Transforming T2DM Treatment in Primary Care: Discerning the Glycemic and Extra-Glycemic Effects of GLP-1 RAs

Chair and Presenter Vanita R. Aroda, MD, and Amy Butts, PA-C, MPAS, DFAAPA, CDCES, BC-ADM, discuss type 2 diabetes in this CME/NCPD/AAPA/IPCE activity titled “Transforming T2DM Treatment in Primary Care: Discerning the Glycemic and Extra-Glycemic Effects of GLP-1 RAs.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4a211i6. CME/NCPD/AAPA/IPCE credit will be available until August 6, 2025.

1. Transforming T2DM

Treatment in Primary Care
Discerning the Glycemic and
Extra-Glycemic Effects of GLP-1 RAs

Vanita Aroda, MD Amy Butts, PA-C, MPAS, DFAAPA,

Director, Diabetes Clinical Research CDCES, BC-ADM
Brigham 8 Women's Hospital Endocrinology Physician Assistant
Harvard Medical School President, American Society of Endocrine

Boston, Massachusetts Physician Assistants

WVU Medicine Wheeling Hospital

Wellsburg Clinic

Wellsburg, West Virginia

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

Copyright

2. Our Goals for Today

Describe the role of GLP-1 RAs in T2DM management to
optimize outcomes and reduce complications

Compare the profiles of current GLP-1 RAs

Equip you with the skills to identify patients with T2DM who
would benefit from treatment with GLP-1 RAs

Provide you with guidance to counsel patients about the
efficacy and safety of GLP-1 RAs in order to help them reach
their health goals

Copyright ©

3. The Problem—We Haven’t Made Progress:
Risk Profile Trends in US Adults With CVD, 1999-201812

Blood Pressure

+ Overall worsening trend after 2010

Overall worsening trend - 49% <
52% with ideal profile (A1C <7% if diabetes or a a ae
5.7% if not) in 2015-2018 + Worst profile in Black adult
Worst profile in Asian adults ee
Body Mass Index
* Overall worsening trend y
RESTE + 18% with ideal profile (BMI <25 kg/m?) in 2015-2018 61

+ Nointeraction of trends with race/ethnicity

+ Overall improving trend a
+ 30% with ideal profile (non-HDL-C <100 mg/dL)
20162018
* Worsening trend in Hispanic adults = Overall worsening trend
+ 22% with ideal profile meeting guideline-
recommended levels in 2015-2018
- Ones —

+ 78% with ideal profile (never smoked or quit RO EAN unchanged)

a a + 1% with ideal profile (HEI score 280) in 2015-2018
A Na + No interaction of trends with race/ethnicity

2 6336 US adults we separe Misty of CO mn
‘a0 eta oc 202280 1201. PeerView.com

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4. Trends in A1C Control (<8%) by Insurance Type:
2022-2021 National Averages’

400 Adults Aged 18-75 Years With T1DM and T2DM With A1C <8%

æ 80 Medicare reporting
g ÉTÉ Medicare PPO
E] - care
€ pandemic Medicare HMO
E —
2 60 Commercial HMO
& Commercial PPO
2 Medicaid HMO
S 40
E
5
2
2
a 20

o

2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

Year .
1. ps Tuna nega orghedsmeasurestcomprehensive-diabetes-car PeerView.com

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5. A1C Risk Profiles Among Adults With CVD

Trends in Ideal Risk Profiles of A1C Among Adults With CVD, 1999-2018

AIC Risk Profiles
"Ideal = Intermediate "Poor

The proportion with ideal A1C values decreased from 100
58.7% in 1999-2002 to 52.4% in 2015-2018

90
80
70
60
50
40

30
1999-2002 2003-2008 2007-2010 2011-2014 2015-2018 10

Time, y

Participants, %

P= .001 for linear trend

1999-2002 2003-2006 2007-2010 2011-2014 2015-2018

Black adults were least likely to have ideal risk profiles for blood pressure
and Asians were least likely to have ideal risk profiles for A1C levels vs White adults (P < .05)

1.600 Y et al. JAC. 2022012) 126-137. PeerView.com

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6. T2DM Is Strongly Associated With Several
Macrovascular and Microvascular Complications!

Coronary heart disease

Provence: 14%.21%
Most raquonty reported formo CVD and most ta ono.

Fisk ol death om CHD is hgh in women than a ran
HR = 1.81 (5% CL, 127-250) vs HR 1.48 (95% CI, 110-199)

Heart failure

Prevalence: 19%:20%
‘Secon most commen in manesiaton of CVD in TZOM
ako HF is up o 24d in men and Sid in woman

Peripheral artery disease

Prevalence: 10%29%
‘Most common int! mares of CVD in T2OM
Prevalence is 18404 higher in women compared wih men

Prevalence: 812%

‘Secon most frequent cause of death in patents
‘wih TZOM ater CHD

Provence simlarin man and women

1. Dal Canto E eta. Eur Prov Cardiol 2019 26(suppl 2)25-32.

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Prevalence: 34%
Most common microvascular complication of diabetes;
responsible for 2.6% of all cases ol bindness worldwide

Prevalence rates are higher in THOM compared
win T20M (17.9% vs 25.2%)

Cardiac autonome neuropathy
Prevalence: 31%-73% in poople wih T2DM
"No difference in prevalence between men and women

Nephropathy

Prevalence: 29%-61%
Leading cause of end-stage renal disease in the adult
‘population worldwide

Female sexis. ik factor for nephropathy in T20M

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7. Coming Full Circle: Prioritizing Early Glycemic Management
to Reduce Microvascular and Macrovascular Complications!

