
29% female; 64 years old (mean)
47%) insulin
MESE 100% had CVD 31%] SGLT2i
32.6 kg/m? 23% had CKD
21%] sulfonylurea
eGFR 65% had CAD ¡9 DRL
CUE Meanaic || 47% had MI [Jas 120
UACR 84% 25% had PAD
22 mg/g 19% had stroke: 11.6% a-glucosidase inhibitor

4. Meal tak Am Moa. 2024267:1-1. PeerView

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21. Reduced MACE in PwT2DM and ASCVD:

Key Findings From SURPASS-CVOT!

Study Design

+ Adults with T2DM and

established ASCVD

+ Intervention: tirzepatide,
titrated to 15 mg QW vs
dulaglutide 1.5 mg QW

+ Phase 3, 30 countries,
-5 years

+ N=13,299

Primary Endpoint

MACE-3 (CV death, MI, stroke) || Kidney function (eGFR)

+ Tirzepatide noninferior to + Slowed decline by 3.54 mL/min/1.73m? at 36 months
dulaglutide + Significant renal benefit in high-risk patients with CKD|

+ 8% lower event rate (P = NS) Glycemic control (A1C)

+ HR 0.92 (95.3% Cl: 0.83-1.01) || + Greater reduction with tirzepatide: -1.73% vs. -0.90%

All-cause mortality + Treatment difference: -0.83% (P < .001)

+ 16% reduction with tirzepatide [| Weight loss

+ HR 0.84 (95% CI: 0.75-0.94) + Tirzepatido: -11.43 kg

+ Dulaglutide: -4.65 kg

+ Difference: -7.1% (P< .001)

Key Secondary Endpoints

Safety and Tolerability '

+ Profiles generally consistent with known effects Conclusion

+ G-related side effects most common, mostly mild-to-moderate MA ESA

+ Discontinuation due to AEs: 13.3% tireepatide vs additional mortality, kidney, glycemic, and weight benefits
10.2% dulaglutide

|. ossinvest. hy cominewerelesesneve-eeese-delalsAlysmounyerotzepa deity us-agonstdemonstate. PeerView

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22. Evidence to Practice

Smart Steps Forward
Integrating Guidelines, Preferences,

and Priorities in T2DM Care

100-2025, PeerView

23. HF Significantly Worsens the Prognosis for T2DM‘2

T2DM increases the overall risk for HF
and is an independent risk factor

HF incidence is extremely high? in
patients with T2DM

- Manifested as HFpEF, HFrEF, and
HFmrEF

— All significantly worsen the prognosis for

+ HFPEF is seen in approximately 50%
of HF cases
= Itis a heterogenous syndrome with
discrete phenotypes, particularly in close
association with metabolic syndrome.

+ Yet, management of HFPEF in T2DM

remains unclear, largely due to the poorly

defined pathophysiology of HFPEF

* Estimated prevalence of 9% to 22% (four times higher than nthe general population) and even higher prevalence in ats age 260 years.
1. Abudureyima M ell. J Mo Gell Bo. 2022:14 mjac028. 2. Dunlay SM etal. Circulation. 2019, 140322940324.

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[rrrerension] [yperinsusinomia] [Obesity } [Dystiiaema) (erisene

mar) (Ars
Ces) (onan

{ T
À mm id

Cardiac remodeling Vascular damage

=) ae) RES) C&S
fibrosis | [stress ) (restriction) | retention

1
G cs

Pericardial restraint

yyy yyy Y 4, \
WWW WEY lem EN
ee Ey eg
A: 27 a
+

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24. Recognizing the Symptoms and Signs

of Heart Failure in PwT2DM'

