The Composite Number Needed to Treat for Semaglutide in Populations with Overweight or Obesity and Established Cardiovascular Disease Without Diabetes

Abstract

Introduction

Number needed to treat (NNT), an outcome measure derived from the estimated risk results of clinical trials, is widely used to demonstrate value to stakeholders by identifying how many patients require treatment to avoid one event of interest. However, NNTs calculated for primary trial endpoints may underestimate a treatment’s value by not considering other outcomes. In this secondary analysis of data from the SELECT cardiovascular (CV) outcomes trial, we aimed to determine the NNT for semaglutide for major adverse cardiovascular events (MACE), in addition to NNTs when other clinically and payer-relevant outcomes are included.

Methods

This study is a secondary analysis of data from the randomized, double-blind SELECT trial (ClinicalTrials.gov NCT03574597) of once-weekly subcutaneous administration of semaglutide compared with placebo in 17,604 patients with overweight or obesity and with established cardiovascular disease (CVD) (39.8 months mean follow-up). The outcomes were NNT_3P-MACE (based upon the trial’s composite primary endpoint of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke), NNT_EXTENDED (inclusive of NNT_3P-MACE, hospitalization for any cause, coronary revascularization, and non-CV death), and NNT_CKM (inclusive of NNT_EXTENDED, glycated hemoglobin level [HbA_1c] ≥ 6.5%, and a 5-point nephropathy composite).

Results

The relative risk reductions observed for the events comprising the NNTs were 20% (NNT_3P-MACE), 20% (NNT_EXTENDED), and 41% (NNT_CKM). At 1 and 4 years post initiation of semaglutide, NNT_3P-MACE was 125 and 58, NNT_EXTENDED was 49 and 25, and NNT_CKM was 20 and 11, respectively.

Conclusion

When clinically and payer-relevant outcomes from the SELECT trial are included in calculations of NNT, semaglutide was associated with greater risk reductions and lower estimates of NNT than for the primary endpoint alone. Our findings suggest that including the broader effects of semaglutide beyond the primary trial endpoint recognizes additional value to stakeholders.

Key Summary Points

Why carry out this study?

Number needed to treat (NNT) is typically derived from the primary endpoints of randomized controlled trials but the value of treatment to stakeholders may be underestimated by not considering other outcomes.

In this secondary analysis we aimed to determine the NNT for semaglutide from the SELECT trial for major adverse cardiovascular events (MACE) and two other composites including a broader range of clinical and biochemical outcomes.

What was learned from the study?

Incorporating additional clinical events and biochemical outcomes resulted in lower estimates of NNT and greater risk reductions than when trial-defined MACE was used alone.

These findings support the broader benefits of semaglutide in this cohort; the reporting of measures such as NNT that derive from a wider view of “value” may aid clinical and payer decision-making.

Introduction

The World Health Organization (WHO) estimates that there are 1.6 billion adults living with overweight (defined as having a body mass index (BMI) of 25–30 kg/m²) and 890 million living with obesity (BMI ≥ 30 kg/m²) [1]. Based on historical prevalence trends, it is estimated that these numbers will increase such that more than half the global adult population will be living with overweight or obesity by 2035 [2]. By 2050, the prevalence of overweight and obesity in US adults aged 25 years and older is projected to be more than 80%: 213 million people, of whom 146 million will have obesity [3].

Overweight and obesity contribute to cardiovascular (CV) risk through their effects on incident risk factors, and independently of other risk factors [4]. Cardiovascular disease (CVD) is the leading cause of death and disability-adjusted life-years (DALYs) related to high BMI; 41% of global BMI-related deaths and 34% of global BMI-related DALYs occur due to CVD in people with obesity [5]. The second-largest cause of high BMI-related DALYs was “diabetes and kidney disease” [5]. Obesity has been identified as the most important risk factor in the development and progression of type 2 diabetes [6], and also as a risk factor for decreased estimated glomerular filtration rate (eGFR) and increased albuminuria (markers of kidney disease) [7, 8]. Genetic evidence suggests a causal link between obesity and chronic kidney disease (CKD) [9], which is itself a major and underappreciated global public health problem [10, 11]. Cardiorenal syndrome, a bidirectional association where dysfunction in the heart or kidneys can induce dysfunction in the other organ is well known [12]. The connections between obesity, CVD, diabetes, and CKD are now viewed as part of a cardiovascular-kidney-metabolic (CKM) syndrome; lifestyle modification and weight loss are encouraged to address dysfunctional adiposity and prevent progression along the CKM continuum [13].

