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Trial · Interventional

TerminatedPhase 2Results postedRegistry data

Trial to Learn About the Study Medicine (PF-07081532) and Rybelsus in People With Type 2 Diabetes and Separately PF-07081532 in People With Obesity

NCTNCT05579977 (opens ClinicalTrials.gov in a new tab)Other idC3991004Other id2022-002834-15

Overview

Status
Terminated
Phase
Phase 2
Enrollment
902 participants (actual)
Sponsor
Pfizer · Industry
Design
Randomized · Quadruple masking
Countries
8 countries

United States, Bulgaria, Canada, Czechia, Hungary, Japan, Poland, Puerto Rico

Start
27 Oct 2022
Primary completion
14 Jul 2023
Completion
22 Sept 2023
First posted
14 Oct 2022
Last update posted
1 Aug 2024
Conditions
Diabetes Mellitus · Obesity

Timeline

1 trial · 1 stopped early · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
202220232024
  1. Ph 2

    Trial to Learn About the Study Medicine (PF-07081532) and Rybelsus in People With Type 2 Diabetes and Separately PF-07081532 in People With Obesity

    NCT05579977

    27 Oct 2022 to 22 Sept 2023

    Terminated

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

The purpose of this study is to find out if PF-07081532 ("the active study drug"), is safe and helps treat people with obesity without diabetes to lose weight, and people with diabetes to keep their blood sugar in good control. Individuals diagnosed with diabetes that are on metformin or individuals with obesity without diabetes will be included in the study. Those participating in the diabetes part of the study, will receive either active study drug, placebo, or an approved treatment called Rybelsus. Those in the obesity part of the study, will receive either active study drug or placebo. The study will last for about 36 weeks except for the first 25% of the participants that enter in which case the study will last for approximately 48 weeks. during this time there will be visits every 4 weeks with phone calls in between.

Interventions

  • PF-07081532Drug
  • PlaceboOther
  • RybelsusDrug

Arms13

  • Experimental

    PF-07081532 20 mg T2DM

    PF-07081532 20 mg daily in T2DM

  • Experimental

    PF-07081532 40 mg T2DM

    PF-07081532 40 mg daily in T2DM

  • Experimental

    PF-07081532 80 mg T2DM

    PF-07081532 80 mg daily in T2DM

  • Experimental

    PF-07081532 160 mg T2DM

    PF-07081532 160 mg daily in T2DM

  • Experimental

    PF-07081532 260 mg T2DM

    PF-07081532 260 mg daily in T2DM

  • Placebo comparator

    Placebo T2DM

    Placebo daily in T2DM

  • Experimental

    PF-07081532 80 mg Obesity

    PF-07081532 80 mg daily in Obesity

  • Experimental

    PF-07081532 140 mg Obesity

    PF-07081532 140 mg daily in Obesity

  • Experimental

    PF-07081532 200 mg Obesity (Option 1)

    PF-07081532 200 mg daily in Obesity

  • Experimental

    PF-07081532 200 mg Obesity (Option 2)

    PF-07081532 200 mg daily in Obesity

  • Experimental

    PF-07081532 260 mg Obesity

    PF-07081532 260 mg daily in Obesity

  • Active comparator

    Rybelsus 14 mg T2DM

    Semaglutide 14 mg daily in T2DM

  • Placebo comparator

    Placebo Obesity

    Placebo in Obesity

Primary outcomes2

Outcomes the sponsor listed as primary.

  1. Placebo-adjusted, Change From Baseline in Percentage of Glycated Hemoglobin (HbA1c) at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

  2. Placebo-adjusted, Percent Change From Baseline in Body Weight at Week 32: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), week 32

    Registry description

    Body weight was measured using a calibrated weighing scale.

Secondary outcomes(20)
  1. Percentage of Participants Who Achieved HbA1C <7% at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

  2. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

  3. Percent Change From Baseline in Body Weight at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    Body weight was measured using a calibrated weighing scale.

  4. Placebo-adjusted, Change From Baseline in HbA1C in the Rybelsus Arm at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    This outcome measure was planned to be analyzed only for rybelsus arm and placebo arm as pre-specified in the protocol.