Symptoms Signs
Typical Less Typical More Specific Less Specific

+ Ankle swelling + Nocturnal + Elevated jugular * Unintentional weight gain (>2 kg/week)
+ Swelling parts of ‘cough venous pressure + Weight loss (in advanced HF) with muscle

the body other + Wheezing « Third heart sound wasting and cachexia

than ankles + Bloated feeling (gallop rhythm) + Tissue wasting (cachexia)
+ Breathlessness + Postprandial + Summation gallop + Cardiac murmur
+ Orthopnea satiety with third and + Peripheral oedema (ankle, sacral, scrotal)
+ Paroxysmal + Loss of appetite fourth heart + Pulmonary rales

noctumal dyspnea + Decline in sounds + Reduced air entry and duliness to percussion
+ Reduced exercise cognitive + Cardiomegaly at lung bases suggestive of pleural effusion

tolerance function + Laterally displaced + Tachycardia
+ Fatigue + Confusion apical impulse + Irregular pulse
+ Tiredness (especially in + Hepatojugular + Tachypnea
+ Inability to the elderly) reflux + Hepatomegaly

exercise + Depression + Cheyne Stokes + Ascites
+ Bendopnea + Dizziness respiration in + Cold extremities

+ Syncope advanced HF + Oliguria
+ Narrow pulse pressure

1. Cr Act al Cordova Diabet! 202120218 PeerView

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25. Heart Failure Screenin

ADA Screening Screening Tests Diagnostic Recommendations
Guidelines for " Criteria for HF for PwT2DM at Risk
Undiagnosed HF Biomarkers of Developing HF
+ NT-proBNP >125 pg/mL or
S f BNP >35 pg/mL Elevated + Lower BP to <130/80
¡creen al = NT-proBNP or amg
adults with BNP + Examination by ECG
diabetes + AIC En at resting stage
i + Routine assessment
| Echocardiography (Objective evidence of microalbuminuria
+ Most useful, noninvasive u + Routine assessment
7 " of cardiogenic
I BNP or diagnostic method for detecting ; of eGFR
NT-proBNP structural changes eS en Ss + Lifestyle changes
e + Measures LVEF ER + RAAS blocker
Poe ce congestions by administration
o diagnostic + Assessment of BMI
do echo + Rarely completely normal in HF modalities or
+ Perform resting ECG in hemodynamic
PwT2DM and hypertension measurements

+, Cerielo A e al Cariovase Diabet 2021:20218.2. ADA Professional Pradice Commitee, Diabetes Care. 2025:48(Supp 1) 5207-5238. PeerView

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26. How Is Kidney Risk Defined in T2DM

International Expert Panel Recommendations?

Persistent Albuminuria

A A2 A3

GFR (estimated or measured),

mUmin/t.73m2 Normal or Mildly Moderately
Increased Increased

<30 mg/g 30-300 mgig

<3 mg/mmol 3-30 mgimmol

‘Severely Increased
>300 mg/g
>30 mg/mmol

Guideline KDIGO

Risk Risk
Category Category

Normal or high

Gu lea Moderate Moderate
Low nisk
02 Milly decreased Moderate Moderate Moderate
risk Moderate:
Mildly to moderately risk
G3a decreased Moderate
45-59
Moderately to severely Dates
Gb decreased
So Very high
Severely decreased risk
S4 4529
Kidney failure
CE
1. Agarvl Act at BM 2025 300:2082071 PeerView

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27. Current Recommenda

+ Liraglutide,
dulaglutide: when
initiating or escalating
dose in patients with
any degree of renal
impairment

2 GR in mLUmint 730,
4. Mounjaro(irzepatide) Prescrbing infemmasen. . ips.

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s for Use of Available

Agents by Renal Status'+2

+ Dulaglutide, tirzepatide:
if reporting severe Gl AEs
+ Semaglutide: monitor
renal function in patients
reporting adverse
reactions that could lead to
volume depletion

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28. International Expert Panel Attempted to Harmonize

Treatment Recommendations Across Disciplines’

1. Agarwal À et al BMY. 2025:290.00820711

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strongly in SGLT2i
favor of = u GLP-1 RA
SGLT2i nSMRA (people
Weakly in GIP/GLP-1 RA E en
geo Er SERA GIPIGLP-1 RA
5 GIPIGLP-1 RA (people with obesity) | (people wit obesity)
5 Weakly Sek nsMRA
5 | against GLP-1 RA (people with CKD) u
E
SGLTA: 110 SGLT2i: 110
Evidence, SEN GLP-1 RA: 109 GLP-1 RA: 109
" GLP-1 RA: 109
Wot tials O GIPIGLP-1 RA: 6 GIPIGLP-1 RA: 6
¡ neMRA: 2 nsMRA: 2
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29. Overview of Approved GLP-1 RAs and GIP/GLP-1 RAs

for MACE and T2DM?

