Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia

Soo Kun Lim; Shaun Wen Huey Lee

doi:10.1371/journal.pone.0296067

. 2024 Mar 6;19(3):e0296067. doi: 10.1371/journal.pone.0296067

Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia

Soo Kun Lim ¹, Shaun Wen Huey Lee ^2,^*

Editor: Yee Gary Ang³

PMCID: PMC10917287 PMID: 38446815

Abstract

Introduction

Chronic kidney disease (CKD) is a global health concern which results in significant economic burden. Despite this, treatment options are limited. Recently, dapagliflozin has been reported have benefits in people with CKD. This study aimed to evaluate the cost–effectiveness of dapagliflozin as an add-on to standard of care (SoC) in people with CKD in Malaysia.

Methods

A Markov model was adapted to estimate the economic and clinical benefits of dapagliflozin in people with Stage 2 to 5 CKD. The cost-effectiveness was performed based upon data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial supplemented with local costs and utility data whenever possible.

Results

In Malaysia, dapagliflozin in combination with SoC was the dominant intervention compared to SoC alone (RM 81,814 versus RM 85,464; USD19,762 vs USD20,644). Adding dapagliflozin to SoC in people with CKD increased life expectancy by 0.46 years and increased quality-adjusted life years (QALY) by 0.41 in comparison with SoC alone (10.01 vs. 9.55 years, 8.76 vs. 8.35 QALYs). This translates to a saving of RM8,894 (USD2,148) with every QALY gained. The benefits were due to the delay in CKD progression, resulting in lower costs of dialysis and renal transplantation. Results were robust to variations in assumptions over disease management costs as well as subgroup of population that would be treated and below the accepted willingness-to-pay thresholds of RM 46,000/QALY.

Conclusion

The use of dapagliflozin was projected to improved life expectancy and quality of life among people with CKD, with a saving RM8,894 (USD2,148) for every quality-adjusted life-year gained and RM7,898 (USD1,908) saving for every life year gained.

Introduction

Chronic kidney disease (CKD) is estimated to affect 8–16% people globally [1, 2]. In people with CKD, they are associated with an increased risk of all-cause and cardiovascular mortality and fractures [3–5]. This has a far reaching impact, and is associated health-related quality of life (HRQoL) impairments, but also has substantial societal and economic impact [6]. As such, there is significant benefits from halting or delaying CKD progression in the general population [7–9].

In Malaysia, the prevalence of CKD has been increasing over the past decade. The National Health and Morbidity Survey (NHMS) in 2011 reported that the prevalence of CKD was 9.07% [10]. This prevalence increased to 15.48% in the recent prevalence study in 2018 [11]. Despite the widespread problem of CKD, treatment options are limited; with only angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) being the only medications that have consistently shown to slow disease progression [12–14]. Recently, sodium-glucose co-transporter-2 (SGLT2) inhibitor were reported to have cardiovascular and renal benefits in addition to improved glycaemic control [15, 16].

The efficacy and safety of dapagliflozin in addition to standard of care (SoC) in people with or without type 2 diabetes (T2DM) with CKD was investigated in the Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) study [17]. Patients on dapagliflozin were found to have a 39% lower risk of the composite primary endpoint of a ≥50% sustained decline in eGFR, onset of kidney failure, or incidence of cardiovascular or kidney-related death (Hazard ratio: 0.61; 95% confidence interval: 0.51 to 0.72; p<0.001).

Given these benefits, there is a need to assess the value of introducing dapagliflozin into a Malaysian national health formulary. Cost-effectiveness analyses represent an important tool to support informed decision making by policy makers. In this study, we assessed the cost effectiveness of the introduction of dapagliflozin in addition to SoC versus SoC in people with CKD from a Malaysian perspective.

Method

Model description

The present model is an adaptation based on the DAPA-CKD cost-effectiveness model which has been published previously [18] and implemented in Microsoft Excel 2019 (Richmond, VA). The model adopted a Malaysian health care perspective with a lifetime analytical horizon. Future cost and QALY were discounted 3% annually [19].

Decision problem approach

The aim of the analysis was to investigate the cost-effectiveness outcomes in the general population with CKD [17], and thus spans a broad range of people with different estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (UACR) ≥200 to ≤5000 mg/g and those with or without T2DM. The intervention and comparator are aligned to those of the informing trial data, where dapagliflozin 10mg was added to SoC compared to placebo in addition to SoC, respectively. The outcomes tracked in the analysis were mortality (all-cause and cardiovascular disease-specific) and CKD progression. The base case analysis was performed in Malaysia, with relevant utility tariffs, and costs applied where available. These individual outcomes are used to estimate the treatment effect on life years, quality-adjusted life years (QALY) and costs.

Model structure

The current model utilises a lifetime Markov state-transition framework with a 1-month cycle [20]. Disease progression was modelled through transitions between discrete health states characterised by CKD stage (defined by eGFR clinical laboratory values) and renal replacement therapy with state-specific utility decrements and outcomes. Health states describing these events were considered transient, i.e., patients remain in the heath state for one cycle, where they incur additional event specific costs and utility decrements. All patients could get worse and move to a more advanced CKD stage over time until they would require renal replacement therapy or could discontinue treatment due to other reasons. In the event a patient discontinue treatment, they are assumed to have the same transition and costs as patients receiving placebo (Fig 1).

Fig 1 — Patients can begin at either of the eGFR health state prior to kidney failure. Once a patient experiences end stage kidney disease (ESRD), they can experience dialysis or transplant. Patients can suffer transient adverse events, incurring associated costs and disutility in the cycle of incidence. Death is end point.

