First-Line Therapy for Type 2 Diabetes With Sodium–Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: A Cost-Effectiveness Study

We read with interest the manuscript by Choi et al. that concluded that “As first-line agents, SGLT2 inhibitors and GLP1 receptor agonists would improve type 2 diabetes outcomes, but their costs would need to fall by at least 70% to be cost-effective.” (1). However, the analysis has two major weaknesses. First, unfortunately, both the Medication treatment algorithms (figure 1) and the Meta-Analytic Effects of SGLT2 Inhibitors on outcomes (table 1) appear outdated. SGLT2 inhibitors may and should be initiated in type 2 diabetes patients with chronic kidney disease (CKD) up to category G4 included [estimated glomerular filtration rate (eGFR) >20 ml/min/1.73 m²] and they are no longer stopped when category G4 is reached (2). The meta-analysis by Alexander et al. on SGLT2 inhibitors and outcomes that found that insufficient data existed for outcomes other than cardiovascular risk factors (3) only included trials up to July 2019 and major trials have been published since, including a large CKD trial which confirmed cardiorenal benefit for dapagliflozin [hazard ratio (95% confidence interval) for end-stage kidney disease: 0.64 (0.50–0.82)] while a major trial testing empagliflozin was stopped early due to clear positive efficacy in people with CKD and results will be made public in November 2022 (4). These data question the assumption of no effect of SGLT2 inhibitors on end-stage renal disease (ESRD, table 1). Second, the only kidney event considered was ESRD. If extrapolated to the cardiovascular field, this would be equivalent to only considering one cardiovascular outcome, i.e., the need for heart transplantation, but not analyzing myocardial infarction or heart failure. The development of CKD is associated with major costs related to hospitalization and diagnosis and treatment of complications such as CKD-mineral bone disease, anemia, metabolic acidosis, hyperkalemia and increased sensitivity to infections such as COVID-19, among others (5) and these additional costs should be considered. In this regard, eGFR was considered a cardiovascular risk factor, apparently obviating the other costs associated to the development of CKD as defined by a low eGFR. Furthermore, albuminuria is another independent cardiovascular risk factor that forms part of the definition of CKD and was not considered in the calculations, as per table 1. While we share the concern of Choi et al about the high cost of effective medication for type 2 diabetes mellitus, weaknesses in the present analysis preclude the application of the conclusions to routine healthcare in 2022.

References

1. Choi JG, Winn AN, Skandari MR, et al. First-Line Therapy for Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists A Cost-Effectiveness Study [published online ahead of print, 2022 Oct 4]. Ann Intern Med. 2022;10.7326/M21-2941.
2. de Boer IH, Khunti K, Sadusky T, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) [published online ahead of print, 2022 Oct 3]. Diabetes Care. 2022;dci220027. doi:10.2337/dci22-0027
3. Alexander JT, Staab EM, Wan W, et al. Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis. J Gen Intern Med. 2022;37(2):439-448.
4. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446
5. ERA-EDTA Council; ERACODA Working Group. Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA. Nephrol Dial Transplant. 2021;36(1):87-94.

Disclosures:

AO has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes. BFF has received grants from Esteve and consultancy or speaker fees or travel support from Astrazeneca, Bayer, Menarini, Novo-Nordisk Boeringer Inheilm and Mundipharma, and wors for Mundipharma-UAM of diabetic kidney disease. BFF is Editor for Nefroplus. SC has received honoraries for consultancy from Otsuka and travel support from Menarini.

This paper is an excellent analysis of the benefits and pitfalls of SGLT-2 Inhibitors and GLP-1 Receptor Agonists (GLP-1 RA) as first-line therapies for type 2 diabetes. It advocates for lower drug costs by using comprehensive cost analyses and a robust incorporation of external data sources. Furthermore, the inclusion of quality of life analyses offers a patient-centered approach to diabetes management.