Focus on multimorbidity: glycemic and weight management
and risk factors related to T2DM comorbidities

¿ON
VE

Lifestyle

®

TANT]
Early

Individual
h management of
with T2DM | multfactorial

risk factors

1. Khan K, Ada VR, Diabetes Caro. 2022:45:766-768.

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z
E
E
é
3
2
<

Lifestyle and
armacatherapy

|

Duration of Diabetes

Early glucose-lowering therapy,
regular assessment, and treatment
intensification to achieve and
maintain goals

Incorporation of
SGLT2i and/or
GLP-1 RA
(oral vs injectable)
in those with
established/high
risk of ASCVD

Goal of reducing
microvascular and
macrovascular
complications

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8. ADA Standards: Holistic Person-Centered Approach
to T2DM Management'

Components of Care : Glycemic Management

Choose approaches that provide the efficacy
to achieve goals

Metformin OR agent(s) including COMBINATION
therapy that provide adequate EFFICACY to achieve
and maintain treatment goals.

Prioritize avoidance of hypoglycemia in

high-risk individuals
+ In general, higher efficacy approaches have greater
likelinood of achieving glycemic goals

Efficacy for Glucose Lowering

Dulaglutide (high dose), semagl
Very High tirzepatide, insulin, combination oral,
combination injectable (GLP-1 RA/insulin)

GLP-1 RA (not listed above), metformin,
SGLT2i, sulfonylurea, TZD

Intermediate __DPP-4i

Principles of Care

4. Davies Mot a. Dietas Caro. 2022:462750-2786 a
2. American Diabetes Associaton Professional Practice Commitee. Diabetes Caro. 2024.47(supal1):5158-S178. PeerView.com

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9. Comparative Efficacy: Differential Effects of Various
Glucose-Lowering Agents for T2DM'

Change in Body Weight, kg Hypoglycemia <70 mg/dL

Comparison: Other
vs Placebo (Random MD (95% CI)
Effects Model)

Trzepatdo 15mg 20222t0-118) Trzepa (049 (0.17 101.6)
Trzepatdo 10 mg 1.86 (209 19-183) Tzapatido 10 mg 327 (866 0 + 088 0100 4.19
Tizopatide 4 m9 153 (209 40-139) SGLTA + GLP-1 RA 547 (61610479) ¡iia
ann See say Re ae Serene Tirzepatide 5 mg 1.32 (0.74 10237)
0 lego 4519 5) Treat 1108510

Bacatbows inulin 150 (222 10-098) Semagluido 2 mg “253 -4.36 10-270) aan temo ETE
¡ola 4:52 (4.8240 422) SGLTZI S48 (4:1110-277) 13

SGLT2 + GLP-1 RA 131 (17110-0391) Dulglside 3 mg 316138210209) SOLTA+OLPARA 1:78 (035 00.18)
BlAsp3O 425 (1.8710 0.69) GLP-1 RA -269(20610-220) Dulaghtide Img 18203019)
Semagutido 2 mg 2418 (4.78 10-050) ¡Glas 005 (03710048) Bosaliuin + SU 280 05810 1349)
Duiagiutide 4.5 mg 4.11 4.5110-0.70) iDegtira a 01003410054) | Dulagltide 4.5 mg He 329 (0.67 10 16.18)
Dulagiido 3 mg 2400 61.44 10-05) Baza insu 152(1:13:0191) Dogkra 4.79((.85t0 1241)
Basalinsum + :990(1.1610.005) Bssalinsuin + SU 1650021327) | Basalinsuin 621 (28210982)
GLPA RA 000011210000) Ban 195(1:1010279) Gr 547 (28010 1068)
saurai 0.45 (0 86 10-006) Basat nbs insti M 36012661454) Buer30 {=m 697 24907259

This meta-analysis of 40 trials concludes with the following hierarchy of treatment options:
rzepatide, then GLP-1 RA + basal insulin FRC, then GLP-1 RA + SGLT2i

1. Caruso |e. eClnicalMediche. 202464: 102181 PeerView.com

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10. GLP-1 RAs Provide Benefits Beyond Glucose Control!

Blood vy | LS total

| RO

Pen 2° rs

ctions ‘Acinar col
lar

¡asc enoting
im nervous system
1 Chylomiron ‘Adpoore

PA Rates aay ke nues)
Soe inesines.
: Namen - eeu — |,
2 Vase 1 Body weight
casado codes Uintonmaten

| Gacdovaciar | Nonfat

Outcomes
pe — |

4. Ussher JR, Drucker DJ Not Rev Cardio 2029,20:483-474.

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11. ADA Standards: Holistic Person-Centered Approach
to T2DM Management!?

