The short-term cost-effectiveness of once-weekly semaglutide versus once-weekly dulaglutide for the treatment of type 2 diabetes mellitus in Colombian adults

Background Type 2 Diabetes Mellitus (T2DM) is a highly prevalent disease worldwide and in Colombia, representing one of the main causes of death and placing a considerable burden on healthcare systems. 13 classes of drugs are approved for the treatment of T2DM, with Glucagon-like Peptide-1 (GLP-1) receptor agonists being a first-line treatment option for patients with or at high risk of certain cardiovascular diseases and chronic kidney disease. The objective of this study is to conduct a short-term cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM, from a third-party payer perspective. Methods Numbers needed to treat were calculated for different single and composite endpoints of the SUSTAIN 7 trial, annual costs for once weekly semaglutide 1.0 mg and dulaglutide 1.5 mg were extracted from the public SISMED database. With these inputs a cost of control model was developed, to obtain the annual cost of bringing one T2DM patient to relevant clinical outcomes by using semaglutide or dulaglutide. Results Semaglutide was considered cost-effective compared to dulaglutide across all pre-specified endpoints, even in the different scenarios evaluated in the sensitivity analyses, and in a particularly pronounced manner for weight loss outcomes. Semaglutide at a dose of 1.0 mg once-weekly was cost-effective compared to dulaglutide 1.5 mg across all outcomes in the short-term, making it an appropriate first-line choice in the treatment of T2DM when deciding between these two GLP-1 receptor agonists. Conclusions This is the first short-term cost-effectiveness study of semaglutide and dulaglutide in T2DM Colombian patients. Our modeled results suggest that once-weekly semaglutide represents a cost-effective option for treating individuals with T2DM in Colombia who are not achieving glycaemia control with metformin, and it would be expected to improve HbA1C, promote greater weight loss and reduce costs from a third-payer perspective compared with treatment with dulaglutide.


Introduction
An estimated 537 million people were living with diabetes worldwide in 2021, and this number is expected to increase based on trends and future projections, suggesting that by 2045 the absolute number of people with diabetes will have increased by 46%. 1 The global prevalence of diabetes is estimated to be over 10%, with the highest prevalence rate observed in low and middle-income countries, meaning that three out of four adults with diabetes live in these regions. 2 In Colombia, the prevalence for type 2 diabetes mellitus (T2DM) ranges from 7.1%-8.5% overall, with wide variations between rural areas (1.4%-7.9%)and urban locations (1%-46%), representing the fifth leading cause of death with a rate of 15 deaths per 100,000 individuals. 3This is a worrying finding, as the burden of diabetes is accompanied by large healthcare expenditures, accounting for 966 billion USD worldwide and 2.6 billion dollars annually in Colombia. 2,3til recently, 12 classes of drugs were approved to treat T2DM, with a further option -the dual targeted tirzepatide-, receiving Food and Drug and Administration (FDA) approval in May 2022. 4,5These treatments are either oral or injectable, aiming to prevent or delay the occurrence of microvascular and macrovascular complications, the main causes of morbidity and mortality in patients with diabetes. 5Enhanced glycemic control can be achieved with glucagon-like peptide-1 (GLP-1) receptor agonists, recommended by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) as a first-line treatment option for individuals with T2DM with or at high risk for cardiovascular disease, heart failure, and/or chronic kidney disease.Furthermore, in these patients a GLP-1 receptor agonist is recommended over insulin when possible, and it is also the preferred addition to basal insulin for combined injection therapy. 6ltiple studies have shown robust evidence with this drug class for cardiovascular benefits among patients with T2DM.A systematic review with meta-analysis that included seven clinical trials showed that, overall, the GLP-1 receptor agonist family reduced major adverse cardiovascular events (MACE), including cardiovascular death, stroke, or myocardial infarction, by 12%. 7Similar findings were also shown in another meta-analysis, demonstrating that GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke), and a 12% relative risk reduction in all-cause mortality. 8Once-weekly semaglutide and dulaglutide are GLP-1 receptor agonists approved for the treatment of T2DM by the FDA, European Medicines Agency (EMA) and the Colombia National Food and Drug Surveillance Institute (INVIMA), 9,10 with demonstrated efficacy in the SUSTAIN clinical trial program for the former and the AWARD trial program for the latter. 11,12e purpose of our study was to conduct a short-term cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM, from a third-party payer perspective, as has been recommended in multiple methodological guidelines for economic evaluations. 13