  5. Percentage of Participants Achieving >=5%, >=10%, and >=15% Body Weight Loss at Week 32 Relative to Baseline: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

  6. Absolute Change From Baseline in Waist Circumference at Week 32: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    Waist circumference was measured at midpoint, between lower margin of last palpable rib and top of iliac crest (approximately 1 inch \[2.54 centimeter {cm}\] above the navel). It was measured by using an anthropometric tape (stretch-resistant).

  7. Absolute Change From Baseline in Waist-to-hip Ratio at Week 32: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    The hip circumference was defined as the circumference around the widest portion of the buttocks. Waist circumference was measured at midpoint, between lower margin of last palpable rib and top of iliac crest (approximately 1 inch \[2.54 cm\] above the navel). The measurements were performed using an anthropometric tape (stretch-resistant).

  8. Change From Baseline in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) at Week 32: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    HOMA-IR was calculated as: fasting plasma insulin (\[FPI\]\*(FPG)/405 and measured in terms of mg/dL\* (milliunits per liter).

  9. Change From Baseline in Homeostatic Model Assessment for Insulin Sensitivity (HOMA-S) at Week 32: Cohort 2 (Obesity)

    Time frame · Baseline (result closest prior to dosing on Day 1), Week 32

    Registry description

    HOMA-S was calculated as (22.5/\[FPI\] \* FPG) \*100 and measured in terms of percentage sensitivity.

  10. Number of Participants With Treatment Emergent Adverse Events (TEAEs): Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were any AEs that occurred on or after the first dose of treatment but before the last dose plus lag time.

  11. Number of Participants With Treatment Emergent Adverse Events (TEAEs): Cohort 2 (Obesity)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were any AEs that occurred on or after the first dose of treatment but before the last dose plus lag time.

  12. Number of Participants With Serious Adverse Events (SAEs): Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    SAE defined as any untoward medical occurrence that, at any dose, met one or more of the following criteria: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect; was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; other important medical events.

  13. Number of Participants With Serious Adverse Events (SAEs): Cohort 2 (Obesity)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    SAE defined as any untoward medical occurrence that, at any dose, met one or more of the following criteria: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect; was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; other important medical events.

  14. Number of Participants Reporting Adverse Events Leading to Permanent Discontinuation From Study Treatment and Study: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    \\ An AE was any untoward medical occurrence in a participants or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs leading to permanent discontinuation from study were those with an AE record indicating the AE caused permanent discontinuation from the study. AEs leading to permanent discontinuation from study treatment were those AEs with an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study.

  15. Number of Participants Reporting Adverse Events Leading to Permanent Discontinuation From Study Treatment and Study: Cohort 2 (Obesity)

    Time frame · From start of treatment up to minimum of 28 days after last dose of treatment administration (maximum up to Week 28)

    Registry description

    An AE was any untoward medical occurrence in a participants or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs leading to permanent discontinuation from study were those with an AE record indicating the AE caused permanent discontinuation from the study. AEs leading to permanent discontinuation from study treatment were those AEs with an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study.

  16. Number of Participants With Hypoglycemic Adverse Events (HAE) According to Titration Dose: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Up to week 28

    Registry description

    Glucose values were monitored using glucometer. Hypoglycemia =plasma/blood glucose value of \<70 mg/dL (3.9 millimoles per liter \[mmol/L\]). Severe HAE: Participant was unable to treat him/herself due to neurological impairment (not age) and required assistance of another person, at least one neurological symptom of memory loss, confusion, uncontrolled behavior etc. Either documented blood glucose\<=54 mg/dL (2.7 mmol/L). Documented symptomatic: An event during which symptoms of HAE were accompanied with plasma/blood glucose \<70 mg/dL and prompt resolution with food intake, SC glucagon, or IV glucose. Probable symptomatic HAE: An event during which symptoms of an HAE were not accompanied by a plasma glucose determination but was presumably caused by a plasma glucose concentration \<70 mg/dL and prompt resolution with food intake, SC glucagon, or IV glucose. Asymptomatic: An event not accompanied by typical symptoms of an HAE, but a plasma/blood glucose value of \<70 mg/dL was reported.