Components of Care Achievement and Maintenance of Weight
Management Goals

Set individualized weight management goals

+ Intensive, evidence-based,
nutrition therapy, eating structured weight
patterns, physical activity | management program

+ Consider medication + Consider metabolic,
for weight loss surgery

+ Prevent complications
Opimze quality of fe The preferred pharmacotherapy should be a GLP-1 RA
€ or dual GIP/GLP-1 RA with greater weight loss efficacy

Very High Semaglutide, tirzep:

High Dulaglutide, liraglutido

Intermediate GLP-1 RA (not covered above), SGLT2i

Neutral DPP-4i, metformin

1, Davies et a. Diabetes Cao
212248 275% 2106.2 Amarean Dietas Associaton Professional Practico Commie, Diabetes Care. 2024:7(supl 1) 1586178 PeerView.com

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12. ADA Standards: Holistic Person-Centered Approach
to T2DM Management!

Components of Care

Ensure Strategies Are in Place to

Detect and Optimize Management
of CV Risk Factors

CV risk factor history, physical, and
screening and ECG NT-proBNP,
surveillance BNP, or hs-cTn
target
<130/80 mmHg

BP lowering

Prevent complications
‘Optimize qualty of fe

Lipid lowering statins

Antithrombotic indicated for secondary
agent prevention

Smoking

cessation oral

Principles of Care

1- Davies Wu et a. Diabetes Care 202245:2755-2785.2. American Diabetes Associaton Prlessena Practice Commitee. Diabetes Care. je
2024:47(suppl 1}$188-S178. 3. Pop-Busul ot al Diabetes Care. 2022:45:1670-1690, PeerView.com

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13. ADA Standards: Holistic Person-Centered Approach
to T2DM Management'

Components of Care) E +CKD
{on maximally tolerated dose of ACEVARB)

Proferably
SGLT2i with primary evidence of reducing CKD progression
Use SGLTZ in people with an eGFR 220 mL/min per 1.73 m?; once
initiated should be continued uni ination of dialysis or transplantation
aan nacos
GLP-1 RA with proven CVD benefit if SGLT2i not tolerated
or contraindicated

If additional cardiorenal risk reduction or glycemic
Goals of Care management needed, consider combination SGLTZUGLP-1 RA

Prevent compac
| See

+ASCVD/Indicators of High Risk
E E

If additional cardiorenal risk reduction or glycemic
management needed, consider combination SGLTZUGLP-1 RA

Principles of Care +HF

SGLT2i with proven HF benet
1 Davies Mi et Diales Caro. 2022:45:2753-2786, A Bir
2. American Dabetes Association Professional Practico Commitse. Diabetes Care, 2024:47(suppl 1) 158-8178. in this population eerView.com

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14. Overview of Approved GLP-1 RAs and GIP/GLP1-RAs
for MACE and T2DM

Indications for T2DM and/or tae + Semaglutide Semaglutide A + Exenatide
Indications for TZDM s Liraglutide' Tirzepatide? Semaglu naalutide Dulaglutides Exenatides Erenat
‘Adjunct to diet and exercise to

improve glycemic control in adults Yes Yes Yes Yes Yes Yes Yes
with T20M

Adjunct to diet and exercise to improve

glycemic control in patients aged 210 years Yes - = - Yes Yes
with T2DM

Reduce risk of MACE in adults with T2DM

and established CVD ves = Nes = des - =
Reduce risk of MACE inadullswilhTDM yes _ _ L Yes _ _

and multiple CV risk factors

Onc Twic
weekly SC

Dosing Frequency ne Sc Daily oral

1-Veteza (agus) PresciBing tomaten. his: aecoseata da govlsupeatia. docaabol2023022341809981 pat
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3. Qzampiesuraghsie)Prscitanglfomaton, ps na accasadata da gougsaita_ docs/abel2023200637:020302 1 pl

Fonts (map) Prog tomaten. hips Ay accessata da porupeatide- Sosa 202021205160 180. pal

5. True (age) Preserbng normalen hips wir accesata ta goviougeaia. Socaabe/2022 12545905 1. pt

&.Byeta oxenatde) Pressing formalin Its nn accoseala ka goviugsaln docs /iabel 20220 17739010) pe. ñ

7. Bydureon BCise (exenatide ER) Prescrbing Information. ps nu accessdala da goviérugsaida.docs/abel2024/2092 10802 pl. PeerView.com

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15. There’s a Lot to Keep Track Of!
Clinical Trials With CV, Metabolic, and Renal Outcomes12

MH

o À rs
Pu EN Cu: Oui Cie
mm) Creme) or rr feo
am CEE
Genaputse 50) (Tizesasce )

sou [1
[o] ES)

MACE, CVD, HF

Cardiac

9

Kidney

Outcomes

m GLP-1RA
m GIPIGLP-1 RA

m GCGIGLP-1 RA

mm GIPIGCGIGLP-1 RA
mm Amylin analog-GLP-1 RA
Drug therapy

MAKE, ACR, CKD

+ pusisnes in progress >
2015 2016 2019 2021 2022 2023 2025 2026 2027
» SURPASS 4 was primarty a gycemie outcomes study wih safety CV assossments because ofthe enriched populaon. > TRIUMPH- i prmariy a weight os tal

batina population ahun CY rk i
1 Moreno-Pérez O eta. Clin Kenoy J. 2024:17(4)-sa0098, 2. hts.uwncinicalral gov PeerView.com

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16. SELECT: Semaglutide Reduces the
Risk of Adverse Cardiovascular Events!