Indications Dulaglutide! Liraglutide? Semaglutide Semaglutide

Gan aes Tirzepatide®
‘Adjunet to diet and exercise to improve glycemic

‘control in adults with T2DM Kes Nes = = =
Adjunct to diet and exercise to improve glycemic Ye Ye

control in patients aged 210 years with T2DM bed es: = = =
Reduce risk of MAGE in adults with T2DM and m a y

established CVD ee bd =: ies u
Reduce risk of MACE in adults with T2DM and at vi

high risk of these events 7 7 = 7 -
Reduce risk of MACE in adults with T2DM and %

multiple CV risk factors ES = = - =
Reduce risk of sustained eGFR decline, ESKD, Ye

and CV death in adults with T2DM and CKD u u = ee u
Dosing Frequency and Route oe Daily SC Daily oral ral PN

Sama GLP.1-base agent have atonal ears when prescritos tor obey.

{truley eig) Praseranginamaten Nip prov acordo gewann 4 ace 2028 12408063 pst

2 Vidoes aguice)Prosaing reden ps vow acorta Ria gan gta doser 250225418000 pl

map rang mater pen process. al PeerVi

À Grange samp) rserbng Information nips we access a ouate cy abal2026 206617502610

5. Mounier (uzepabe) Prescribing Information. nips www. accusscate ka go Er gratas, ecs/1abal202521 5886409 DPA. eerview

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30. Change in A1C

a > © a .

a
at do
as v2
23 22
ta |] 35
2E - SE
ee 28
ae 35
EEN 33
Se 8
88: FR
E 8
2 se
ö
Liraglutide I Douce D Semaalutide EH Seragluidecral gg Tizepatide
1.8 mg QD 1.5 mg QW SC 1 mg QW 14 mg QD 15 mg QW
PeerView

1.Kang YM el al. Diabetes Obes Metab, 2025,27:3728-3748.

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31. Approach to Incorporating a GLP-1 RA Therapy

in Insulin-Treated Patients With T2DM!

Insulin Regimen

Basal insulin only

8

Intensive insulin

Suggested Changes in Insulin Therapy Based on Current A1C and
Current Insulin Regimen at the Time of GLP-1 RA Initiation

therapy (eg, mutiple daily
Injections or pump therapy)

A
A

O

atc <

Reduce basal insulin by 20%
Consider further reduction of basal insulin (e 9.,
50%) with escalating doses of GLP-1 RA,
depending on glucose profile

Consider reducing or holding basal insulin before
initiating the maximum dose of GLP-1 RA based on
current fasting blood glucose levels

Reduce all insulin therapy by 20% initially
Consider holding prandial insulin and further
‘reducing basal insulin with escalating doses of
GLP-1 RA

Prandial insulin may be added back, if indicated,
once the maximum dose of GLP-1 RA is reached

AIC 28.0%

+ No change in insulin therapy unless there is
‘concem about barriers to taking insulin or the
patient is on a >0.5 uniVkg insulin dose, in which
case consider a 20% reduction in basal insulin

+ Consider reducing basal insulin by 220% with
escalating doses of GLP-1 RA, depending on
glucose profile

+ No change in insulin therapy unless there is
concem about barriers to taking insulin or the
patient is on a >0.5 unit/kg dose of basal insulin, in
which case consider a 20% reduction

+ Consider reducing insulin by 220% with escalating
doses of GLP-1 RA with an attempt to reduce or
minimize prandial insulin first

discuss the daily dose of insulin patients are actually taking versus the dose prescribed.