Model input

Disease progression and mortality

Disease progression was captured using parameters based upon the DAPA-CKD trial [17] data supplemented with locally relevant information where applicable [21]. For each arm, a transition matrix describing the movement between CKD health states were derived based on patient level data of the DAPA-CKD study [17] (S1 and S2 Tables). These are separated for the first 4 months of follow-up and from month 5 onwards to account for the differences in decline in eGFR observed initially. The model also captured the incidence of all-cause mortality. A constant rate of discontinuation was used.

Treatment-related adverse events

Dapagliflozin, like many other SGLT-2 inhibitors has a well-established safety profile. As such, in the current model, only grade 3 to 5 adverse events that have been found to be significantly different in the DAPA-CKD study [17] were accounted for, including volume depletion, fractures, diabetic ketoacidosis, severe hypoglycaemic events and amputation. The generalised estimating equation using Poisson distribution was used to estimate the recurrent events including volume depletion, fractures, diabetic ketoacidosis, severe hypoglycaemia and amputations.

Health-related quality of life utilities and costs

In this analysis, the utility inputs for patients CKD 2–5 were derived from the DAPA-CKD [17] study as these unavailable in Malaysia. For utility data on CKD Stage 1, dialysis and transplant, these were sourced from published literature from Malaysia (S3 Table). Adverse event-related utility decrements are applied to health state utilities multiplicatively in accordance with ISPOR guidelines [22]. The cost of each event and medication cost were derived from published literature and the Malaysian Ministry of Health (Tables 1 and 2). All costs were inflated to 2022 values based upon the recommendations by Turner and colleagues [23] and presented in the local currency unit as RM, and adjusted to USD to aid in the interpretation, assuming 1USD = RM4.14 [24]. Analysis of cost was conducted from the perspective of the public sector, and other indirect costs were not included.

Table 1. Cost inputs used in the current study.

	Used cost, RM^* (USD)	SE, RM (USD)	Reference
Annual drug acquisition costs
Dapagliflozin	463.55 (111.97)	0.01 (0.00)	IMS Market Intelligence
SoC	46.32 (11.19)	0.01 (0.00)	IMS Market Intelligence
Annual disease state management costs per annum ⁺
CKD 1, >90ml/min per 1.73 m²	343.91 (83.07)	46.00 (11.11)	Calculated from micro-costing of study by Azmi [25] and Saminathan [11]
CKD 2, 60–89 ml/min per 1.73 m²	484.07 (116.93)	29.52 (7.13)
CKD 3a, 45–59 ml/min per 1.73 m²	425.63 (102.81)	54.45 (13.15)
CKD 3b, 30–44 ml/min per 1.73 m²	1,287.52 (310.99)	82.39 (19.90)
CKD 4, 15–29 ml/min per 1.73 m²	1,726.12 (416.94)	27.84 (6.72)
CKD 5 (pre-RRT); <15 ml/min per 1.73 m²	3,194.31 (771.57)	11,909.60 (2876.71)
Dialysis	44,731.40 (10,804.69)	1,118.29 (270.12)	Surendra et al. [26]
Transplant (initial cost)	117,805.11 (28,455.34)	1,982.69 (478.91)	Bavanandan et al. [27]
Transplant (maintenance cost)	25,281.64 (6106.68)	632.04 (152.67)	Bavanandan et al. [27]
Adverse event costs
Volume depletion	1,330.90 (321.47)	350.32 (84.62)	Pooled estimate of outpatient, inpatient data from 2 tertiary hospitals
Severe hypoglycaemic events	8,802.57 (2126.22)	462.78 (111.78)	Aljunid et al. [28]
Fractures	7,862.22 (1890.39)	391.31 (94.52)	Choo et al. [29]
Diabetic ketoacidosis	8,802.57 (2126.22)	462.78 (111.78)	Assumed same as severe hypoglycaemia
Amputation	6,868.35 (1659.02)	459.94 (110.10)	Feisul et al. [30]

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*inflated to 2022 value. Volume depletion was defined as an event that resulted in loss of fluid such as dehydration, hypovolemia, or hypotension requiring hospitalisation

Table 2. Utility inputs used in this study.

Parameter	Mean (SE)	Reference
Health state utility
CKD 1, >90ml/min per 1.73 m²	0.93 (0.005)	Rizal et al. [31]
CKD 2, 60–89 ml/min per 1.73 m²	0.87 (0.005)	DAPA-CKD trial
CKD 3a, 45–59 ml/min per 1.73 m²	0.88 (0.002)	DAPA-CKD trial
CKD 3b, 30–44 ml/min per 1.73 m²	0.88 (0.002)	DAPA-CKD trial
CKD 4, 15–29 ml/min per 1.73 m²	0.87 (0.003)	DAPA-CKD trial
CKD 5 (pre-RRT); <15 ml/min per 1.73 m²	0.85 (0.009)	DAPA-CKD trial
Dialysis^**	0.85 (0.17)	Surendra et al. [32]
Transplant	0.95 (0.05)	Bavanandan et al. [27]
Adverse event utility decrements
Volume depletion	0.05 (0.01)	DAPA-HF trial [33]
Severe hypoglycaemic events	0.19 (0.00)	Shafie et al. [34]
Fractures	0.072 (0.031)	DAPA-CKD trial
Diabetic ketoacidosis	0.01 (0.01)	DAPA-CKD trial
Amputation	0.266 (0.05)	DAPA-CKD trial