+ Overweight and obesity are key pathophysiological drivers of the
incidence and progression of CVD

+ At mean follow-up of 39.8 months in patients with pre-existing CVD and
overweight or obesity but without diabetes, semaglutide 2.4 mg was
shown to be superior to placebo in reducing the incidence of death from
cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

+ Aprimary cardiovascular end-point event occurred in 6.5% of
patients in the semaglutide group vs 8.0% of patients in the e
placebo group (HR, 0.80; 95% Cl, 0.72 to 0.90; P< .001)

« However, some of the patients developed diabetes
during the trial

4. Linco AM at al. N Engl Med. 2023; 389:2221-2292, PeerView.com

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17. SELECT Trial: Selected Metabolic Endpoints’

None of the participants had T2DM at baseline, but some developed T2DM during the trial

= a Semaglutide Placebo a
Change in Glycemic Status DES | HR (95% Cl)

AIC 26.5%, % patients 35 12.0 0.27 (0.24 to 0.31)

ACES TR 213 50.4 0.33 (0.30 to 0.36)

(patients with baseline <5.7%), % patients

Change From Randomization to Week 104 Difference (95% Cl)

Systolic BP, mmHg (mean [SE]) -3.8 (0.2) -0.5 (0.2) -3.3 (-3.8 to -2.9)
AAC, % change (mean [SE]) -0.3 (0) 00) -0.3 (-0.3 to -0.3)
hs-CRP, mean % change -39.1 -2.1 -37.8 (-39.7 to -35.9)
LDL-C, mean % change ES 2.2 (-3,2 to -1.1)
3.2 -15.6 (-16.7 to -14.6)

Triglycerides, mean % change

1. Lincoff AM eta N Engl Mod 2028:388:2221-2232 PeerView.com

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18. Low-Dose Semaglutide Reduced Steatosis
But Not Stiffness in MASLD!

mer PRET
[7] Foiowap
a e a
a a a
STR A en re wo CE
Time on Treatment, wk
Subgroup. n m) =
US SON MAR Estat in Liver Stress
= am acer Em u EsimatedMean Liver Steatosis
os AN A in Fa À
Non-Hispanie/Non-Latino 34100) 33 (100) Led ls ETRo70 Placebo
ER
Be] aoe) am i {Sse
a so
ta ren CCR D ria, ena
ATT À "| somgausoe
ERA ny a ee
are 282, Jen ME. TE ira
= del TE

1. li A tal. Aliment Pharmaool Ther. 2021:54:1150-1161

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19. SURPASS-3: MRI Substudy'

Man aged 59 years on metformin and an SGLT2i randomized to tirzepatide 5 mg QW

Baseline Week 52

BMI: 44.8 kg/m*, body weight: 134.2 kg; WC: 139.7 em; BMI: 36.2 kg/m? body weight: 108.4 kg; WC: 124.4 cm:
AIC: 78.1 mmolmol (9.3%); FSG: 10.3 mmol (186 mg/dL) AIC: 43.2 mmolimol (6.1%); FSG: 5.9 mmol. (107 mg/dL)
1. Gastaldi A ct a. Dabotologia.2021:64(suppl 1):8219-8220. PeerView.com

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20. Tirzepatide Improved Fibrosis in MASH:
Topline Results From SYNERGY-NASH122

MASH Resolution Without 21-Stage Improvement in Fibrosis
z Worsening Fibrosis Without Worsening MASH
Fi
380
& 60 51 513 549 mTZP 15 mg
5
à 40 265 mTZP 10 mg
$ = TZP 5 mg
g 20 Placebo
2
à 0
Weight change—No T2DM Weight change—With T2DM
=
a 413
E
Ê
5 11.4
2 12 1.
4 13.7
9 20 18.1 -20
Y Voopdinch Ret a. Aliment Prarneco Ther 202; 6017-92, 2. Lomb Reta. N Engl Mad, 2024:391:20010. PeerView.com

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21. HF Significantly Worsens the Prognosis for T2DM'2

+ T2DM increases the overall risk for HF and Coro)

is an independent risk factor

+ HF incidence is extremely high* in

ERA]

[operensien] [Esperinsaremia]. [ovesiy] (Prewisems) (ten

patients with T2DM
— Manifested as HFpEF, HFrEF, and
HEMER ==) E E E ae E)

— All significantly worsen the prognosis
for T2DM J T 1

HFPEF is seen in approximately 50% uni G woran
of HF cases a
Cardiac remodeling _ Vascular damage

- Itis a heterogenous syndrome with
discrete phenotypes, particularly in

Oy

PO yy
close association with metabolic AAA Sra A sais A nl
mation abi _

syndrome.