Pharmacotherapies may be used as adjunctive options to assist weight loss in people with BMI over 30 for whom lifestyle/behavioral modification is unable to achieve weight loss goals [13, 14], and may also be used in other specific populations, e.g., people with BMI > 26 with obesity-related complications [14]. Relatively modest weight loss (5–10%) has been shown to have a positive impact on a broad range of metabolic and CV risk factors in patients with overweight or obesity, regardless of their diabetes status [15, 16], but until relatively recently there was limited evidence to suggest a beneficial effect of such weight loss on hard CV outcomes [17].

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs used for the treatment of type 2 diabetes and obesity [18]. Early research focused on their ability to regulate blood glucose levels [19], but they have since been shown to have broad effects throughout the body, including weight loss, the attenuation of inflammation and hypertension, and a reduction of CV risk that translates to prevented CV events in key patient populations [20]. In the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, semaglutide, a GLP-1 RA, was found to be superior to placebo in reducing risk of a composite major adverse cardiovascular event (MACE) endpoint (consisting of first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke) in participants with established CVD and overweight or obesity but without diabetes [21]. This trial represented a watershed moment in the clinical management of these patients; since publication of the SELECT trial results, semaglutide is now approved for use by the US Food and Drug Administration (FDA) to reduce the risk of MACE in adults with established CVD and obesity or overweight [22], in addition to regulatory approval by the European Medicines Agency (EMA) and other major markets. It is also included in the European Society of Cardiology guideline for the management of chronic coronary syndromes as the only GLP-1 RA with proven beneficial effect on MACE in patients with chronic coronary syndromes without diabetes but with overweight or obesity [23].

In addition to the primary outcome of SELECT, nominally statistically significant risk reductions were also seen in secondary efficacy endpoints, including heart failure composite endpoint, all-cause mortality, coronary revascularizations, sustained weight loss for 104 weeks, a 5-point nephropathy composite endpoint, and patients developing biochemical diabetes (at least one post-randomization glycated hemoglobin [HbA_1c] ≥ 6.5%) [21]. These risk reductions are clinically relevant and of interest to patients and clinicians, as well as to health system administrators and payers because of their associated healthcare resource use. However, they have not received the same attention as the trial’s primary results, and further investigation is needed to understand the broader benefit of semaglutide therapy.

Number needed to treat (NNT), an outcome measure derived from the estimated risk results of randomized controlled trials, is widely used to assess treatment benefit [24, 25]. NNT is an absolute effect measure that describes the number of patients who must be treated with one therapy versus another for one patient to encounter one additional outcome of interest within a defined time period [26, 27]. The experienced event can be a clinically positive outcome (e.g., an avoided stroke), but may also be a negative (e.g., an adverse event related to the therapy, giving a number needed to harm). Although NNT is a useful tool to translate treatment efficacy into clinical practice, its derivation requires care; for example, when multiple competing risks (outcomes that preclude the occurrence of outcomes of interest) and other outcomes of interest beyond the primary trial endpoint exist, multiple hierarchical NNTs should be calculated to capture the overall effect of treatment on different events [24, 28]. Similarly, because NNT are specific to the results of a given comparison between two therapies [29], interpretation of NNT should be contextual, and requires the impact of factors such as trial follow-up length or population baseline risk to be considered [25]. Nevertheless, the usefulness of NNT is recognized by its inclusion within the Consolidated Standards of Reporting Trials (CONSORT) statement [30, 31]. Within the CONSORT statement, there is an appreciation that “therapies found to be beneficial in a narrow range of patients generally have broader application in actual practice” [31]. While this assertion is made within the context of trial vs. real-world patient populations, it is also relevant when considering NNTs for therapies like semaglutide that have diverse treatment effects. This secondary analysis aimed to demonstrate the broader benefits of semaglutide use by determining both the NNT for semaglutide in terms of the primary CV composite of the SELECT trial and NNTs that capture additional clinically and payer-relevant outcomes reported as part of the secondary efficacy endpoints [21]. A more holistic assessment of benefit to patients is expected to impact on the therapy’s value, as perceived by decision-makers.