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** Based on haemodialysis

CKD: chronic kidney disease; RRT: renal replacement therapy; SE: standard error

Probabilistic and deterministic analyses

One-way deterministic analysis (DSA), and probabilistic sensitivity analysis (PSA) were conducted to assess the robustness of the analyses. Model parameters were varied within a range of standard error (SE). Variations between ± 10% for probability and cost by ± 20% were applied when there were no specific ranges. A PSA was also carried out to assess the uncertainty of all the parameters simultaneously. We assumed a beta distribution for transitional probability and gamma distribution for cost data. The model was calculated using 1,000 Monte Carlo simulations and presented in several ways. Firstly, the incremental cost-effectiveness ratios (ICERs) were presented in terms of QALYs and life years. To ease in interpretation, we also presented the results as an incremental net monetary benefit (NMB), where the predicted incremental costs and incremental QALYs is estimated using the Malaysian willingness-to-pay (WTP) threshold of one GDP of RM46,000/QALY [35].

Results

Base case analysis

In this study, we predicted that people with CKD treated with dapagliflozin will experience additional health benefits due to an increase in life expectancy and lower rates of CKD progression. Dapagliflozin treatment was estimated to increase life-years (10.01 versus 9.55) and QALYs (8.76 versus 8.35) compared to those on SoC. This is expected to translate to a lower lifetime total cost in those treated with dapagliflozin compared to SoC group (RM 81,814 versus RM 85,464; USD19,762 vs USD20,644), suggesting that the use of dapagliflozin is dominant (cost saving with increased health benefits) in people with CKD (Table 3). The benefits of dapagliflozin were mainly due to the delay in CKD progression, where patients spent a longer time in CKD stage 1 to 3b (6.9 versus 6.0 years) where the benefits are more pronounced.

Table 3. Cost-effectiveness results (per-patient).

Outcome	Dapagliflozin + SoC	SoC	Incremental
Total costs, RM (USD)	81,814 (19,762)	85,464 (20,644)	-3,650 (-882)
Drug acquisition, RM (USD)	3,229 (780)	442 (107)	2,787 (673)
Disease management cost, RM (USD)
Stage 2	392 (95)	384 (93)	8 (2)
Stage 3a	759 (183)	690 (167)	69 (17)
Stage 3b	3,901 (942)	3,363 (812)	538 (130)
Stage 4	4,170 (1007)	4,148 (1002)	22 (5)
Stage 5	1,031 (249)	1,113 (269)	-83 (-20)
Dialysis, RM (USD)	49,381 (11,928)	55,123 (13,315)	-5,742 (-1,387)
Transplant, RM (USD)	16,013 (3,868)	17,496 (4,226)	-1,483 (-358)
Adverse events, RM (USD)	2,898 (700)	2,680 (648)	218 (53)
Total life years gained	10.01	9.55	0.46
Total QALYs gained	8.76	8.35	0.41
Incremental NMB	22,528
ICER (Cost/QALY), RM (USD)	-RM 8,894 (-2,148)

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ICER: incremental cost-effectiveness ratio; NMB: net monetary benefit; QALY: quality adjusted life year; SoC: standard of care; Assuming 1USD = RM4.14

Subgroup and sensitivity analyses

Results of the model were robust to changes in assumptions, with all estimates falling below the willingness to pay threshold. The tornado plots show how much the results associated with lower and upper parameter values deviate from the mean values result (Fig 2). Larger cost savings were observed if the model only simulated the effects for the 10 years, when the cost of adverse events were varied, and when the health state utility were varied. Probabilistic analysis found that in 99.9% of simulations were below the RM 46,000/QALY (USD11,111/QALY) gained threshold (Fig 3).

Fig 3 — The established willingness to pay threshold is indicated by the line, and any values below the line are considered dominant.

Discussion

In this cost effectiveness study, analysis indicates that CKD patients treated with dapagliflozin in addition to SoC would-be a dominant treatment in Malaysia. In particular, the current population will incur a smaller lifetime total cost and slightly gain in life-years and QALYs compared with SoC alone. The analysis showed that there was a saving of RM7,898 (USD1,908) saving for every life year gained and RM8,894 (USD2,148) for every quality adjusted life year gained. Most of these benefits were mainly due to the delay in eGFR decline progression across different disease population. Importantly, the potential benefits associated with delayed CKD progression to dialysis from dapagliflozin can lead to a reduction in the economic burden of CKD treatment in the country. Based upon data from the previous National Health and Morbidity Survey, assuming a prevalence of 15.4% of the Malaysian population have CKD, there will be 3.72 million Malaysians with CKD. As such, the use of dapagliflozin in this population would potentially translate to a savings of RM 13.5 billion (USD 326.2 million) in long term savings if all this population is treated.

The results one-way deterministic analysis also confirmed the cost savings of add-on dapagliflozin in all different scenarios assumed. For example, even when the health state cost (disease management cost) were smaller than those listed, the use of dapagliflozin on top of SoC was still cost-effective. When we simulated the scenario a total of 1,000 times, the results were similar to our base case, showing the robustness of the analyses. Indeed, the results showed that in 99.9% of instances, the use of dapagliflozin in addition to SoC was cost-effective.