.
Go

Pericardial restraint

y 4 \

WH, LVEDP, LV Arterial Pericardial pe
+ Yet, management of HFpEF in T2DM OR Cee ee oa ae
remains unclear, largely due to the poorly \ y Y
defined pathophysiology of HFPEF ( HFPEF )
> Esimato prevalence of 9%-22% (4 times higher than in De genera population) and even higher prevalence in ads aged 260 years à rs
A. Abudureyima M e al. J Mal Col Bol. 2022: 14(5}:mjacO28. 2. Dunlay SM etal. Circulation. 2018, 140.0204-0024, PeerView.com

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22. Fast Facts: STEP-HFpEF DM!

STEP-HFpEF DM Pat ants Had Baseline Treatment
‘elated HFpEF and T2DM and HF History

N=616 83% used B-blocker]
44% female; 69 years old (median)
82% used ACEI, ARB, or ARNI
Median BM | | ua 85% had HTN
er 20% Black | | 39% hadar 61% used loop diuretics
64% had .
ere tad 24% had CAD
33% used SGLT2i
Median 5
Median LVEF
Weal Median A1C 56% 32% used MRA
RCD 6.8% NYHA Class Il
3.5 mg/L 71% 18% |had HF hospitalization within 1 year

Median KCCQ-CSS: 59.4 points

1. Kosbor MN ot al N Engl J Mod. 2024:390:1364-1407. PeerView.com

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23. STEP-HFpEF DM: Semaglutide Effectively Targets
Obesity-Related HFpEF in People With T2DM'

Change in KCCQ-CSS

yÉ Pe At 1 year, semaglutide led to larger reductions
3 in dual primary endpoints in patients with
3 nes ósea ty-related HFPEF and T2DM
a
i Pe
Bean
5 Change in Bodyweight
2 o
3 #
E Estats ren
E LE raie pots
3 NES
ho tartans 3 Pe
Semagpuice, 310 zo a 281 so ge
Pe mm m % 3 Man.
Bo
Semaglutide reduced A1C, despite well- 8
controlled glycemia at baseline, without an da
increase in clinically significant hypoglycemia CIR à 5 à 2 &
a Time Since Randomization, wk
de nn El im tra e em Este oem ay ae ic mel aid
SE oran Be ini Dee os de .
ester Ma W Eng Med 200430 1394 407 me mm m m mm = PeerView.com

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24. Looking To the Future: Once-Weekly Cagrilintide/Semaglutide
for Glycemic Control and Weight Loss‘
+ Cagrilintide/Semaglutide = Once-weekly, fixed dose combination

¥ 2.4 mg cagri (Amylin RA) + 2.4 mg sema (GLP-1 RA)
+ N=92 randomized to cagri/sema or sema or cagri for 32 wks

Cagri/Sema Sema Cagri

Mean AA1C, % 2.2 -1.8 0.9
Mean A Bodyweight, % -15.6 5.1 -8.1>
Mean A Fasting Plasma Glucose, mg/dL -59.4 -45.0 -30.6°
mmol/L 3.3 25 1,70

Adverse Events, % participants 68% 71% 80%

In patients with T2DM, at 32 weeks, cagri/sema resulted in significantly greater improvements
in glycemic control vs cagri and significantly greater weight loss vs sema and cagri.
Mild or moderate GI AEs most commonly reported; no level 2 or 3 hypoglycemia

* 292 acuts with TZDM and a BM of 27 kg/m or higher on metformin with or without an SGLTZ inhibitor.» When compared to CAGRISEMA, at 32 weeks tho mean

change la uc 4050 therapy was sigricanty greater a
4. Frias JP et al. Lance! 2025:402(10403) 720-720 PeerView.com

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25. Retatrutide: A Triple Agonist of GLP-1, GIP, and Glucagon
Receptors Showing Promise for Metabolic Syndrome’

3 RCTs, including 685 participants with overweight adults,
with or without T2DM

+ At 24 weeks, retatrutide significantly reduced fasting blood sugar levels
(-21.09 mg/dL), A1C (-0.95%) and weight (-10.54 kg)

+ Decreased SBP (-5.70 mmHg) and DBP (-1.68mm Hg)

+ Improvement in serum HDL cholesterol (-2.01 mg/dl) and triglyceride
levels (-21.64 mg/dl)

+ Risk ratios for all adverse and serious adverse events were 1.16 and
1.01, respectively

1.Nacom H et al. ACC 24. Abstract 1413-215. Sw jace oxgidoi 10. 1016/80736-1097152224152003802 0. PeerView.com

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26. Looking Ahead at GLP-1 RA Research'®

Smoking Cessation Without Weight Gain Alzheimer Disease

+ Exenatide for smoking cessation and + EVOKE and EVOKE+ examining
prevention of weight gain neuroprotective disease-modifying

+ Semaglutide 2.4 mg on changes in weight, effects of semaglutide in early
mechanisms controlling appetite, satiety Alzheimer's disease
and food intake within smoking cessation Parkinson's Disease

Smoking Cessation + Phase 2 study of lixisenatide

+ Semaglutide and its effects on nicotine showed improvements
intake, cravings, and changes in In progression. E
body weight of motor disability .