  17. Number of Participants With Hypoglycemic Adverse Events According to Titration Dose: Cohort 2 (Obesity)

    Time frame · Up to week 28

    Registry description

    Glucose values were monitored using glucometer. Hypoglycemia =plasma/blood glucose value of \<70 mg/dL (3.9 mmol/L). Severe HAE: Participant was unable to treat him/herself due to neurological impairment (not age) and required assistance of another person, at least one neurological symptom of memory loss, confusion, uncontrolled behavior etc. Either documented blood glucose\<=54 mg/dL (2.7 mmol/L). Documented symptomatic: An event during which symptoms of HAE were accompanied with plasma/blood glucose \<70 mg/dL u and prompt resolution with food intake, SC glucagon, or IV glucose. Probable symptomatic HAE: An event during which symptoms of an HAE were not accompanied by a plasma glucose determination but was presumably caused by a plasma glucose concentration \<70 mg/dL and prompt resolution with food intake, SC glucagon, or IV glucose. Asymptomatic: An event not accompanied by typical symptoms of an HAE, but a plasma/blood glucose value of \<70 mg/dL was reported.

  18. Number of Participants With Vital Sign Abnormalities: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Up to week 28

    Registry description

    Vital signs included blood pressure and pulse rate and were measured with the participants in a seated position after at least 5 minutes of rest for the participant. Criteria for abnormalities included: Systolic Blood Pressure (millimeter of mercury \[mmHg\]): value more than (\>) 200 and value less than (\<) 90; Diastolic blood pressure: value \> 100 and \< 40; Pulse rate: (beats per minute \[BPM\]): value \< 40 and \> 110.

  19. Number of Participants With Vital Sign Abnormalities: Cohort 2 (Obesity)

    Time frame · Up to week 28

    Registry description

    Vital signs included blood pressure and pulse rate and were measured with the participants in a seated position after at least 5 minutes of rest for the participant. Criteria for abnormalities included: Systolic blood pressure (mmHg): value \> 200 and value \< 90; Diastolic blood pressure: value \> 100 and \< 40; Pulse rate: (BPM): value \< 40 and \> 110.

  20. Number of Participants With Clinical Laboratory Abnormalities: Cohort 1 (Type 2 Diabetes Mellitus)

    Time frame · Up to week 28

    Registry description

    Hematology: platelets (10\^9/L)\< 0.5\*lower limit of normal (LLN); leukocytes\< 0.6\*LLN and \>1.5\*upper limit of normal (ULN); lymphocytes and neutrophils \<0.8\*LLN and \>1.2\*ULN; basophils, eosinophils, monocytes:\>1.2\*ULN; prothrombin time (sec) \>1.1\*ULN; prothrombin international normalized ratio \>1.1\*ULN; clinical chemistry: bilirubin (mg/dL), indirect bilirubin:\>1.5\*ULN; aspartate and alanine aminotransferase, gamma glutamyl transferase (U/L):\>3.0\*ULN; urea nitrogen and creatinine (mg/dL)\>1.3\* ULN;HDL cholesterol (mg/dL)\<0.8\*LLN; LDL (mg/dL)\>1.2\*ULN, Triglycerides (mg/dL):\>1.3\*ULN; Potassium (milliequivalents per liter) \< 0.9\*LLN and \> 1.1\* ULN; calcium (mg/dL)\< 0.9\*LLN, Thyroxine (nanograms/dL\<0.8\*LLN and \>1.2\*ULN, HbA1C (%)\>1.3\*ULN; Amylase, Lipase (U/L) and Glucose -Fasting (mg/dL)\>1.5\*ULN; urinalysis: pH\> 8; urine glucose, ketones, protein, hemoglobin, nitrite and leukocyte esterase\>=1. Number of participants with abnormalities in any of the laboratory parameters is reported.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Placebo-adjusted, Change From Baseline in Percentage of Glycated Hemoglobin (HbA1c) at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

GroupValue
Placebo (T2DM)not posted
PF-07081532 20mg (T2DM)not posted
PF-07081532 40mg (T2DM)not posted
PF-07081532 80mg (T2DM)not posted
PF-07081532 160mg (T2DM)not posted
PF-07081532 260mg (T2DM)not posted
Rybelsus 14mg (T2DM)not posted
Primary outcome· Baseline (result closest prior to dosing on Day 1), week 32

Placebo-adjusted, Percent Change From Baseline in Body Weight at Week 32: Cohort 2 (Obesity)