Methods

Data Source and Study Design

This study is a post hoc secondary analysis of data from the randomized, double-blind, event-driven SELECT trial (NCT03574597) of once-weekly subcutaneous administration of semaglutide compared with placebo in 17,604 patients with established CVD and obesity. Of these patients, 8803 were randomized to receive once-weekly subcutaneous administration of semaglutide and 8801 received placebo. A total of 17,061 patients completed the trial, with a mean follow-up period of 39.8 ± 9.4 months.

The design [32], baseline characteristics [33], and primary results [21] of SELECT have been reported in detail along with additional analyses on specific subpopulations and outcomes [34–38].

Ethical Approval and Informed Consent

The SELECT trial protocol was reviewed by national and institutional regulatory and ethical authorities in each participating country, and the trial was conducted at 804 sites across 41 countries. All patients provided written informed consent before beginning any trial-related activity. The SELECT study was conducted in line with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The present analysis did not require informed consent or institutional/ethical review board approval since the analysis does not report any new studies with human participants or animals performed by any of the authors and was based on the previously conducted clinical trial. Any clinical data were anonymized for the purpose of the study.

Study Cohort

The full inclusion and exclusion criteria have been published previously [21]. Briefly, patients were eligible to participate in the SELECT trial if they were aged ≥ 45 years of age, had a BMI of ≥ 27 kg/m², and had established CVD (defined as one or more of the following: prior myocardial infarction [MI], prior ischemic or hemorrhagic stroke, or symptomatic peripheral artery disease [PAD]). Key exclusion criteria were a previous diagnosis of diabetes or HbA_1c ≥ 6.5% (48 mmol/mol) as measured at screening.

Outcomes

The outcomes of this analysis were three NNTs: one based on the primary endpoint of SELECT, NNT_3P-MACE, and two additional NNTs based on a broader set of cardiovascular (NNT_EXTENDED) and cardiovascular-kidney-metabolic (NNT_CKM) endpoints and outcomes from the SELECT trial.

NNT_3P-MACE was based on the primary CV endpoint of SELECT (a composite including death from CV causes, non-fatal MI, or non-fatal stroke, an approach typical within the literature).

NNT_EXTENDED was calculated based on the primary CV composite endpoint, plus the confirmatory secondary endpoint of death from any cause, hospitalization for any cause, and coronary revascularization.

NNT_CKM was calculated based on the same events as for NNT_EXTENDED, in addition to the following clinical and subclinical events that are relevant from a holistic, CKM syndrome perspective: progression to biochemical diabetes (at least one post randomization HbA_1c ≥ 6.5%), and a 5-point nephropathy composite. This latter composite consisted of death from renal causes, initiation of dialysis or transplant, onset of eGFR < 14 mL/min/1.73 m², persistent 50% reduction in eGFR relative to baseline, or onset of persistent macroalbuminuria (a measure of kidney damage, urinary albumin-to-creatinine ratio > 300 mg/g).

Endpoints considered for each NNT, and the hierarchy formed as additional endpoints are added, are shown as Fig. 1.

Fig. 1.

