Orforglipron Compared with Placebo as an Add-On to Titrated Insulin Glargine:​ Results From ACHIEVE-5 ​

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FDC, fixed-dose combination.​
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ACHIEVE-5 study code is NCT06109311.​
Abbreviations: OFG=orforglipron; PBO=placebo; QD=once daily; SGLT2=sodium-glucose co-transporter-2; T2D=type 2 diabetes.​

ªParticipants already on metformin and/or SGLT-2 inhibitors will continue these medications until the end of the study.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BCRP=breast cancer resistance protein; BMI=body mass index; CYP3A=cytochrome P450 3A; eGFR=estimated glomerular filtration rate; HbA1c=hemoglobin A1c; OATP=organic anion transporting polypeptide; OFG=orforglipron; PBO=placebo; P-gp=P-glycoprotein; QD=once daily; SGLT2=sodium-glucose co-transporter-2; T2D=type 2 diabetes; ULN=upper limit of normal.

^aBased on the last 3 fasting SMBG values; ^bDose should be decreased by 1-2 units or 2-4 units if multiple episodes of non-severe hypoglycemia were recorded during the assessment period at any time during the day, and/or if ≥1 episode meeting criteria for severe hypoglycemia (events requiring assistance of a third person to administer therapy) or was associated with SMBG value <54 mg/dL (<3.0 mmol/L) during the assessment period; ᶜ If only 1 hypoglycemic episode with SMBG value ≥54 mg/dL (≥3.0 mmol/L) and ≤70 mg/dL (≤3.9 mmol/L) was recorded, insulin dose should not be changed.

Abbreviations: HbA1c=hemoglobin A1c; SMBG=self-monitored blood glucose.

^aEndpoints were strongly controlled for type 1 error (multiplicity) using a graphical testing procedure.
Abbreviations: HbA1c=hemoglobin A1c.

Note: Study completion is defined as the participant completing both the treatment period and the safety follow-up period, regardless of completion of the study intervention.

Notes: Data are shown as mean (SD) unless stated otherwise. Data from all randomized participants.

Abbreviations: n=number of subjects in the specified category ; N=number of participants in the population; SD=standard deviation .

Notes: Data are shown as mean (SD) unless stated otherwise. Data from all randomized participants with non - missing data.

Abbreviations: BMI=body mass index; FSG=fasting serum glucose; HbA1c=hemoglobin A1c; n=number of subjects in the specified category ; N= number of participants in the population; OFG=orforglipron; PBO=placebo; SD=standard deviation; SGLT2=sodium - glucose co - transporter - 2; T2D=type 2 diabetes.

Orforglipron vs. placebo: #p<0.05 ##p<0.01, and ###p<0.001. Comparison to placebo not controlled for family-wise error rate. Arrows indicate when the maintenance doses of orforglipron 2.5 mg, 9 mg, and 17.2 mg are achieved. ​

Notes: Data in line plot are raw mean (SE); other data are MBE (SE) unless stated otherwise. EE analysis was conducted using MMRM on randomized participants and EE data points set. ​

Abbreviations: EE=efficacy estimand; FSG=fasting serum glucose; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=total number of participants; SD=standard deviation; SE=standard error.​

Orforglipron vs. placebo: ***p<0.001. p-values are for MBE change difference vs. placebo. Arrows indicate when the maintenance doses of orforglipron 2.5 mg, 9 mg, and 17.2 mg are achieved. ​
Notes: Data in line plot are raw mean (SE); all other data are MBE (SE) unless stated otherwise. EE analysis was conducted using MMRM on randomized participants and EE data points set. TRE analysis was conducted using ANCOVA on randomized participants and TRE data points set, with missing data imputed 50 times. ​

Abbreviations: ANCOVA=analysis of covariance; EE=efficacy estimand; HbA1c=hemoglobin A1c; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=total number of participants; SD=standard deviation; SE=standard error;TRE=treatment regimen estimand.​

p-values are for risk difference vs. placebo. *** = p<0.001. ## = p<0.01 and ### = p<0.001 for comparisons to placebo not controlled for Family-wise error rate (HbA1c <5.7% data). All analyses were prespecified. ​