Results of this study are in line with published cost-effectiveness study conducted worldwide, including in the UK [36], Thailand [37] and in US [38]. In the study by Varareesangthip in Thailand, the authors similarly found that the add-on dapagliflozin was cost-saving compared to SoC alone in Thailand. The benefit of dapagliflozin was similar to our study where the cohort experienced a delayed CKD progression as it reduces the requirement for dialysis and kidney transplantation, which can offset the costs of dapagliflozin and early CKD treatment.

Nevertheless, there are certain limitations to our model which warrants some discussion. Firstly, the current model does not incorporate the cost savings due to a reduction in heart failure since this information was unavailable in the DAPA-CKD trial. Secondly, as our study population includes mostly people with early stage CKD, it may not reflect the population of those recruited in the DAPA-CKD study. Our analysis assumes that the practice is to treat and start patients early on dapagliflozin treatment where the benefits are more likely to be seen where it can delay disease progression. The analysis represents patients eligible for treatment in Malaysia and thus may not be extrapolated to other countries.

Our model also assumes the broad CKD population, and does not include subgroup analysis such as those with or without diabetes or those with or without heart failure. A higher cost savings is expected especially among those who have diabetes given the greater treatment effects [39, 40]. Importantly, as there is a scarcity of information related to the disease transition matrix in Malaysia, data from the DAPA-CKD was used. The disease transition matrix and utility values may not reflect the results if the study was implemented in locally. Another limitation was that our model did not include the indirect costs such as productivity loss or transportation costs associated with treatment in our study due to the lack of publicly available data in Malaysia. Finally, our model assumes that the population will stop receiving treatment when they require dialysis in line with current practice. Other potential clinical benefits of using sodium glucose cotransporter-2 inhibitors, such as weight loss, improved glycaemic control and reduction in blood pressure were also not captured in this analysis.

Conclusion

In summary, we found that the adding dapagliflozin to Soc would be cost saving in people with CKD in Malaysia and demonstrates the potential reduction in kidney events. These findings should be verified in a real-world analysis to help healthcare providers make clinical decision on its use in the future.

Supporting information

S1 Checklist. CHEERS 2022 checklist.

(DOCX)

pone.0296067.s001.docx^{(19.8KB, docx)}

S1 Table. CKD transition matrix—Dapagliflozin + SoC—Mean (SE).

(DOCX)

pone.0296067.s002.docx^{(19.5KB, docx)}

S2 Table. CKD transition matrix–Placebo + SoC–Mean (SE).

(DOCX)

pone.0296067.s003.docx^{(18.7KB, docx)}

S3 Table. Modelled baseline characteristics.

(DOCX)

pone.0296067.s004.docx^{(15.4KB, docx)}

Acknowledgments

The authors thank Dr Hooi Lai Seong for her expert reviews, facilitating the team to validate data inputs, as well as providing editorial assistance. Authors acknowledge this analysis was based on the Dapa-CKD trials published.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study is funded by AstraZeneca Malaysia. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0296067.r001

Decision Letter 0

Yee Gary Ang

29 Jun 2023

PONE-D-23-16324Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in MalaysiaPLOS ONE

Dear Dr. Lee,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please kindly consider the reviewers' comments and make appropriate changes as needed

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PLOS ONE

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Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

**********

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Reviewer #3: Yes

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Reviewer #1: Thank you for the opportunity to review the manuscript entitled "Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia" The study is well conducted and the manuscript well written. I have a few minor comments.

Abstract. It would be preferred if the authors could add under methods that the population in the study was CKD 2-5

Further under results Change to Dapagliflozin in combination with SoC vs SoC alone

And under introduction, A published Markov model .. I suggest that you omit published here.

In the text of the manuscript you frequently refer to DAPA CKD study, please add ref #17 at each of these referrals.

Page 23 add abbreviation SGLT-2 inhibitor which I also believe should be used as a key word.

Please also check the use of spacebar, sometimes used twice and sometimes missing.

For table 1 and 2 change major hypoglycemia to severe hypoglycemia in line with the international classification.

Reviewer #2: Comment

In general, the study follows the standard guidelines of conducting cost-effectiveness studies. Some comments should be addressed before acceptance.

1.This study was conducted from the perspective of the public sector. Why excluded indirect costs from the analysis?

2.What is the unit for adverse event costs? Is it cost per event or cost per admission? How did authors apply these costs in the Markov model? Was it applied only one cycle or all cycles?

3.Why cost of CKD3a was lower than that of CKD2?

4.All costs should be inflated to 2022 instead of 2021.

5.Why did utility of CKD3a, 3b higher than utility of CKD2? In addition, utility of CKD2 is equal to CKD4? Utility of pre-RRT (CKD5) is equal to dialysis? All these data reflect the real situation?

6.How did authors apply utility decrement of adverse events? Did author apply to all cycles or specific cycle? Utility decrement of major hypoglycemic events is quite high (0.19). If this adverse event occurs 5-6 times, the initial utility will become almost zero?

7.Table 3 base-case result: author should display the total cost of each CKD state (if possible). This would help support the conclusion of the study that dapagliflozin arm incurred greater costs of early CKD stage.

8.Tornado diagram: the range of each parameter and axis title should be clearly specified. The longest bar is secondary/tertiary care population only. What is this parameter related to this study? Is it costs, effects, or utility? The third bar from above is adverse event? Which adverse event author referred to? Which health state utility was in the diagram? Explanation of the result should be added in the text.

9.Cohort population (Supplement file). Baseline characteristics of DAPA-CKD trial are quite different from those in this study. For DAPA-CKD, the average age is about 61 years. There is no CKD1 at initial (might be few). The majority of the population are CKD3a (31%), CKD3b (44%). However, this study the starting age is 48.80. The majority of the population are CKD1 (25%), CKD2 (31%). Would these differences have an effect on the findings of this study?