Endpoints considered for each calculated NNT from the SELECT clinical trial outcomes. CR coronary revascularization, CV cardiovascular, HbA1c glycated hemoglobin, HHF hospitalization for heart failure, HUA hospitalization for unstable angina, 3P-MACE three-point major adverse cardiovascular events, MI myocardial infarction, NNT number needed to treat, Other hosp hospitalization for any other cause

Statistical Analysis

The data were analyzed as time to first event, with the absolute risk of experiencing outcomes calculated at 1-, 3-, and 4-year timepoints post semaglutide initiation. Cumulative incidences of all NNTs were estimated using the Aalen-Johansen method; NNT_EXTENDED and NNT_CKM are comprehensive and assumed no competing events, while NNT_3P-MACE was calculated with all-cause mortality as a competing event. NNTs were calculated as per the approach outlined by Altman and Andersen [39]. The NNTs were calculated at a given timepoint from the SELECT time to first event analysis using the formula 1/(S_a − S_c) where S_a and S_c represent the estimated survival probabilities for the active and control conditions at the given timepoint, respectively. For descriptive purposes, the distribution of events contributing to each NNT is presented based on the overall trial experience, and would approximately correspond to the trial average of 39.8 months of follow-up [21].

Results

Risk Reduction and NNT Outcomes

Primary and secondary endpoints from the SELECT trial have been presented previously [21]. The relative risk reduction of the primary CV composite endpoint (death from CV causes, non-fatal MI, or non-fatal stroke) in participants receiving semaglutide was 20%. Treatment with semaglutide reduced the relative risk for the broader clinically and payer-relevant outcomes included in NNT_EXTENDED by 20% and reduced the relative risk for the outcomes included in NNT_CKM by 41%. The contributions of each event type to the individual NNTs during the mean 39.8 months of follow-up are given in Table 1, along with approximate NNTs at this timepoint based on these descriptive statistics.

Table 1.

Contributions of each event type to total event counts and subsequent NNTs over the SELECT trial observation period (39.8 months mean follow-up)

	Events, semaglutide (%)	Events, placebo (%)	Excess events on placebo (%)	NNT (39.8 months mean F/U)
NNT3P-MACE
Primary CV composite endpoint	569 (100)	701 (100)
MI	239 (42.0)	330 (47.1)	91 (68.9)
Stroke	154 (27.0)	175 (25.0)	21 (15.9)
CV death	176 (30.9)	196 (28.0)	20 (15.2)
Total events	569 (100)	701 (100)	132 (100)	67
NNTEXTENDED
All cause hospitalization	2560 (83.2)	2765 (81.8)	205 (67.9)
MI	168 (5.5)	219 (6.5)	51 (16.9)
Coronary revascularization	132 (4.3)	170 (5.0)	38 (12.6)
Stroke	106 (3.4)	112 (3.3)	6 (2.0)
CV death	89 (2.9)	91 (2.7)	2 (0.7)
Other death	22 (0.7)	22 (0.7)	0 (0.0)
Total events	3077 (100)	3379 (100)	302 (100)	29
NNTCKM
Biochemical diabetes (HbA1c ≥ 6.5%)	215 (6.4)	769 (18.8)	554 (75.1)
All cause hospitalization	2506 (74.9)	2591 (63.5)	85 (11.5)
MI	162 (4.8)	202 (4.9)	40 (5.4)
Coronary revascularization	129 (3.9)	160 (3.9)	31 (4.2)
5-point nephropathy	120 (3.6)	149 (3.7)	29 (3.9)
Stroke	105 (3.1)	107 (2.6)	2 (0.3)
Other death	21 (0.6)	21 (0.5)	0 (0.0)
CV death	86 (2.6)	83 (2.0)	− 3 (− 0.4)
Total events	3344 (100)	4082 (100)	738 (100)	12

CKM cardiovascular-kidney-metabolic, CV cardiovascular, F/U follow-up, HbA1c glycated hemoglobin, 3P-MACE three-point major adverse cardiovascular events, MI myocardial infarction, NNT number needed to treat

Cumulative incidence functions across the trial period at 1, 2, 3, and 4 years for the three sets of considered endpoints are shown in Fig. 2; the resulting NNTs at these timepoints are shown in Table 2. The 1- and 4-year NNTs were calculated to be 125 and 58 for NNT_3P-MACE, 49 and 25 for NNT_EXTENDED, and 20 and 11 for NNT_CKM. The NNT from 1 to 4 years for the primary CV composite endpoint, the broader selection of CV endpoints, and the broadest CKM-relevant endpoints are plotted across this time period in Fig. 3.