Notes: Data are proportion of participants (%) achieving HbA1c targets <7∙0%, ≤6∙5%, and <5∙7% for the EE analysis conducted using logistic regression model on randomized participants and EE data points set, with missing data imputed 50 times. ​
Abbreviations: EE=efficacy estimand; HbA1c=hemoglobin A1c; MBE=model-based estimate; N=total number of participants; SE=standard error.​

Orforglipron vs. placebo: # p<0.05, ## p<0.01, ### p<0.001. Comparison to placebo was not controlled for Family-wise error rate.

Notes: Data are MBE (SE). Analysis was conducted using MMRM on randomized participants and EE data points set.

Abbreviations: EE=efficacy estimand; MMRM=mixed model for repeated measures; N=total number of participants in EE data set; SE=standard error; SMBG=self-monitored blood glucose.

Orforglipron vs. placebo: ***p<0.001. p-values are for MBE change difference vs. placebo. Arrows indicate when the maintenance doses of orforglipron 2.5 mg, 9 mg, and 17.2 mg are achieved.

Notes: Data in line plot are raw mean (SE); all other data are MBE (SE) unless stated otherwise. EE analysis was conducted using MMRM on randomized participants and EE data points set. TRE analysis was conducted using ANCOVA on randomized participants and TRE data points set, with missing data imputed 50 times. All analyses were prespecified.

Abbreviations: ANCOVA=analysis of covariance; EE=efficacy estimand; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=total number of participants; SD=standard deviation; SE=standard error; TRE=treatment regimen estimand.

Orforglipron vs. placebo: # p<0.05, ## p<0.01, ### p<0.001 . p - values are for risk difference vs. placebo. All analyses were prespecified. Comparison to placebo was not controlled for Family - wise error rate .

Notes: Data are Group Mean (SE) (%) unless stated otherwise. Analysis was conducted using logistic regression model on randomized participants and EE data points set, with missing data imputed 50 times.

Abbreviations: EE=efficacy estimand; MBE=model - based estimate ; SE=standard error.

^a Death is also included as serious AE and discontinuations due to AE.​

Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of study intervention. ​

Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n=number of participants with events meeting specified criteria; N=number of participants in analysis population; TEAE=treatment-emergent AE.​

a Death is also included as serious AE and discontinuations due to AE.

Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of study intervention.

Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n=number of participants with events meeting specified criteria; N=number of participants in analysis population ; TEAE=treatment - emergent AE.

Numbers for hypoglycemia exclude hypoglycemic events occurring after initiation of any new anti-hyperglycemic therapy. ^aSevere hypoglycemia is characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia.

Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of study intervention.

Abbreviations: AE=adverse event; n=number of participants with events meeting specified criteria; N=number of participants in analysis population.

Note: Data are MBE (SE) unless stated otherwise. Safety analysis was conducted using MMRM on safety participants (N=544) and safety data points set.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; MBE=model - based estimate; SD=standard deviation; SE =standard error; SFU=safety follow - up.

Arrows indicate when the maintenance doses of orforglipron 2.5 mg, 9 mg, and 17.2 mg are achieved.

Notes: Data are MBE (SE) unless stated otherwise. Safety analysis was conducted using MMRM on safety participants (N=544) and safety data points set.

Abbreviations: MBE=model-based estimate; MMRM=mixed model for repeated measures; N=total number of participants in the estimand guiding safety data set; SD=standard deviation; SE=standard error; SFU=safety follow-up.

Arrows indicate when the maintenance doses of orforglipron 2.5 mg, 9 mg, and 17.2 mg are achieved.

Notes: Data are MBE (SE) unless stated otherwise. Safety analysis was conducted using MMRM on safety participants (N=544) and safety data points set.

MBE=model - based estimate; MMRM=mixed model for repeated measures; N=total number of participants in the estimand guiding safety data set; SD=standard deviation; SE=standard error.