Alcohol Use Disorder

+ Semaglutide on alcohol-related outcomes in
adults with AUD
1. ts cinicakna.govstusyNCTOS610890, 2. ps nick. ges NCTOB 17S7TE. 3. tp cnica gostucyNCT08530877.

4° ia ri ea gout NCTOSS20775. 5, Nips Calc Go SUCYINCTOATF FEI 6. hps/icsricakras ow'stugyNNCTOST? 705, is
7. Rubin R JAMA, 2024,391:1519-1521. 8, Meissner WG et al. N Engl J Mod. 2024:300-1176-1185, PeerView.com

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27. ADA and KDIGO Consensus Recommendations
for PwT2DM + CKD’

Lifestyle Healthy diet Physical activity Smoking cessation Weight management

scrrzi RAs inhibitor
Pirst-Ine Initate i eGFR 220; Metformin ecco
drug therapy | continuo uni if GFR 230 intensity
dialysis or transplant
Regular reassessment of
<lycemia, albuminuria, BP,
GVO risk, and lipids | | |
Y
Additional GLPA RAI Nonsteroidal MRA Dinydropyridine CCB Antpiateiet Ezetimibe, PCSKSI, or
isk-based | needed to achieve ACR 230 mg/g andlor rate if ‘agent for Teosapent ethy! i
isk-bae individualized and normal needed to achieve clinical indicated based on
therapy lycemic target potassium Individualized BP target ASCVD ASCYD risk and lipids
Other glucose-towering Steroidal MRA if
drugs if needed to nooded for resistant
achieve individvalized hypertension 20M Only
E de met Exit All patients (T1DM and T2DM)
1 American Diabetes Association Professional Practico Commitoo, Diabetes Caro. 2024.47(supp 1) 5219-5230 PeerView.com

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28. Fast Facts: FLOW!

FLOW Participants Had T2DM an Baseline Treatment
Pre-Existing CKD and HF History

N = 3,533

30% female; 66.6 years old (mean)

83% used SGLT2 ir

80.2% used lipid-lowering drug

23.9% Asian | | Baseline SBP
138.6 mm H
Median BMI | | 4.504 Black SES mme) 61.4% used insulin
32 kg/m Baseline DBP
15.7% Latinx 76.2 mm Hg
60.2% used ARB
Pred or HF Megan ae 50.4% used diuretics
22.9% we mLimin/t.73 mi

[35.1% used ACE inhibitor}

1. Perkovic Vet al. Now Engl J Mod 2024:391:109-121

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29. Effect of Semaglutide on CKD in PwT2DM!

First Major Kidney Disease Event

Patents, %
zesesags

EE

% y uR=0761954 01,086.00)
Br

First Kidney-Specific Component Event

HR 2070 (08% 01,088.95)

Total eGFR Slope

Time Since Randomization, mo

Time Since Randomization, mo

alos E

zo 3

ia ‘ Somagutdo À

3 ‘ &

Be TENIA E
» $ Pracobo
a ia = | tence in arate, 116 muni 73m
y Fer]

Somaghuide maguice Pot
>
DIA STE rs = Zu"

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
semaglutide group. Risk of MACE was 18% lower, and the risk of death (any cause) was 20%

1.Porkovi Veta. Now Engl J Mod 2024:391:109-121

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lower, in the

semaglutide group vs

placebo. More serious AEs were reported with placebo

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30. Diabetic Nephropathy and HEDIS"

Patient
has
diabetes

Start
ACEI/ARB

Annual urine
microalbumin
screen

Simplified Diabetic Nephropathy Screening Protocol

Annual BMP
and
microalbumin
screen

Worsening
kidney
damage?

1. Curran RL et al, Gin Disbotos. 2020.38:287-290.

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Completing any
item in a green box

will give you credit
for HEDIS measure

Refer to
nephrology

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31. Current Recommendations for Use of GLP-1-Based Agents
by Renal Status!17.a

Not recommended

Use with caution Monitor renal fun:

+ Exenatide BID:
CrCl <30 mL/min
+ Lixisenatide: eGFR <15

+ Exenatide ER:
eGFR <45

+ Lixisenatide,
dulaglutide,
semaglutide,
tirzepatide: if reporting

+ Exenatide BID: renal transplant; when
initiating or escalating dose in patients with
CrCL 30-50 ml/min

+ Lixisenatide, liraglutide, dulaglutide: when seven Gl AES.

initiating or escalating dose in patients with any
degree of renal impairment

+ Exenatide ER: monitor
for AEs that may lead to
hypovolemia in patients
with renal transplant

2 eGR In mLini4.73 m.
yet (xenatde)Presibing information. ivan accessata ta govirugeatta_docafabel 2022217739040 pct
2. Adán sonado) Presrtin Informaten. ips un accesadota da govlrugeatän doce1abeU20232004712007n.pc