Fig. 2.

Cumulative incidence curves for different endpoint sets at 1, 2, 3, and 4 years post semaglutide initiation. AR absolute risk, CKM cardiovascular-kidney-metabolic, CV cardiovascular, 3P-MACE three-point major adverse cardiovascular events

Table 2.

Calculated NNT for different endpoint sets at 1, 2, 3, and 4 years post semaglutide initiation

	Timepoint
	1 year	2 years	3 years	4 years
NNT3P-MACE	125	125	87	58
NNTEXTENDED	49	32	30	25
NNTCKM	20	14	12	11

CKM cardiovascular-kidney-metabolic, 3P-MACE major adverse cardiovascular events, NNT number needed to treat

Fig. 3.

Number needed to treat to prevent one additional event up to 4 years post semaglutide initiation. CKM cardiovascular-kidney-metabolic, CV cardiovascular, 3P-MACE three-point major adverse cardiovascular events, NNT number needed to treat

Discussion

This secondary analysis of the SELECT trial calculated NNT using the primary CV composite endpoint of the trial, in addition to two composite NNTs that included consideration of semaglutide’s effects on hospitalizations, and cardiovascular-, kidney-, or diabetes-related outcomes. In NNT_CKM, we included subclinical events (e.g., HbA1c ≥ 6.5%, changes in eGFR) that, while not being hard outcomes, would be expected to form part of a clinician’s decision-making processes when reviewing therapy and which may then incur additional costs. The relative risk reductions associated with the broader NNTs (NNT_EXTENDED, 20%; NNT_CKM, 41%) were comparable to or greater than for the primary CV composite endpoint (20%). The 1- and 4-year NNTs were calculated to be 125 and 58 for NNT_3P-MACE, 49 and 25 for NNT_EXTENDED, and 20 and 11 for NNT_CKM, respectively, indicating a broad benefit of semaglutide beyond the primary endpoint of SELECT.

The largest driver of difference between NNT_3P-MACE and NNT_EXTENDED is the inclusion of hospitalization events, as a function of their greater incidence compared with the primary CV composite. The largest driver of difference between NNT_EXTENDED and NNT_CKM is the inclusion of biochemical diabetes and the substantial reduction in rates of this event between placebo and semaglutide arms (see Table 1). Compared with NNT_3P-MACE (based on the primary CV composite endpoint), the addition of all-cause hospitalization (ACH) in the time to first-event analysis reduces the counts of other fatal and non-fatal events, suggesting ACH is a precursor to more severe events. For example, MI event count in the semaglutide arm decreased from 239 to 168, suggesting that 71 patients in the semaglutide arm were hospitalized prior to experiencing an MI. Similar observations can be made for stroke and CV death. As a result of including ACH, the contribution of CV death and non-CV “other” death to NNT_EXTENDED is relatively low. The decrease in NNT where ACH is incorporated indicates semaglutide’s efficacy in reducing the incidence of these earlier events with serious fatal and non-fatal sequelae. The observed reduction in NNT achieved by the inclusion of additional endpoints beyond the primary endpoint speaks to the limitations of a restricted definition of benefit. Patients and clinicians may be most interested in how a therapy can prevent fatal and non-fatal major CV events, and hence NNT_3P-MACE. However, the prevention of (initially) less costly and less serious but more common outcomes, such as hospitalizations or progression to biochemical diabetes (as represented in NNT_CKM), may be of equal relevance to health system administrators and payers seeking to manage limited resources in the face of the obesity epidemic.