Ethical compliance
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.It is considered research without ethical risks, in accordance with resolution 8430 of 1993 of the Colombian Ministry of Health. 13

REVISED Amendments from Version 1
The new version contains the suggestions given by reviewer 2.
1. Adding a paragraph in the discussion: In Colombia, insurers (payers) are recognized as key players in the healthcare system.These payers have spent 30 years building their expertise in managing healthcare system resources and have had to adapt quickly to the inclusion of greater benefits, including the introduction of new medications, many of which are highcost.This puts the short and long-term sustainability of health insurers in Colombia at risk.Payers in Colombia are gradually shifting towards a more detailed examination of the cost-effectiveness relationship of different health technologies.Due to operational issues, expertise, and human talent, these reviews have not yet been carried out in the long term.Additionally, due to operational considerations and variability in the insured population over time, there is currently no interest in conducting these analyses over long time horizons.In this line of thought, payers have an interest in short-term analysis and cost savings for the system.We believe that using this cost-control economic study design provides a valuable tool for these types of participants in the Colombian healthcare system in the short term (1 year), enabling them to make decisions regarding the prioritization of medications and the access granted to each molecule.

Reorganization of sections: methodology and results.
Any further responses from the reviewers can be found at the end of the article A cost of control model was created using Microsoft Excel to assess numbers needed to treat (NNT) as well as relative and absolute costs according to the criteria and results of SUSTAIN 7, randomized controlled trial (Figure 1 and Table 1).SUSTAIN 7 considers clinical parameters such as weight, glycated hemoglobin, and hypoglycemia results (Table 1).This clinical trial allowed a head-to-head comparison of semaglutide and dulaglutide in the primary clinical outcomes of interest for disease control and weight reduction. 14e analysis was conducted from the perspective of payers in Colombia, who bear 100% of the cost of these medications in the country, over a one-year time horizon.This time frame was selected for two main reasons: the low motivation of these actors in the Colombian health system for economic studies with longer time horizons, given the variability of the insured population over time that does not encourage the management of populations with chronic diseases with a longterm view, and the growing interest of payers in short-term studies with models that allow them to better manage available resources and generate savings for insurers.
For the time horizon selected, discount values were not used either.Likewise, 40 weeks of follow-up data from SUSTAIN 7 were considered to determine efficacy and were not extrapolated beyond the trial period.This allowed the reduction of the uncertainty of the modeled results.Drug prices for once weekly semaglutide 1.0 mg, and dulaglutide 1.5 mg were based on the 2021 costs derived from the SISMED database (Medication Price Information System, by its acronym in Spanish), which includes information on the prices of essential medicines in Colombia. 15No other cost data was considered for the analysis in our study and 100% adherence was assumed for the two drugs once a week.
The higher doses contained in SUSTAIN 7 such as semaglutide 1 mg and dilaglutide 1.5 were used for modeling in this study (Table 2) 14 with n=600 patients.The NNT was calculated in absolute terms for each comparator.For placebos,  NNTs are calculated assuming that zero patients in the group being compared achieve the specified outcome (Table 3).The absolute cost of control was calculated by multiplying the annual cost of treatment for each medication by the NNT of the selected data.The conservative approach was from the once-weekly semaglutide perspective, addressing a full year of treatment costs, thus extending beyond 40 weeks of SUSTAIN 7. Relative costs of control were calculated by reference to the cost of control at semaglutide 1.0 mg once a week.
One-way sensitive analyses were performed around the base case, such as varying the percentage of patients meeting each target by an approximation of the standard error (SE).This was done with the following formula in equation 1, where n is the number of patients in the arm of SUSTAIN 7 and p is the percentage of patients achieving each endpoint: Additionally, cost of control calculations were performed for the best-and worst-case pricing scenarios for semaglutidethe best scenario being when costs are the lowest possible for semaglutide and the highest for dulaglutide, and the worst being the opposite situation-, taking into account the range of prices (minimum and maximum) that were obtained from the SISMED database.