Reviewer #3: Although it is an interesting study , however I have the following comments :

-Treatment related adverse events did not include urinary tract infection and genital infection

- Comparison between diabetic versus non diabetic patients ( it is expected that the annual costs associated with diabetes is high)

-You should mention in the limitations of the study that there is a difference between a clinical outcome in clinical trials and outcomes observed in real world practice

- The results of this cost effective analysis can not be generalized to other countries

**********

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Reviewer #1: Yes: Johan Jendle

Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2024 Mar 6;19(3):e0296067. doi: 10.1371/journal.pone.0296067.r002

Author response to Decision Letter 0

19 Jul 2023

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

We take note of the journal’s requirement. The revised manuscript has been revised to the journals requirement including file naming.

2. Thank you for stating the following financial disclosure:

"This project is supported by AstraZeneca Malaysia."

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

We take note. We have now revised the statement to also include the following.

This study is funded by AstraZeneca Malaysia. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"This project is supported by AstraZeneca Malaysia."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

We take note. This is now included in our revised cover letter and on the online submission to state the following

This study is funded by AstraZeneca Malaysia. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

We take note. We will not be able to provide the model for other users due to the confidentiality of data but we are happy to provide the information to other people upon reasonable request

We take note and have ensured that the document complies with PLOS One requirement

Reviewer #1 had the following comments:

Comment #1. Thank you for the opportunity to review the manuscript entitled "Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia" The study is well conducted and the manuscript well written. I have a few minor comments.

We thank the reviewer for the encouraging comments and appreciate the efforts and time taken to review our manuscript. We have addressed these comments as delineated below.

Comment #2. It would be preferred if the authors could add under methods that the population in the study was CKD 2-5

We thank the reviewer for the suggestion. We have now edited the sentence as follow

A Markov model was adapted to estimate the economic and clinical benefits of dapagliflozin in people with Stage 2 to 5 CKD

Comment #3. Further under results Change to Dapagliflozin in combination with SoC vs SoC alone

We thank the reviewer for the suggestion. The revised sentence now reads as follow:-

In Malaysia, dapagliflozin in combination with SoC was the dominant intervention compared to SoC alone (RM 81,814 versus RM 85,464; USD19,762 vs USD20,644).

Comment #4. And under introduction, A published Markov model .. I suggest that you omit published here.

We thank the reviewer for the suggestion. We have removed the word published as suggested in our introduction of our abstract. Our revised abstract methods now reads as follow:-

A Markov model was adapted to estimate the economic and clinical benefits of dapagliflozin in people with Stage 2 to 5 CKD

Comment #5. In the text of the manuscript you frequently refer to DAPA CKD study, please add ref #17 at each of these referrals.

We thank the reviewer for the suggestion. We have now included the reference to each of these referrals to clarify this.

Comment #6. Page 23 add abbreviation SGLT-2 inhibitor which I also believe should be used as a key word.

We thank the reviewer for the suggestion. We have included SGLT-2 inhibitor as a keyword as proposed.

Keywords: chronic kidney disease; cost-effectiveness; dapagliflozin; SGLT-2 inhibitor

Comment #7. Please also check the use of spacebar, sometimes used twice and sometimes missing.

We thank the reviewer for the suggestion. We have checked to ensure that these are consistent throughout our manuscript.

Comment #8. For table 1 and 2 change major hypoglycemia to severe hypoglycemia in line with the international classification.

We thank the reviewer for highlighting this. We have now edited the tables and changed major to severe hypoglycaemia as suggested.

Reviewer #2 had the following comments

Comment #1. In general, the study follows the standard guidelines of conducting cost-effectiveness studies. Some comments should be addressed before acceptance.

We thank the reviewer for spending their invaluable time on our manuscript.

Comment #2.This study was conducted from the perspective of the public sector. Why excluded indirect costs from the analysis?

We take note of the suggestion. We only included the direct costs in our model as the indirect costs such as rent, utilities, administrative expenses are currently unavailable in Malaysia. As such, we are unable to account for the indirect cost into our model. We have now included this very important observation in our revised discussion under study limitations. The revised discussion now read as follow:-

Another limitation was that our model did not include the indirect costs such as rentals, administrative costs or manpower costs associated with treatment in our study due to the lack of publicly available data in Malaysia.

Comment #3.What is the unit for adverse event costs? Is it cost per event or cost per admission? How did authors apply these costs in the Markov model? Was it applied only one cycle or all cycles?

We agree this was unclear. The cost for adverse events represents cost per event which may include hospital admission. The cost was derived from published literature whenever possible. Similar to the model developed by Ewen and colleagues, we accounted for events aligned to those related to DAPA-CKD study, where an individual can experience these events multiple times during the cycle. We have now edited the methods section as follow:-

In the current model, only volume depletion, fractures, diabetic ketoacidosis, severe hypoglycaemic events and amputation were accounted for based upon the results of the DAPA-CKD study. The generalised estimating equation using Poisson distribution was used to estimate the recurrent events including volume depletion, fractures, diabetic ketoacidosis, severe hypoglycaemia and amputations.

Comment #4.Why cost of CKD3a was lower than that of CKD2?

We do note that there appears to be some minor discrepancy in our costs. However, as such costs were not routinely collected in Malaysia, we had to rely on data reported into literature. Nevertheless, these costs data have been validated by our experts who suggest that this may be due to the higher and more aggressive treatment of these individuals.