NNT is specific to the results of a given comparison [25]; they are calculated from the absolute risk reduction between two treatment options in a single study, rather than from an absolute measure of clinical effect, and are sensitive to baseline risk, timeframe, and the outcomes considered. However, the reduction in composite NNTs observed in our analysis aligns with the broad beneficial effects on CV outcomes reported for semaglutide across indications [40]. A systematic review of eight CV outcome trials of GLP-1 RAs in patients with type 2 diabetes reported substantial variation of NNTs calculated to prevent one MACE, ranging from 83 to 429 at 1 year, 30 to 129 at 3 years, and 16 to 68 at 6 years [41]. Although the SELECT trial differs from the trials reviewed, most significantly in the recruitment of a population without diabetes (and hence potentially at lower baseline risk), it is encouraging that our calculated NNT_3P-MACE falls within the ranges reported, contributing to the face-validity of our analysis.

The use of NNT as a tool to communicate value to stakeholders has advantages and disadvantages. NNTs are a simple measure that can provide valuable information alongside cost-effectiveness analyses when evaluating treatment benefits. They cannot replace the use of cost-effectiveness analyses [42], since they do not capture opportunity costs or healthcare costs, do not consider health-related quality of life benefits of treatment, are not readily comparable between trials [43], and cannot account for the costs and morbidity of multiple events experienced by individual patients. NNT are typically calculated based upon a low number of specific outcomes, e.g., primary trial endpoints, that are of clear significance to stakeholders. However, the standard approach to calculating NNT is unable to quantify the impact of competing risks where these exist. A simple resolution is to derive multiple NNTs with different events considered (hence, different competing risks) to capture the overall effect of a therapy [28].

The use of multiple, hierarchical NNTs addresses the issue of competing risks (e.g., non-CV death in NNT_3P-MACE), while also recognizing the significance of a therapy’s broader treatment effects. There is already an appreciation within the medical literature that a narrow focus within outcomes trials misses the wider benefits of GLP-1 RAs across the CKM spectrum, and there are calls to review the design and analysis of outcomes trials in the CKM space to include more endpoints [44]. In this case, an approach to NNTs as reported here could become more common in the future to better communicate the total value of these drugs to healthcare systems.

A strength of this study is that our outcomes are derived from a major, pivotal clinical trial; the data underlying the NNT are specific, consistently measured, and are from a relevant clinical cohort across multiple countries and settings. Thus, the results generated should be robust, and well generalizable in this specific patient cohort. There have been six publications to date that consider the results of the SELECT trial, none of which calculate a NNT, either for the primary or composite endpoints [21, 34–38]. By presenting therapeutic effects on an absolute scale, NNTs help facilitate the practice of evidence-based medicine [45]. Furthermore, the hierarchy of NNTs presented in this study cannot be computed from the previous publications, owing to their dependence on the joint distribution of the individual components of the composite endpoints. Accordingly, our study takes a novel approach compared with the wider literature; the broad benefits of treatment with semaglutide are presented in a way that can inform clinical decision-makers, and which may have implications for the future of NNTs for multi-indication treatments.

Our study has limitations: the generalizability of the results of the SELECT trial to a real-world clinical population of patients with overweight or obesity and established CVD or to a population without established CVD is unknown, and the generalizability of our results is similarly uncertain. In addition, our assessment of value is limited by the design of outcome assessments in SELECT, in that any effect of semaglutide therapy on other obesity-related complications (e.g., sleep apnea, osteoarthritis, or atrial fibrillation) and their related healthcare resource use is uncertain. NNTs to prevent incidence of these outcomes cannot be calculated. We do not present subgroup analysis; it is likely that patients with comorbidities relevant to the outcomes assessed in our NNT models, such as those with prediabetes, would (all other things being equal) be associated with lower values of NNTs, which may have implications for clinical decision-making. Also, we recognize that presenting additional NNTs considering individual endpoints or groupings of endpoints (e.g., NNT_{5-point MACE}, NNT_{Major adverse kidney events}) would be useful to some readers or would allow a degree of comparison between the results of different trials. In the current analysis, we have limited the number of NNTs presented to aid clarity. Finally, within the SELECT trial, the recording of a single HbA1c value ≥ 6.5% was defined as “progression to diabetes” [21]. There is uncertainty about whether patients reporting this would be expected to clinically present and be diagnosed with diabetes, as well as the extent to which the avoidance of such progression commensurately avoids all important clinical sequelae, and this may introduce a risk of overestimation in terms of “prevented diabetes.” However, as a subclinical outcome, the relevance and importance to patients of maintaining blood sugars below the hyperglycemic range to avoid a formal diabetes diagnosis is likely to mean its inclusion in our analyses is a valid approach to capturing value. This is particularly prescient, given the increasing awareness of how type 2 diabetes impacts on other components of CKM syndrome [13].