GroupValue
Placebo (Obesity)not posted
PF-07081532 80mg (Obesity)not posted
PF-07081532 140mg (Obesity)not posted
PF-07081532 200mg (Obesity,5 Steps)not posted
PF-07081532 200mg (Obesity,4 Steps)not posted
PF-07081532 260mg (Obesity)not posted
Secondary and other outcome results(6)
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Percentage of Participants Who Achieved HbA1C <7% at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

GroupValue
Placebo (T2DM)not posted
PF-07081532 20mg (T2DM)not posted
PF-07081532 40mg (T2DM)not posted
PF-07081532 80mg (T2DM)not posted
PF-07081532 160mg (T2DM)not posted
PF-07081532 260mg (T2DM)not posted
Rybelsus 14mg (T2DM)not posted
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

GroupValue
Placebo (T2DM)not posted
PF-07081532 20mg (T2DM)not posted
PF-07081532 40mg (T2DM)not posted
PF-07081532 80mg (T2DM)not posted
PF-07081532 160mg (T2DM)not posted
PF-07081532 260mg (T2DM)not posted
Rybelsus 14mg (T2DM)not posted
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Percent Change From Baseline in Body Weight at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

GroupValue
Placebo (T2DM)not posted
PF-07081532 20mg (T2DM)not posted
PF-07081532 40mg (T2DM)not posted
PF-07081532 80mg (T2DM)not posted
PF-07081532 160mg (T2DM)not posted
PF-07081532 260mg (T2DM)not posted
Rybelsus 14mg (T2DM)not posted
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Placebo-adjusted, Change From Baseline in HbA1C in the Rybelsus Arm at Week 32: Cohort 1 (Type 2 Diabetes Mellitus)

GroupValue
Placebo (T2DM)not posted
Rybelsus 14mg (T2DM)not posted
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Percentage of Participants Achieving >=5%, >=10%, and >=15% Body Weight Loss at Week 32 Relative to Baseline: Cohort 2 (Obesity)

GroupValue
Placebo (Obesity)not posted
PF-07081532 80mg (Obesity)not posted
PF-07081532 140mg (Obesity)not posted
PF-07081532 200mg (Obesity,5 Steps)not posted
PF-07081532 200mg (Obesity,4 Steps)not posted
PF-07081532 260mg (Obesity)not posted
Secondary outcome· Baseline (result closest prior to dosing on Day 1), Week 32

Absolute Change From Baseline in Waist Circumference at Week 32: Cohort 2 (Obesity)

GroupValue
Placebo (Obesity)not posted
PF-07081532 80mg (Obesity)not posted
PF-07081532 140mg (Obesity)not posted
PF-07081532 200mg (Obesity,5 Steps)not posted
PF-07081532 200mg (Obesity,4 Steps)not posted
PF-07081532 260mg (Obesity)not posted

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
Placebo (T2DM)Participants randomized to receive a single dose of PF-07081532-matching placebo QD orally.1 / 751 / 7523 / 75
PF-07081532 20mg (T2DM)Participants randomized to receive PF-07081532 20 mg QD orally.0 / 730 / 7331 / 73
PF-07081532 40mg (T2DM)Participants randomized to receive PF-07081532 20 mg QD orally for 4 weeks, followed by 40 mg QD orally.0 / 723 / 7246 / 72
PF-07081532 80mg (T2DM)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 60 mg QD orally for 4 weeks, followed by PF-07081532 80 mg QD orally.0 / 733 / 7337 / 73
PF-07081532 160mg (T2DM)Participants randomized to receive PF-07081532 20 mg QD 40 mg QD, 60 mg QD, 80 mg QD and 120 mg QD orally for 4 weeks, followed by PF-07081532 160 mg QD orally.0 / 721 / 7241 / 72
PF-07081532 260mg (T2DM)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD, 80 mg QD, 140 mg QD and 200 mg QD orally for 4 weeks, followed by PF-07081532 260 mg QD orally.0 / 742 / 7451 / 74
Rybelsus 14mg (T2DM)Participants randomized to receive Rybelsus 3 mg QD and 7 mg QD each for 4 weeks followed by 14 mg QD.0 / 731 / 7332 / 73
Placebo (Obesity)Participants randomized to receive a single dose of PF-07081532-matching placebo QD orally.0 / 641 / 6442 / 64
PF-07081532 80mg (Obesity)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 60 mg QD orally for 4 weeks, followed by PF-07081532 80 mg QD orally.0 / 662 / 6650 / 66
PF-07081532 140mg (Obesity)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 60 mg QD, 80 mg QD,120 mg QD orally for 4 weeks each followed by PF-07081532 140 mg QD orally.0 / 642 / 6448 / 64
PF-07081532 200mg (Obesity,5 Steps)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 60 mg QD, 100 mg QD,160 mg QD orally for 4 weeks each followed by PF-07081532 200 mg QD orally.0 / 651 / 6555 / 65
PF-07081532 200mg (Obesity,4 Steps)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 80 mg QD, 140 mg QD orally for 4 weeks each followed by PF-07081532 200 mg QD orally.0 / 662 / 6659 / 66
PF-07081532 260mg (Obesity)Participants randomized to receive PF-07081532 20 mg QD, 40 mg QD and 80 mg QD, 140 mg QD, 200 mg QD orally for 4 weeks each followed by PF-07081532 260 mg QD orally.0 / 642 / 6453 / 64