| Insulin titration is based on patients’ total daily dose of insulin, but care must be taken to frankly

1. Ehrhardt NM ela. Cin Diabetes. 2024:42:341-95.

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Copyright © 2000-2025, PeerView

32. GLP-1 RAs Do Not Increase Risk of Suicidality in Pw

or PwO: Evidence From a Meta-Analysis of RCTs

‘Summary Estimates for Subgroup and Sensitivity Analyses of Studies Comparing
Glucagon-Like Peptide Receptors Agonists and Placebo Comparators

Risk Ratio (95% Cl)

Comparison
All studies comparing GLP-1 RAs and placebo
Participants with diabetes

Participants without diabetes

History of suicidality or depression as exclusion criterion
Columbia Suicide Severity Rating Scale included
Albiglutide

Dulaglutide

Efpeglenatide

Exenatide

Liraglutide

Lixisenatide

Semaglutide

1. EbrahimiP et al. JAMA Poychätıy 2025.82 888-805,

PeerView.com/ZSR827

0.76 (0.48-1.21)
0.76 (0.44-1.33)
0.76 (0.34-1.75)
0.76 (0.46-1.26)
0.81 (0.60-1.10)
0.72 (0.21-2.48)
0.54 (0.10-2.85)
1.01 (0.04-24.7)
0.84 (0.25-2.81)
0.87 (0.40-1.86)

5.00 (0.24-104.1)
0.55 (0.20-1.25)

PeerView

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33. Incretin Therapies and Thyroid Cancer Risk: Recent Evidence

Author, Year (GLP-1 RA Users,N) Study Focus Key Findings

= Evaluation ofthyroid cancer risk in No increased thyroid cancer risk vs metformin
Saeta a 208 CHA) GLP-1 RA users with thyroid nodules _ users (RR 0.99)

‘Scandinavian cohort study No increased thyroid cancer risk (HR 0.93) for

Pasternak et al, 2024 (= 145K)? comparing GLP-1 RA use vs DPP-4i — GLP-1 RA users

Baxter et al, 2025 (=98kP International multsite cohort study No increased thyroid cancer risk vs DPP-41 (HR 0.81)

Risk of thyroid tumors with GLP-1 RA

Morales el al, 2025 (=460k)* ened pi rbd

No increased risk vs SGLT2, DPP-4i, or sulfonylurea

No Increased Risk

Meta-analysis of 45 RCTS in T2DM,
Huet al, 2022 (=94K an No significant effect on thyroid cancer (RR 1.30)

Bezin et al, 2023 French national study on GLP-1 RA Increased thyroid cancer risk with GLP-1 RA, especially with
(0=3.7M PwT2DM6 use and thyroid cancer 1-3 years of use (HR 1.58).

Obesity cohort analysis of GLP-1 RA Liraglutide increased thyroid cancer risk (HR 1.70) and

Lowy etal 2025 CLIMENON and cancer risk respiratory cancer risks; semaglutide reduced cancer risks

Meta-analysis of 44 RCTS in T2DM increased thyroid cancer risk with GLP-1 RA (RR 1.62);
and obesity NNH = 1,699

Duchemin et al, 2025 (=48K)*

+ Most RWE shows no increased risk of thyroid cancer over ~3-5 years
+ Signals of possible increased risk may be due to residual confounding, surveillance bias, or true drug heterogeneity
+ MTC cases were extremely rare, limiting statistical power

1.Balochanta 8 eta. Surg Res 2025:312: 104-10. 2, Pstemak eta EU. 2024285 20762253. Baxter SM tal. Thyoid 2025:35:6078 >
4 Moales DR et al. Diabetes Care 2025.48 1.9.5 Hu Vret al Front Endocmol 20223-42785 6. Bei Jet a. Diabetes are 202846 84-990, PeerView

7. Lew Set al, Cancers, 2025:17:78. 8, Duchemin Leta. Diabetes Obes Metab, 2025.27:4607.4610.

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34. GLP-1 RA Therapies and Sight-Threatening Complications:

Real-World Evidence (TriNetX Database)!

