Type 2 diabetes is associated with multimorbidity, microvascular and macrovascular complications, and increased mortality (1). A holistic approach to treatment with multifactorial risk-reduction strategies is recommended to improve long-term diabetes outcomes (2). In this post hoc analysis of the Peptide Innovation for Early Diabetes Treatment (PIONEER) 1–8 trials (excluding PIONEER 6), we evaluated the efficacy of oral semaglutide versus placebo or active comparators in reducing four cardiometabolic risk factors.
In the PIONEER trials, in adults aged ≥18 years with type 2 diabetes, once-daily oral semaglutide 3, 7, or 14 mg was compared with one or more of the following: placebo (PIONEER 1, 4, 5, and 8), empagliflozin 25 mg (PIONEER 2), sitagliptin 100 mg (PIONEER 3 and 7), and liraglutide 1.8 mg (PIONEER 4). Here, we assessed the proportion of participants with reductions of ≥1 percentage points (%-point) glycated hemoglobin (HbA1c), ≥5% body weight (BW), ≥5 mmHg systolic blood pressure (SBP), and ≥0.5 mmol/L LDL cholesterol. For each end point, we estimated an odds ratio for oral semaglutide 14 mg (or flexible dose adjustment, for PIONEER 7) versus placebo or active comparator using the trial product estimand. We also assessed the proportion of participants and corresponding estimated odds ratios for achievement of any two or three of the end points during the respective trials. Data were from the on-treatment-without-rescue-medication period for all randomized participants. Binary end points were analyzed with a logistic regression model, and missing values for continuous end points that contribute to the binary end point were imputed with an ANCOVA model.
The proportion of participants reaching a defined reduction in each individual risk factor at the end of treatment was greater with oral semaglutide versus placebo or active comparators in all trials, except for comparable proportions for SBP ≥5 mmHg in the PIONEER 2 and 7 trials (Fig. 1A). The odds of reaching an HbA1c reduction of ≥1%-point were significantly greater with oral semaglutide versus placebo or active comparator in all trials (P < 0.001 for all comparisons, apart from liraglutide 1.8 mg in PIONEER 4 [P = 0.048]) (Fig. 1A). The odds of reaching a BW reduction of ≥5% were significantly greater with oral semaglutide versus placebo or all active comparators (all P < 0.001), except for the comparison with empagliflozin 25 mg in PIONEER 2 (P = 0.116) (Fig. 1A). The odds of reaching an SBP reduction of ≥5 mmHg were significantly greater with oral semaglutide versus placebo in PIONEER 1, 4, and 5 and versus sitagliptin 100 mg in PIONEER 3 (all P < 0.05); the odds were not significantly greater in PIONEER 2, 4 (vs. liraglutide 1.8 mg), 7, or 8 (Fig. 1A). Additionally, the odds of reaching a reduction in LDL cholesterol of ≥0.5 mmol/L were significantly greater with oral semaglutide versus placebo in PIONEER 1 and 4 and with oral semaglutide versus empagliflozin 25 mg in PIONEER 2 (all P < 0.05) (Fig. 1A).
Once-weekly oral semaglutide vs. comparator for achieving either A) an individual end point or B) multiple end points per trial. Data show the proportion of participants and estimated odds ratio (EOR) per trial for achieving A) an individual end point of HbA1c reduction of ≥1%-point, BW reduction of ≥5%, SBP reduction of ≥5 mmHg, or LDL cholesterol reduction of ≥0.5 mmol/L or B) any two or three end points. Observed data are from the on-treatment-without-rescue-medication period. The odds ratios were estimated with use of the trial product estimand. For binary end points, analyses were conducted with a logistic regression model for each of the 1,000 imputed complete data sets, with pooling by the Rubin rule to draw inference. Missing values for continuous end points that enter the binary end point were imputed with use of an ANCOVA-based sequential multiple imputation model. End points were analyzed at end of trial (week 26 for PIONEER 1 and 5; week 52 for PIONEER 2, 4, 7, and 8; and week 78 for PIONEER 3). empa, empagliflozin; flex, flexible dose adjustment; lira, liraglutide; sema, semaglutide; sita, sitagliptin.