Base case annual costs
The annual base cost for semaglutide and dulaglutide were calculated using the SISMED database, with similar costs per patient for both medications.Semaglutide 1.0 mg had a monthly cost of $486.946Colombian pesos ($5.843.355annually), while dulaglutide 1.5 mg had a monthly cost of $489.762Colombian pesos ($5.877.144pesos annually) (Table 4). 16ble 3. NNT calculation for one of the SUSTAIN 7 outcomes.ARR=Absolute Risk Reduction.

Numbers needed to treat (NNT)
The NNTs for all outcomes were larger for dulaglutide, with the most important differences compared to semaglutide being in the weight loss outcomes, particularly for achieving a weight loss ≥10%, with an NNT of 3.7 for semaglutide and 12.5 for dulaglutide (Figure 2). 16

Cost of control
The previous values were used to estimate the cost per patient successfully reaching the SUSTAIN 7 outcomes.Six SUSTAIN 7 endpoints allowed calculation of the absolute cost of control for the high-dose arms of the drug.According to Table 5, the cost to achieve control was less for the drug semaglutide.Regarding the composite outcome of HbA1c <7%, no weight gain, and no hypoglycemia, which is particularly important -this HbA1C goal is considered appropriate for most T2DM patients by the ADA 2022 guidelines, 17 when it is not associated with significant hypoglycemia-, the cost per patient reaching this endpoint was $7.888.529 for semaglutide, compared to $10.108.687 with dulaglutide.This means that an expenditure 28% greater would have to be spent on dulaglutide to bring one patient to this target (Figure 3). 16

Sensitivity analyses
Sensitivity analyses showed that variations in cost assumptions, where worst case scenarios for semaglutide (those where the price of this drug was highest and that of dulaglutide was lowest) were considered, did not change the finding that the cost of reaching the composite endpoint with semaglutide was lower than the cost with dulaglutide after one year of     treatment, with semaglutide having a cost per patient of $8.151.369,compared to $10.006.649 with dulaglutide, representing an expenditure 22% higher (Figure 4).Considering the one-way sensitivity, we reduced that by decreasing the proportion of patients reaching targets by one standard error (SE) with semaglutide once a week and increasing the patients reaching this target with dulaglutide by one SE, the cost of control of semaglutide once a week was lower by endpoints (Table 5).In this way, these analyzes support the conclusions of the base case analysis.

Discussions
We conducted an evaluation of the short-term cost-effectiveness of the GLP-1 receptor agonists semaglutide and dulaglutide, with cost-effectiveness assessed through the development of a cost of control model, in order to evaluate the numbers needed to treat (NNT) as well as the absolute and relative costs of bringing a single patient to each of the prespecified composite and single endpoints in the SUSTAIN 7 trial, which demonstrated a higher efficacy with semaglutide for all outcomes. 14e calculations from our analysis suggest that achieving clinically relevant endpoints from SUSTAIN 7 would result in economic savings with once weekly semaglutide, compared to dulaglutide after one year of treatment.9][20][21][22] In this study, we synthesized the effectiveness and expenditure evidence and found that semaglutide was associated with the lowest cost per patient reaching disease control for all endpoints, findings that were reaffirmed in our sensitivity analyses.
This study has important implications for stakeholders considering this is the first cost-effectiveness analysis to date comparing subcutaneous semaglutide and dulaglutide in the Colombian diabetic population, potentially allowing a better allocation of resources.[20][21][22] In Colombia, insurers (payers) are recognized as key players in the healthcare system.These payers have spent 30 years building their expertise in managing healthcare system resources and have had to adapt quickly to the inclusion of greater benefits, including the introduction of new medications, many of which are high-cost. 23This puts the short and long-term sustainability of health insurers in Colombia at risk.Payers in Colombia are gradually shifting towards a more detailed examination of the cost-effectiveness relationship of different health technologies.Due to operational issues, expertise, and human talent, these reviews have not yet been carried out in the long term.Additionally, due to operational considerations and variability in the insured population over time, there is currently no interest in conducting these analyses over long time horizons.In this line of thought, payers have an interest in short-term analysis and cost savings for the system. 24,25We believe that using this cost-control economic study design provides a valuable tool for these types of participants in the Colombian healthcare system in the short term (1 year), enabling them to make decisions regarding the prioritization of medications and the access granted to each molecule.
This study has several limitations.First, we restricted our comparison to semaglutide versus dulaglutide.It is important to acknowledge that there are other available molecules in the Colombian market.Second, we limited the costs in the analysis to drugs, as they were expected to be the major drivers of the cost-effectiveness of semaglutide and dulaglutide.Therefore, this model did not account for all potential costs.Third, the analysis takes a third-payer perspective over a short-term horizon.Alternative perspectives and time horizons may result in variable cost-effectiveness estimations, and as such, additional cost-effectiveness studies for these molecules with longer time horizons would be a welcome complement for our study.Fourth, we included prices disregarding potential discounts or refunds, which payers might need to consider in their decision-making processes.