No. of Events

with

GLP-1RA GLP-1RA

Entire cohort (N = 185,066)

Diabetic retinopathy son
NAION 96
Neovascular glaucoma me,
Blindness 2513
Pre-existing DR subgroup (n = 32,695)

POR 1,121
DME 7,390
Neovascular glaucoma 434
NAION 34
Vitreous hemorrhage 1135
Laser photocoagulation 698
Vitrectomy 445
Treatment with anti-VEGF medications 296
Composite treatment outcome 2341
Blindness 4,280

1. Ramsey DJ etal. JANA Netw Open. 2025 862526921

PeerView.com/ZSR827

Without

79
559
3,051

1,039
7,425
562

1,542
894
72
355

2,547

1,833

HR (95% CI)

1.07 (1.03-1.11)
1.26 (0.94-1.70)
0.82 (0.73-0.93)
0.77 (0.73-0.82)

1.06 (0.97-1.15)
0.98 (0.95-1.01)
0.76 (0.68-0.88)
0.91 (0.57-1.45)
0.74 (0.68-0.80)
0.79(0.71-0.87)
0.62 (0.55-0.70)
0.84 (0.72-0.98)
0.92 (0.87-0.97)
0.69 (0.65-0.75)

Favors | Does not favor
GLP-1 RAS! GLP=1 RAS

AI
=}
= |
1

CE
Il Pre-existing DR subsroup|

08 10 12 14 18 18
Hazard Ratio (95% CI)

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Copyright © 2000-2025, PeerView

35. Minimizing and Managing Adverse Effects

of GLP-1-Based Medications’?

AE Suggest

ns for Minin

ing or Managing MEAL Plan: Diet and Exercise Guidance
for Patients Taking GLP-1-Based Agents

GI + Gradual dose escalation to minimize GI symptoms
discomfort — -= Consider dose reduction or discontinuation if Maintain muscle.
(general) symptoms persist + 20-30 g protein per meal
+ Eat smaller, more frequent meals Energize and balance
isos + Avoid high fat foods, aloho and carbonated + Snacks between meals
+ Use antiemetics for severe cases (eg, ondansetron) sr Siow cigsetiig foods
Avoid GLP-1 AEs
+ Ensure proper hydration 5
Vomiting + Consider smaller, frequent meals + Constipation: increase fiber, stay hydrated
+ Use antiemetics if necessary + Nausea: avoid fried foods, eat whole
Increase fiber and water intake ne = en o
Det + Use OTC antidiamheal medications as needed Dour ES ose ol Ea

Increase dietary fiber and hydration
Constipation + Consider stool softeners or laxatives (eg, psyllium,

polyethylene glycol)
Physical activity
i + Use proton pump inhibitors or H2 blockers for on
Dyspepsia nora roi (og, omeprazalo Tarot) Aerobic exercise: 150 min/wk

+ Strength training: 30 min, 2-3x/wk

1. Kushner RF et al. JAMA. 2025 July 29. Online ahead of print. 2. Wharton S et al Postgrad Med. 2022:134:1,14-19. Ji
3. Mehrash etl JANA Item Med. 2025,185 1180. PeerView

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36. Slower Uptitration Improves Adherence and Reduces AEs‘

Aim: This study examined whether a slower flexible titration regimen of semaglutide vs
the label recommended regimen results in better adherence and reduce GI AEs

Increase by 5 clicks n=51
ce (0.0875 mg) TI xq 0
+
Start 5 cicks AG flexible tiation EEE 0
(0.0675 mg/wk) ES É 2
BBs
te 80
— Flexible
i E : 7] = Label
ES 60
Time, wk 0 4 8 12 16 20 24 28
5 4 68 2 6 oo 2 ‘Tina

+ In the flexible regimen, the dose was determined by counting “clicks”
made by the dose selector dial

+ Semaglutide was started at 5 clicks (0.0675 mg) and increased by
5 clicks/wk until a dose of 1 mg/wk (74 clicks) was achieved

+ If Gl AEs occurred, patients were instructed to delay dose escalation
until resolution 7

1. Ear Rell Diabetes Core. 202548:1607-161. PeerView

Aslower and more flexible titration regimen of
semaglutide resulted in better adherence

and fewer semaglutide-related AEs

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37. 282 adults with T2DM
‘AIC 27.0% lo 39.5%
EMI 225 kg/m?