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies1

Studies that cite this trial.

Studies with results

0 studies on this page

Indexing hint: Systematic review · 2025

Emerging pharmacotherapies for obesity: A systematic review.

Kokkorakis et al. 2025Pharmacological reviewscited by 60

PMID 39952695DOI 10.1124/pharmrev.123.001045PUB-39952695

Full text at the publisher
Publisher page

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

  • DerivedAmin NB, Frederich R, Tsamandouras N, Haggag AZ, Schuster T, Zmuda W, Palmer A, Vasas S, Buckley G, Smith TR, DuBrava SJ, Zhu Q, Johnson M. Evaluation of an oral small-molecule glucagon-like peptide-1 receptor agonist, lotiglipron, for type 2 diabetes and obesity: A dose-ranging, phase 2, randomized, placebo-controlled study. Diabetes Obes Metab. 2025 Jan;27(1):215-227. doi: 10.1111/dom.16005. Epub 2024 Oct 16. PMID 39415344

Eligibility

Who could join, as posted.

Sex
All
Age
from 18 Years up to 75 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
Inclusion Criteria: T2DM * T2DM inadequately controlled with metformin * BMI ≥23.0 kg/m2 (≥20.0 kg/m2 in Japan) * HbA1C of 7% to 10% (53-86 mmol/mol) * FPG ≤270 mg/dL (15 mmol/L) Obesity * BMI ≥30.0 kg/m2 * HbA1C ≤6.4% (47 mmol/mol) * FPG ≤126 mg/dL (7 mmol/L) Exclusion Criteria: * Any of the following: Active/current, symptomatic gallbladder disease; History of pancreatitis in the prior 2-months;History of Type 1 Diabetes Mellitus, or secondary forms of diabetes; Any condition affecting drug absorption; Medical history of active liver disease (other than non-alcoholic hepatic steatosis) * Use of pharmacological agents with approved indication for weight loss * T2DM:Use of any agent (other than metformin)for the explicit purpose of glycemic control;History of diabetic ketoacidosis;Proliferative retinopathy or maculopathy requiring acute treatment; * Obesity: Previous or planned weight reduction surgery; Major depressive disorder or other severe psychiatric disorders; Any lifetime history of a suicide attempt; PHQ-9 score ≥15; Response of "yes" to Question 4 or 5, or on any suicidal behavioral question on the C-SSRS * Clinically significant cardiovascular conditions * Uncontrolled blood pressure * Personal or within first-degree relative family history of MTC or MEN2 * Other medical or psychiatric condition that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study * Any of the following central lab results: Fasting C-peptide \<0.8 ng/mL; ALT or AST ≥2.5x ULN; Direct bilirubin \>ULN or T Bili \>1.5x ULN except when participants have a history of Gilbert syndrome ; TSH \>1.5x ULN or \<LLN; Serum calcitonin \>ULN; Serum amylase or serum lipase \>ULN; eGFR \<45 ml/min/1.73 ; Active Hepatitis B, or Hepatitis C; A positive urine drug test for illicit drugs

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