Conclusions
This is the first short-term cost-effectiveness study of semaglutide and dulaglutide in T2DM Colombian patients.Our modeled results suggest that once-weekly semaglutide represents a cost-effective option for treating individuals with T2DM in Colombia who are not achieving glycaemia control with metformin, and it would be expected to improve HbA1C, promote greater weight loss and reduce costs from a third-payer perspective compared with treatment with dulaglutide.Additional cost-effectiveness studies are war-ranted to evaluate the long-term cost-effectiveness of these molecules in the Colombian diabetic population.

Underlying data
All data underlying the results are available as part of the article and no additional source data are required.
Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).
for each therapy is based on prices in Columbia.Clearly, Semaglutide is more potent at the doses chosen, so will demonstrate dominance for each outcome, based on lower NNT and similar price structures.However, both Dulaglutide and Semaglutide come in higher doses now, so that is worthy of discussion and consideration of secondary analysis.At least discussing the more potent versions of each drug now available worldwide.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Partly

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?Yes Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Cardiology
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

George Gourzoulidis
Health Through Evidence, Athens, Greece "An estimated 537 million people were living with diabetes worldwide in 2021, and this number is expected to increase based on trends and future projections, suggesting that by 2045 the absolute number of people with diabetes will have increased by 46%".Please provide refs.

1.
Why is a cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM necessary? 2.
Cost of control model -figure of the model?Can the authors describe the model?3.
The study is weak in methods sections, the authors have to present the cost inputs of the model.Moreover, since this is a cost-effectiveness, the authors have to report why they do not take into account the QALYS?

4.
Why the one-year horizon was selected? 5.
The results have to be separated to clinical and cost outcomes.6.

Are sufficient details of methods and analysis provided to allow replication by others? No
If applicable, is the statistical analysis and its interpretation appropriate?Partly Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Economic EvaluationHealth Services ResearchOutcomes ResearchHealth Technology AssessmentHealthcare Economics
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
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Figure 1 .
Figure 1.Design of the SUSTAIN 7 randomized controlled trial.

Figure 2 .
Figure 2. Numbers needed to treat to bring one patient to target with once-weekly semaglutide 1.0 mg, and dulaglutide 1.5 mg.HbA1C, glycated hemoglobin.

Figure 4 .
Figure 4. Relative cost of control with once-weekly semaglutide 1.0 mg and dulaglutide 1.5 mg versus onceweekly in the worst scenario of cost for semaglutide (index = 100.000).HbA1C, glycated hemoglobin.

Table 1 .
Proportion of patients reaching target with once weekly semaglutide 1.0 mg, and dulaglutide 1.5 mg, all in combination with metformin, in the SUSTAIN 7 trial.

Table 2 .
Example cost of control calculation based on the proportion of patients achieving a HbA1c target <7%.

Table 4 .
Colombian drug prices per month of treatment according to SISMED in 2021 Colombian pesos (COP) (December 2021).

Table 5 .
Absolute annual cost of control outcomes with once-weekly semaglutide 1.0 mg, and dulaglutide 1.5 mg in 2021 Colombian pesos (COP).Calculations in the base cost, best and worst scenarios for semaglutide.