3. Bycureon 8Ciue(exenatido ER) Preserbing Information. psn accosacata fa govirugenid_docafabel202472097 1080230 pdl

4. Vetoca (agus) Preserbing infomation, Mapa va accossónt da govupeatän cabo 2023022941030. pat

5. Trulety (dsoguise) Proserbng Information. Mis: viva access a goviougeala_socsabe/2022 1284692081 pet

$ Grom (era) Prosrtaag inomatn, Rips hw acessdaa {Sn gouges, doeshobol2024209097s020502188 pat a

7. Mourjar (üzepatde) Preserbin Information. ups www accossdata fa govidrugsatlda_docsabel/2023/2158660rg 1500250060 pat PeerView.com

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32. Case Discussion: Gina, a Woman Aged 59 Years

BMI: 37.2 kg/m?; height: 63 inches (160 om); weight 210 Ib (95 kg) Visit Notes U
AIC: 8.7%; BP: 145/90 mmHg Marketing manager for a professional
TC: 190 mg/dL; LDL-C: 160 mg/dL; HDL-C: 38 mg/dL; TG: 250 mg/dL. CEA ED

eGFR: 48 mL/min/1.73 m? Divorced, lives with her 2 teens

Medical history: Hypertension, dyslipidemia, T2DM (7 years), atrial Frequent restaurant and takeout meals;
fibrillation has access to a gym at her office, but too

Current medications ‘embarrassed to go

= Metformin ER 1,500 mg QD, Last visit with PCP 6 months ago;
Glyburide 5 mg QD current visit to review her medications

Dapagliflozin 10 mg QD
Benazepril/HCTZ 20 mg/25 mg QD
Rosuvastatin 40 mg QD

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33. CV and Metabolic Effects of GLP-1 RAs, GIP/GLP-1 RAs,
and SGLT2is in Adults With T2DM1-3

SGLT2 inhibitors + GLP-1 RAs reduce

GLP-1 RAs reduce + Stroke

All-cause mortality and
MACE compared with SGLT2 inhibitors reduce
usual care (but not DPP4
inhibitors, insulin,

or tirzepatide)

CKD progression,
CHF hospitalization
Severe hypoglycemia

A meta-analysis of newer medications in adults with T2DM
found positive outcomes with SGLT2s and GLP-1 RAs.
Serious AEs and severe hypoglycemia seem to be less

frequent with SGLT2is and GLP-1 RAs vs insulin
or sulfonylurea.

Tirzepatide, a GIP/GLP-1 RA,
had a significant effect on lipid
metabolism, blood pressure,
weight and A1C vs GLP-1 RAs,
insulin, and placebo.

1. Drake Teta Ann Int Mod. 2024:177(8)618-632. 2, Sethi et al. ACG 24. Abstract 1116-11, . Lv Kt al Dibotos Mead Syndr Obas. 2024;17:701714, rView.com

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34. Factors That May Affect the Adherence to
and Persistence With GLP-1 RAs in People With T2DM

Mixed Findings in Claims Studies Reasons for Treatment Factors Associated With Higher Adherence
9 Discontinuation* and Persistence*

Inadequate blood glucose

management Initiating treatment with low dose

Gastrointestinal adverse events Ease of use of injection device

O Preference for oral medication Weekly dosing rather than daily
was higher than to daily over injection or twice daily dosing
medications

Injection-related concerns
Another large database study also Early (within 6 months) weight loss
found higher adherence with weekly AACR ms ds

ith daily GLP-1 RAS?

High cost Early (within 6 months) A1C level reduction

another claims study found
better adherence to dulaglutide, a once- Injection site reaction
daily medication, vs semaglutide, a
once-weekly medication? Inadequate body weight reduction

Inconvenience of injection schedule -

("Weis otal Patent Pet Adhereno,2029,14:2307.235.3, Poonaly WN oa Dadas Thar 2000 0175 107 a
3. Mody R et al. Clin Ther. 2022:44 537-554. 4. Los DSU, Lee H. Diabotol Metab Syndr. 2022-14:12. PeerView.com

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35. Establishing a “Virtuous Cycle” in
Comprehensive Obesity Management in PwT2DM12

- > Plan is

Goal is met vorn

In a clinical trial program
for a GLP-1-based
therapy in PwT2DM,
improved glycemic
control and reduced
weight was associated
with adoption of other
healthful behaviors
(dietary modifications,
increased exercise)

Distress is
reduced;
meaningful
benefits are
noticed

Intervention
is attempted

the goals

Encourages
‘adherence
to plan

New goals
are added

1. Valls. tnt Gin rect. 2016:70:196-205. 2. Malz LS otal. Patent 2022:15:367-377. PeerView.com

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36. Case Discussion: Carl, a Man Aged 63 Years

+ BMI: 36.7 kg/m?; height: 70 inches (178 cm); weight 256 Ib (116 kg) Visit Notes
AIC: 7.8%; BP: 150/92 mmHg + District manager at high-end
+ eGFR: 86 mL/min/1.73 m2 department store

TC: 250 mg/dL; LDL-C: 160 mg/dL; HDL-C: 35 mg/dL; TG: 210 mg/dL Married, 4 adult children, 2 grandchildren