Once-weekly oral semaglutide vs. comparator for achieving either A) an individual end point or B) multiple end points per trial. Data show the proportion of participants and estimated odds ratio (EOR) per trial for achieving A) an individual end point of HbA1c reduction of ≥1%-point, BW reduction of ≥5%, SBP reduction of ≥5 mmHg, or LDL cholesterol reduction of ≥0.5 mmol/L or B) any two or three end points. Observed data are from the on-treatment-without-rescue-medication period. The odds ratios were estimated with use of the trial product estimand. For binary end points, analyses were conducted with a logistic regression model for each of the 1,000 imputed complete data sets, with pooling by the Rubin rule to draw inference. Missing values for continuous end points that enter the binary end point were imputed with use of an ANCOVA-based sequential multiple imputation model. End points were analyzed at end of trial (week 26 for PIONEER 1 and 5; week 52 for PIONEER 2, 4, 7, and 8; and week 78 for PIONEER 3). empa, empagliflozin; flex, flexible dose adjustment; lira, liraglutide; sema, semaglutide; sita, sitagliptin.
A greater proportion of participants across all the analyzed PIONEER trials also met the composite outcomes of reductions in any two or three end points with oral semaglutide versus placebo and all active comparators (Fig. 1B). The odds of meeting two and three end points were significantly greater with oral semaglutide versus any comparator across all trials (all P < 0.05) (Fig. 1B).
Cardiovascular (CV) diseases are the leading cause of mortality in individuals with type 2 diabetes; therefore, controlling cardiometabolic risk factors is vital, given their strong association with CV disease (2). Our analysis showed that the odds of reaching reductions in four cardiometabolic risk factors were greater with oral semaglutide versus comparators in most of the trials analyzed. Although our analysis did not include investigation of the effect of multifactor risk reduction on CV outcomes due to the relatively short trial lengths and, therefore, minimal numbers of events to analyze, the CV safety and benefit of glucagon-like peptide 1 receptor agonists have previously been demonstrated (3–5).
In our analysis we used robust individual participant data from multiple phase 3 trials covering a wide variety of populations, comparators, and background medications, with minimal missing values. Limitations of our analysis included variations in trial length, with some trials being short (only PIONEER 3 extended beyond 52 weeks), leading to a lack of recorded CV events available for assessment of CV benefit or safety.
In summary, this analysis of seven PIONEER trials indicates that oral semaglutide 14 mg (or flexible dosing, in PIONEER 7) was generally more effective at improving multiple cardiometabolic risk factors—including HbA1c, BW, SBP, and LDL cholesterol—versus placebo and active comparators. Therefore, oral semaglutide has the potential to improve the multimorbidity and adverse cardiometabolic profile associated with type 2 diabetes.
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Acknowledgments. The authors thank Johanna Eliasson, Jesso George, and Lasse L. Nielsen from Novo Nordisk for their review of and input into the manuscript, as well as the participants, investigators, and trial site staff for the PIONEER trials (Clinical trial reg. nos. NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02849080, and NCT03021187, ClinicalTrials.gov). Medical writing support was provided by James Parkinson and William Townley of Apollo, OPEN Health Communications (London, U.K.), and funded by Novo Nordisk A/S, in accordance with Good Publication Practice guidelines (www.ismpp.org/gpp-2022).
V.R.A. is an editor of Diabetes Care but was not involved in any of the decisions regarding review of the manuscript or its acceptance.
Funding. K.K. is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands, NIHR Global Research Centre for Multiple Long-Term Conditions, Multiple Long-Term Conditions Cross-NIHR Collaboration, NIHR Leicester Biomedical Research Centre, and the British Heart Foundation Centre of Research Excellence.
Duality of Interest. This trial was funded by Novo Nordisk A/S. The study sponsor was involved in study design; data collection, analysis, and interpretation; and the writing of the manuscript. V.R.A. reports receiving consultancy fees from Applied Therapeutics, Fractyl Health, Mediflix, Novo Nordisk A/S, Pfizer, and Sanofi and research grant support (to institution) from Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Corcept Therapeutics, Eli Lilly, Fractyl Health, Novo Nordisk A/S, Pfizer, Rhythm Pharmaceuticals, and Servier. B.M. and M.T.A. are employees of and shareholders in Novo Nordisk A/S. J.J.M. has received grants from Merck Sharp & Dohme (MSD), Novo Nordisk, and Sanofi and lecture/other fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novo Nordisk, Sanofi, and Servier. P.K. is an employee of Novo Nordisk India Private Limited. T.V. has served on scientific advisory panels, been part of speakers’ bureaus, and served as a consultant to or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead Sciences, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi, and Sun Pharmaceuticals. K.K. has served as a consultant to, and received speaker fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, Roche, Sanofi, and Servier; has served on advisory boards for AstraZeneca, Eli Lilly, MSD, Novo Nordisk, and Sanofi; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. All authors were involved in the study design, in conducting the study and data collection, or in analyzing data. All authors were involved in the interpretation of data and critically reviewing, editing, and approving the manuscript. V.R.A. and M.T.A. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Frank B. Hu.