Conclusion

When the broader treatment effects of semaglutide were explored using both the primary and key secondary outcomes of the SELECT trial, composite NNTs which include clinically and payer-relevant events and biochemical outcomes were associated with greater risk reductions and lower NNTs compared with NNT_3P-MACE based on the trial’s primary CV composite endpoint alone. While calculations of NNT cannot replace cost-effectiveness analyses, they can provide insight for a range of stakeholders in the healthcare system.

Author Contributions

Christopher Lübker and Jens Magelund Tarp conceptualized and designed the study. Jens Magelund Tarp was responsible for data analysis. All authors (Christopher Lübker, Jigish Bhavsar, Ruben Duque do Vale, Scott S. Emerson, Emil Nørtoft, Jorge Plutzky, Geraint Roberts, Jens Magelund Tarp, A. Michael Lincoff) contributed to the interpretation of results, preparation and critically reviewed the manuscript, and had final approval of the submitted and published versions.

Funding

This work was supported by Novo Nordisk who provided support for model development, analysis and medical writing for this study. The journal’s Rapid Service and Open Access Fees were funded by Novo Nordisk.

Data Availability

Bonafide researchers with approved research proposals may request aggregated data, which will be subject to Novo Nordisk data sharing and protection policies.

Declarations

Conflict of Interest

Christopher Lübker is an employee and shareholder of Novo Nordisk A/S. Jigish Bhavsar is an employee of Novo Nordisk Inc. and shareholder of Novo Nordisk A/S. Ruben Duque do Vale is an employee and shareholder of Novo Nordisk A/S. Scott S. Emerson declares having received consulting honoraria from Amylyx, AstraZeneca, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, 89 Bio, BioAge, BioAtla, Bristol Meyer Squibb, BridgeBio, Daiichi Sankyo, Denovo, Fore Therapeutics, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, NSABP, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, SOLVD, Sutro Biopharma, and TG Therapeutics. Emil Nørtoft is an employee of Novo Nordisk A/S. Jorge Plutzky declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Inc., Merck, MJH Life Sciences, Novartis, and Novo Nordisk and has received a grant, paid to his institution, from Boehringer Ingelheim. Geraint Roberts is an employee of HEOR Ltd., who received fees from Novo Nordisk A/S in relation to this study. Jens Magelund Tarp is an employee of Novo Nordisk A/S. A. Michael Lincoff declares having received research grants paid to his institution from AbbVie Inc., AstraZeneca, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Inc., and Novartis and has served as a consultant for Akebia Therapeutics Inc, Alnylam Pharmaceuticals Inc., Ardelyx, Eli Lilly and Company, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, Entity, and ReCor Medical.

Ethical Approval

The SELECT trial protocol was reviewed by national and institutional regulatory and ethical authorities in each participating country, and the trial was conducted at 804 sites across 41 countries. All patients provided written informed consent before beginning any trial-related activity. The SELECT study was conducted in line with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The present analysis did not require informed consent or institutional/ethical review board approval since the analysis does not report any new studies with human participants or animals performed by any of the authors and was based on the previously conducted clinical trial. Any clinical data were anonymized for the purpose of the study.