Dulaglutido 0.75 mg or 1.5 mg 26 mo
0-3 oral antinyperglycemic agents 23 mo

E o weeks
8
>
€
30 sTicepatde, 15 mg or MTD
2
2 0 = Duaguie, 4 mg or MTD
2 2 213

20

24
o
H a ss 7
AIC Target, %

4. Bilings LK etal. Ann Intern Med. 2025,178.909:619.

PeerView.com/ZSR827

& 10
E 824

80
3 40 376 46
be a
Sy = 08
5 25 210 215

Weight Loss, %
PeerView

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38. Case Studies

Copyright © 2000-2025, Peerview

39. Case Study

Patient overview

+ Female patient, aged 52 years

+ 5-y history of T2DM, HTN, and dyslipidemia

+ Nonsmoker, sedentary lifestyle

+ Has gained weight over the past year
despite lifestyle changes

Lab values

+ BMI: 34.0 kg/m?
* AIC: 8.4%
+ TC: 173 mg/dL, HDL-C: 46 mg/dL

BP: 137/79 mmHg
+ eGFR: 55 mL/min/1.73 m?

Medication list N
+ Statin (moderate dose)

+ Metformin

+ Antihypertensive y

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PeerView

40. Case Study

Patient overview
Female patient, aged 52 years

+ 5-y history of T2DM, HTN, and dyslipidemia RiskiAseesement With

1
Nonsmoker, sedentary lifestyle PREVENT A1C Model

Has gained weight over the past year
despite lifestyle changes Outcome 10-y

k,% 3

Lab values CvD 14.9 50.2

+ BMI: 34.0 kg/m?
+ A1C:8.4% ASCVD 8.9 31.5
+ TC: 173 mg/dL, HDL-C: 46 mg/dL.

BP: 137/79 mmHg HF 10.4 41.5
eGFR: 55 mL/min/1.73 m2

Medication list

+ Statin (moderate dose)
+ Metformin

+ Antihypertensive

1 ps professional newt orgenguielnes-and tement reventikcaclalo/reventcaclato, PeerView

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41. Case Study #2

Patient overview

+ Male patient, aged 64 years

+ 10-y history of T2DM, HTN, and obesity
+ Miwith PCI 3 y ago

Lab values

+ BMI: 31.0 kg/m?

+ A1C:8.0%

+ TC: ?,HDL-C:?
BP: ?

+ eGFR: 58 mL/min/1.73 m?

Medication list
+ Metformin =
+ DPP-4i
+ Valsartan:
+ Metoprolol
+ Aspirin
Rosuvastatin PeerView

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42. Case Study #2

Patient overview

+ Male patient, aged 64 years

+ 10-y history of T2DM, HTN, and obesity
+ Miwith PCI 3 y ago

Lab values

+ BMI: 31.0 kg/m?

+ A1C:8.0%

+ TC:?,HDL-C:?

+ BP:?

+ eGFR: 58 mL/min/1.73 m2

Medication list
+ Metformin

+ DPP-4i

+ Valsartan:

+ Metoprolol

+ Aspirin

+ Rosuvastatin

PeerView.com/ZSR827

980
a

PREVENT equations are
inappropriate (he has already
hadan event)

ACC risk criteria: very high-risk

(one major ASCVD event +
multiple high-risk conditions
[hx PCI, T2DM, HTN, CKD])

International expert consensus:
higher risk of complications

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43. Early treatment
intensification may
prevent the progression
of cardio-renal-metabolic
disease, increasing
patients’ healthy lifespan

PeerView

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