Comment #5.All costs should be inflated to 2022 instead of 2021.

We agree. We have revised this to the 2022 value as suggested as the GDP values in 2022 were not available at the time of our study. These have now been revised the results throughout our manuscript based upon these new costs and results.

Comment #6.Why did utility of CKD3a, 3b higher than utility of CKD2? In addition, utility of CKD2 is equal to CKD4? Utility of pre-RRT (CKD5) is equal to dialysis? All these data reflect the real situation?

Yes, we agree that these values may not be ideal. However, as described earlier, information related to utility are rarely collected in a Malaysian population. As such, we have utilised the values related to those collected from the DAPA-CKD study instead. This may not be ideal in this situation but represent the best available evidence. We have similarly requested for two experts to verify this who also agreed with our inputs. This is described in our methods as follow:-

In this analysis, the utility inputs for patients CKD 2-5 were derived from the DAPA-CKD[1] study as these unavailable in Malaysia. For utility data on CKD Stage 1, dialysis and transplant, these were sourced from published literature from Malaysia

Comment #7.How did authors apply utility decrement of adverse events? Did author apply to all cycles or specific cycle? Utility decrement of major hypoglycemic events is quite high (0.19). If this adverse event occurs 5-6 times, the initial utility will become almost zero?

We agree this was unclear. The model utilises a Markov state-transition framework where disease progresses through transition between discrete health state characterised by CKD stage with state specific utility decrement and outcome. As the reviewer correctly pointed out, adverse event is considered a transient event, i.e patient remains in the health state for one cycle and then incur event specific cost and utility decrement. These utility decrement only occurs during that cycle and patient will similarly have a utility value for their respective CKD.

Comment #8.Table 3 base-case result: author should display the total cost of each CKD state (if possible). This would help support the conclusion of the study that dapagliflozin arm incurred greater costs of early CKD stage.

We thank the reviewer for the excellent suggestion. We have edited the results to conform with the suggestions of the reviewer as follow:-

Comment #9.Tornado diagram: the range of each parameter and axis title should be clearly specified. The longest bar is secondary/tertiary care population only. What is this parameter related to this study? Is it costs, effects, or utility? The third bar from above is adverse event? Which adverse event author referred to? Which health state utility was in the diagram? Explanation of the result should be added in the text.

We agree this was unclear and can lead to confusion. We have now included and added a description of these results to clarify this. Our revised results now read as follow:-

Comment #10..Cohort population (Supplement file). Baseline characteristics of DAPA-CKD trial are quite different from those in this study. For DAPA-CKD, the average age is about 61 years. There is no CKD1 at initial (might be few). The majority of the population are CKD3a (31%), CKD3b (44%). However, this study the starting age is 48.80. The majority of the population are CKD1 (25%), CKD2 (31%). Would these differences have an effect on the findings of this study?

We take note of the reviewer’s concern. As highlighted by the reviewer, there are some differences in terms of the population but we believe that the beneficial effects may be applicable to a broader population. We have included these important points in our study discussion under limitations as follow

Nevertheless, there are certain limitations to our model which warrants some discussion. Firstly, the current model does not incorporate the cost savings due to a reduction in heart failure since this information was unavailable in the DAPA-CKD trial. Secondly, our study assumes that the DAPA-CKD population closely mimics the general population in Malaysia. Our analysis assumes that the practice is to treat and start patients early on dapagliflozin treatment where the benefits are more likely to be seen where it can delay disease progression. The analysis represents patients eligible for treatment in Malaysia and thus may not be extrapolated to other countries.

Reviewer #3 had the following comments.

Comment #1. Although it is an interesting study , however I have the following comments : -Treatment related adverse events did not include urinary tract infection and genital infection

We agree this is a common and important adverse event for people taking SGLT-2 inhibitors. However, given that these events are considered transient and does not incur significant cost to the healthcare system, we did not account for these in our model. Only Grade 3-5 adverse events were included in our model. To clarify this, we have included this in our revised methods as follow:-

Dapagliflozin, like many other SGLT-2 inhibitors has a well-established safety profile. As such, in the current model, only grades 3 to 5 adverse events that have been found to be significantly different in the DAPA-CKD study[1] were accounted for, including volume depletion, fractures, diabetic ketoacidosis, severe hypoglycaemic events and amputation.

Comment #2 Comparison between diabetic versus non diabetic patients ( it is expected that the annual costs associated with diabetes is high)

We thank the reviewer for the suggestion. However, we were unable to account for these due to the limited information that were available from the DAPA-CKD study which did not report this very important observation. To clarify this, we have included this in the discussion under study limitations as follow:-

Comment #3 You should mention in the limitations of the study that there is a difference between a clinical outcome in clinical trials and outcomes observed in real world practice

We agree and thank the reviewer for this very important suggestion. We have included this in our revised discussion section as follow:-

As the disease transition matrix and utility values were derived from the DAPA-CKD study, this may not reflect the results if the study was implemented in a real-world setting.

Comment#4 The results of this cost effective analysis can not be generalized to other countries

We agree. We have revised the discussion section as requested. The revised discussion limitation are as follow

The analysis represents patients eligible for treatment in Malaysia and thus may not be extrapolated to other countries.

Attachment

Submitted filename: Cover letter revision.docx

pone.0296067.s005.docx^{(96.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0296067.r003

Decision Letter 1

Yee Gary Ang

31 Jul 2023

PONE-D-23-16324R1Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in MalaysiaPLOS ONE

Dear Dr. Lee,

==============================

We have sent the manuscript to 2 reviewers.