+ Medical history: T2DM (12 years), hyperlipidemia, hypertension, fatty liver Uneasy about taking all of
disease (MASLD) these medications

+ Current medications He hates to give himself a daily injection
= Metformin 1000 mg BID and the frequent blood glucose monitoring
= Sitagliptin 100 mg QD Athis recent birthday his children were
SE pushing him to find a way to get healthy;

child #2 is getting married in 8 months
= Atorvastatin 40 mg QD and he's dreading seeing old friends
= Lisinopril 20 mg QD and family

= Hydrochlorothiazide 25 mg QD

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37. Applying the “3Es” to Manage GI AEs"

"3Es"

Escalation to an
appropriate dose

Education and

Explanation

1. Wharton $ eta. Postgrad Med, 2022:134:1,16-19

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Effective

management
of GI AEs

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38. Guidance

GLP-1 RAs: Anticipatory Guidance

Reason
Educate about signs and symptoms.

to report

Caution
Risk of gallbladder disease
Educate about signs and symptoms of

Gallbladder
isease'
Cases reported, causality not established; not as
pancreatitis; discontinue if suspected

well studied in patients with h/o pancreatitis

In someone with proliferative diabetic

& Pancreatitis?
Current evidence suggests that GLP-1 RAS are
not associated with increased incidence of DR;
increase in diabetic retinopathy complicationswas retinopathy, continue monitoring with
ophthalmologist per usual standards

OT
o observed in one trial and attributed to rapid
glucose lowering
Monitor renal function if severe
gastrointestinal intolerabilty, as this may

Gastrointestinal intolerability (nausea,
Renal function® dehydration) may precipitate change
impact volume status and renal function
1. File JL eta, JAMA Intem Med, 2016:176:1474-1481. 2. Stor

in renal function
Het al Diabetes Obes Matab. 2017:19908-908,

3 Stenberg iM ot a Diabetes Care. 2017.40 566972. 4. Viebol ñ
bates Care. 2018;41:2330-2338. 6. KDIGO Diat PeerView.com

Diabotes Obes Metab. 2010:20 680-807.
08 Work Group. Kio) Int 2022,102(58):81.9127.
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5. Doures A etal

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39. Slower Titration Improves Tolerability of
GLP-1 RAs in T2DM'

Exenatide BID 5mg
Lixisenatide | 10 mg ap]

lutide
Exenatide QW 20mg
Dulaglutido [GS] 0:75 mg» 4.5 mg aw

Tirzepatide | 25 mg aw 10 mg aw 12.5 mg QW 15 mg QW

Semaglutide SC | 025mgaw

Semaglutide oral |_3mg QW

®

70 2 ” 6
Time After Initiating Treatment, wk.

+ GIAEs are common and occur mainly after initiation of treatment or after a dose increase
+ Peak plasma concentrations may determine the time when these symptoms are most likely to occur
+ Starting at lower than a maintenance dose and slowiy increasing to the desired steady state minimizes GI AEs

+ Agents with slower absorption (exenatide QW, dulaglutide) can be initiated at their final dose

+ Ped doin schedule according to Posting Iomatin; du dosing shad recommended by D, ra. En
‘nous A ot Molo Mai 2081461011022 Hips in seca 1 DEN Y PeerView.com

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40. Triggers/Reasons for Switching GLP-1 RAs‘?

AAC target not met and/or loss of Dulaglutide or liraglutide

‘glycemic control or semaglutide SC O
Desire for additional weight loss Liraglutide or semaglutide SC Increased weight loss
CV disease EME Improved CV outcomes

or semaglutide SC
Multiple CV risk factors Dulaglutide Improved CV outcomes
Dulaglutide or exenatide ER

Poor adherence Emma gite se Improved adherence
Decline in renal function to Dulaglutide or liraglutide : :
cs EAS Continue to receive a GLP-1 RA
GIAEs Switch to another GLP-1 RA Increased tolerance
Nonmedical reason (formulary, patient Consider switching as .
Preference, cost, insurance mandate) requested/mandated cio

Up to 25% of patients switch in their first year of treatment
4. Jain AB otal Int Gin Pract 2021,75.019731.2. Amandoz JP e al. Cin Diab. 2020:38:390-402. PeerView.com

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41. Key Takeaways

+ GLP-1 RAs are an increasingly + Additional trials are underway
important tool in our toolbox, and there - GLP-1 RAs as treatments for
are important indication differences MAFLD/NASH/MASH, DKD, and HF
between agents

— Higher doses of GLP-1 RAs for T2DM

+ Early glycemi t red
a ed - Additional dual and triple incretin

risk of microvascular and macrovascular A A
therapies for greater weight

complications 4
E 2 5 loss/glycemic management and other
+ Higher levels of weight loss (215%) benefits on comorbidities of T2DM
are associated with better T2DM 7 PS
+ It's important to take a holistic,

management
E life-course view of managing T2DM
+ Patients are more likely to adhere to

GLP-1 RAs if they are provided with
anticipatory guidance about how they will
feel after initiation

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