Please make the changes as indicated.

==============================

Please submit your revised manuscript by Sep 14 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have sucessfully responded to the comments and the manuscript is now suitable for publication.

Reviewer #2: Overall, authors have addressed almost all comments. However, some issues need to be clarified. Authors should use track change in the text for the revised version.

The baseline characteristics of cohort population in DAPA-CKD trial are quite different from those in this study. The majority of cohort population in this study is at the early stage of CKD. The term “closely mimic” in the second limitation might not be appropriate.

Another point is indirect cost. In general, indirect costs are related to productivity loss or time loss. Manpower costs or administrative costs are considered as direct cost in economic analysis.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Johan Jendle

Reviewer #2: No

**********

PLoS One. 2024 Mar 6;19(3):e0296067. doi: 10.1371/journal.pone.0296067.r004

Author response to Decision Letter 1

1 Aug 2023

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Dear Prof Ang,

Thank you for kindly considering our article. Based upon the comments from both reviewers, we have made the changes as requested as follow:-

Reviewer #1 had the following comment. The authors have successfully responded to the comments and the manuscript is now suitable for publication.

Thank you

Reviewer #2 had the following comments.

Comment # 1. Overall, authors have addressed almost all comments. However, some issues need to be clarified. Authors should use track change in the text for the revised version.

We take note. The submission includes a track changes as per journal requirement.

Comment #2. The baseline characteristics of cohort population in DAPA-CKD trial are quite different from those in this study. The majority of cohort population in this study is at the early stage of CKD. The term “closely mimic” in the second limitation might not be appropriate.

We agree. We have now revised the sentence to read as follow:-

Secondly, as our study population includes mostly people with early stage CKD, it may not reflect the population of those recruited in the DAPA-CKD study.

Comment #3. Another point is indirect cost. In general, indirect costs are related to productivity loss or time loss. Manpower costs or administrative costs are considered as direct cost in economic analysis.

We agree. We have now revised the sentence to read as follow

Another limitation was that our model did not include the indirect costs such as productivity loss or transportation costs associated with treatment in our study due to the lack of publicly available data in Malaysia.

We trust that these changes will meet the requirements of the reviewer.

Yours truly

Shaun Lee

On behalf of the authors

Attachment

Submitted filename: Cover letter revision 2.docx

pone.0296067.s006.docx^{(15.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0296067.r005

Decision Letter 2

Yee Gary Ang

10 Nov 2023

PONE-D-23-16324R2Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in MalaysiaPLOS ONE

Dear Dr. Lee,

==============================

We invited 4 reviewers with mixed comments.

Please address the remaining comments

==============================

Please submit your revised manuscript by Dec 25 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #4: (No Response)

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: There is no further comment. All comments have been addressed. The findings of the study are beneficial to healthcare system in Malaysia.

Reviewer #4: In the present manuscript the authors aimed to evaluate the cost-effectiveness of dapagliflozin in Malaysian population with CKD. Please find my minor concerns:

1. The authors stated that “Disease progression was captured using parameters based upon the DAPA-CKD trial” Is there any local study to assure this approach?

2. I really suggest to revise the content of the Introduction. There are numerous repetition, for instance: “Complications associated with CKD include increased risk of all-cause and cardiovascular mortality, kidney disease progression, and fractures” and, “CKD is also associated with an increase in cardiovascular diseases and overall mortality”. OR “has substantial societal and economic impact” and “In addition, it is also associated health-related quality of life (HRQoL) impairments and increase in healthcare costs”. Also, the English needs revision (e.g., “to improved glycaemic control.”

3. I did not understand why the cost of CKD grade 2 is higher compared to CKD 3a (Table 1)?

4. Please explain in Table 1, what means volume depletion in the current study

I want to wish you the best of luck as you move forward with the publication process. I have no doubt that your hard work and commitment to your research will lead to a successful and impactful publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Johan Jendle

Reviewer #2: No

Reviewer #4: No

Reviewer #5: No

**********

PLoS One. 2024 Mar 6;19(3):e0296067. doi: 10.1371/journal.pone.0296067.r006

Author response to Decision Letter 2

26 Nov 2023

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Dear Prof Ang,

Thank you for kindly considering our article. Based upon the comments from both reviewers, we have made the changes as requested as follow:-

Reviewer #4 had the following comment

Comment #1. The authors stated that “Disease progression was captured using parameters based upon the DAPA-CKD trial” Is there any local study to assure this approach?

We take note of the reviewer’s comment. In our model, we used the benefits of delay in disease progression using dapagliflozin based upon the data from DAPA-CKD as this information was unavailable locally. Currently, dapagliflozin is only available in Malaysia as a restricted access for people with diabetes at a very limited number. However, disease progression for people with chronic kidney disease was based upon the data from Malaysia’s renal registry. This is described in the methods section as follow.

Disease progression and mortality

Disease progression was captured using parameters based upon the DAPA-CKD trial[17] data supplemented with locally relevant information where applicable[21].

We have also edited the discussion section as a study limitation as follow:-

Importantly, as there is a scarcity of information related to the disease transition matrix in Malaysia, data from the DAPA-CKD was used. The disease transition matrix and utility values may not reflect the results if the study was implemented in locally.

Comment #2. I really suggest to revise the content of the Introduction. There are numerous repetition, for instance: “Complications associated with CKD include increased risk of all-cause and cardiovascular mortality, kidney disease progression, and fractures” and, “CKD is also associated with an increase in cardiovascular diseases and overall mortality”. OR “has substantial societal and economic impact” and “In addition, it is also associated health-related quality of life (HRQoL) impairments and increase in healthcare costs”. Also, the English needs revision (e.g., “to improved glycaemic control.”

We take note and thank the reviewer for pointing this out. We have now revised the content of the introduction to be more succinct as follow:-

Chronic kidney disease (CKD) is estimated to affect 8–16% people globally[1, 2]. In people with CKD, they are associated with an increased risk of all-cause and cardiovascular mortality and fractures.[3-5] This has a far reaching impact, and is associated health-related quality of life (HRQoL) impairments, but also has substantial societal and economic impact.[6] As such, there is significant benefits from halting or delaying CKD progression in the general population.[7-9]

In Malaysia, the prevalence of CKD has been increasing over the past decade. The National Health and Morbidity Survey (NHMS) in 2011 reported that the prevalence of CKD was 9.07%.[10] This prevalence increased to 15.48% in the recent prevalence study in 2018.[11] Despite the widespread problem of CKD, treatment options are limited; with only angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) being the only medications that have consistently shown to slow disease progression.[12-14] Recently, sodium-glucose co-transporter-2 (SGLT2) inhibitor were reported to have cardiovascular and renal benefits in addition to improved glycaemic control.[15, 16]

Comment #3. I did not understand why the cost of CKD grade 2 is higher compared to CKD 3a (Table 1)?

We agree. This information may be confusing but the information was derived from our literature review from a study by Azmi and colleagues which reported a higher cost for CKD grade 2. One plausible reason could be the costing approach used but these were not significantly different between both groups and was considered minor. Nevertheless, we have validated these values with our experts who agreed these are within the usual range of RM 400-500 as per practice in Malaysia. We hope this will help clarify the doubts of the reviewer.

Comment #4. Please explain in Table 1, what means volume depletion in the current study

We agree this was unclear. We used the definition of the DAPA-CKD study which stated the following, Volume depletion was defined as an event that resulted in loss of fluid such as dehydration, hypovolemia, or hypotension requiring hospitalisation. To clarify this, we have included the definition as a footnote in Table 1.

Reviewer #5: I would like to express my sincere gratitude to you for taking the time and effort to address all the comments and feedback provided on your manuscript. Your dedication to refining your work and incorporating the suggested improvements is greatly appreciated. I want to wish you the best of luck as you move forward with the publication process. I have no doubt that your hard work and commitment to your research will lead to a successful and impactful publication.

We wish to thank the reviewer for the encouraging comments.

We trust that these changes will meet the requirements of the reviewer.

Yours truly

Shaun Lee

On behalf of the authors

Attachment

Submitted filename: Cover letter revision 3.docx

pone.0296067.s007.docx^{(17.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0296067.r007

Decision Letter 3

Yee Gary Ang

6 Dec 2023

Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia

PONE-D-23-16324R3

Dear Dr. Lee,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Yee Gary Ang, MBBS MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #4: All the comments have been addressed. The article has been revised English-wise and other methodological issues have been resolved.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #4: Yes: PARHAM SADEGHIPOUR

**********

PLoS One. doi: 10.1371/journal.pone.0296067.r008

Acceptance letter

Yee Gary Ang

12 Dec 2023

PONE-D-23-16324R3

PLOS ONE

Dear Dr. Lee,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. CHEERS 2022 checklist.

(DOCX)

pone.0296067.s001.docx^{(19.8KB, docx)}

S1 Table. CKD transition matrix—Dapagliflozin + SoC—Mean (SE).

(DOCX)

pone.0296067.s002.docx^{(19.5KB, docx)}

S2 Table. CKD transition matrix–Placebo + SoC–Mean (SE).

(DOCX)

pone.0296067.s003.docx^{(18.7KB, docx)}

S3 Table. Modelled baseline characteristics.

(DOCX)

pone.0296067.s004.docx^{(15.4KB, docx)}

Attachment

Submitted filename: Cover letter revision.docx

pone.0296067.s005.docx^{(96.9KB, docx)}

Attachment

Submitted filename: Cover letter revision 2.docx

pone.0296067.s006.docx^{(15.1KB, docx)}

Attachment

Submitted filename: Cover letter revision 3.docx

pone.0296067.s007.docx^{(17.2KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia

Soo Kun Lim

Shaun Wen Huey Lee

Roles

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Method

Model description

Decision problem approach

Model structure

Fig 1. Markov model diagram of this study.

Model input

Disease progression and mortality

Treatment-related adverse events

Health-related quality of life utilities and costs

Table 1. Cost inputs used in the current study.

Table 2. Utility inputs used in this study.

Probabilistic and deterministic analyses

Results

Base case analysis

Table 3. Cost-effectiveness results (per-patient).

Subgroup and sensitivity analyses

Fig 2. Changes relative to the base case incremental cost-effectiveness ratio assuming different scenarios or subgroups of interest.

Fig 3. Cost-effectiveness plane scatterplot.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Yee Gary Ang

Roles

Author response to Decision Letter 0

Decision Letter 1

Yee Gary Ang

Roles

Author response to Decision Letter 1

Decision Letter 2

Yee Gary Ang

Roles

Author response to Decision Letter 2

Decision Letter 3

Yee Gary Ang

Roles

Acceptance letter

Yee Gary Ang

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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