A critique of the article is that weight loss is likely underestimated when using injectable GLP-1 RA, and thus improved quality of life and reduced costs of care are underestimated. The authors cite a meta-analysis by Alexander JT et al, which found a mean weight loss of 1.84kg across randomized controlled trials of GLP-1 RA longer than 52 weeks (1). However, there are significant differences in weight loss achieved among various injectable GLP-1 RA, with semaglutide (Ozempic) leading the way. The SUSTAIN-6 trial showed 4.3kg weight loss at week 104 with 1mg compared to placebo (2); SUSTAIN-Forte compared the newly approved 2mg dose and showed even greater weight loss of 6.9kg in just 40 weeks (3). The increased weight loss is significant because weight loss of >7.5% is associated with decreased joint replacement surgery, a major cost benefit not included in the study (4). Moreover, Ozempic is covered by most Medicare plans and was recently added to the state Medicaid formulary in California. By neglecting the additional benefits and increasing availability of Ozempic, it negatively distorts the cost benefit of GLP-1 RA. 

Another critique is that quality of life was assumed to be lower with GLP-1 RA injections without accounting for patient preference. Once weekly injections may be more desirable for patients who have high pill burdens or aversion to daily insulin injections.  A study by Poon et al found that 75% of injection-naive patients with type 2 diabetes preferred dulaglutide once weekly injections over insulin glargine (5).

While the overall cost of prescribing the medication and use of medical supplies was taken into account, the cost of clinic utilization was not. In our experience, titrating insulin requires far more frequent appointments than injectable GLP-1 RA.

This article provides a thought-provoking analysis on the costs and benefits of using SGLT-2 inhibitors and GLP-1 RA as first-line therapies, though we believe it overestimates the costs of GLP1-RA while underestimating the benefits, especially once-weekly options such as semaglutide.

REFERENCES

1. Alexander JT. The longer-term benefits and harms of glucagon-like peptide-1 receptor agonists: a systematic review and meta-analysis. Journal of General Internal Medicine 2022; 37(2): 415-438.
2. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. NEJM 2016; 375: 1834-1844.
3. Frias JP, et al. Efficacy and safety of once-weekly semaglutide 2.0mg versus 1.0mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomized, phase 3B trial. Lancet Diabetes Endocrinology 2021; 9(9): 563-574. 
4. Jin, X., Gibson, A.A., Gale, J. et al. Does weight loss reduce the incidence of total knee and hip replacement for osteoarthritis?—A prospective cohort study among middle-aged and older adults with overweight or obesity. Int J Obes 45, 1696–1704 (2021). https://doi.org/10.1038/s41366-021-00832-3
5. Poon JL, Boye KS, Thieu VT, Norrbacka K, Hassan SW, Gelhorn HL. Preferences for attributes of medications among patients with type 2 diabetes: a cross-medication class comparison of injection therapies. Curr Res Diabetes Obesity J. 2018;6(5):555700.

We appreciate the two concerns raised by Carriazo et al; however, their concerns, while partially valid are unlikely to change the main findings.  Indeed clinical trials have been published since the meta-analysis by Alexander et al, which have identified a benefit of SGLT2 inhibitors for end-stage kidney disease (ESKD).  Our main results modeled the changes in cardiovascular risk factors, including estimated glomerular filtration rate (eGFR) for SGLT2 inhibitors and included a benefit, which translates in the model to a benefit in ESKD for patients when they are on an SGLT2 inhibitor.  But an important factor to consider is that this article is comparing a change in the cascade of care, and only changes the initial treatment, so any effects of the initial drug class is muted in the face of the lifetime risk of diabetic complications. We agree that the model is limited in that it does not include CKD endpoints, other than ESKD. A major reason for this exclusion was because published clinical trials are non-standard in their definitions of kidney disease outcomes and use different eGFR cutoffs in their definitions. Synchronization of kidney disease outcomes in trials would greatly improve the field and allow for future modeling work to include more intermediate outcomes.

We appreciate the concerns raised by Carriazo et al and Aziz et al; however, these concerns are unlikely to change the main findings. As both comments suggest, it is challenging to maintain up-to-date cost-effectiveness analyses, since new evidence is constantly emerging. However, in our model, we compared cascades of care, so changes only in the effectiveness of the initial treatment has small effects.

Specifically, in regards to Carriazo et al, our study already models an improvement in estimated glomerular filtration rate (eGFR) for SGLT2 inhibitors, which translates in the model to a benefit in ESKD for patients when they are on an SGLT2 inhibitor.  We do agree with their comment that the model is limited in intermediary CKD endpoints. A major reason for this exclusion was because published clinical trials are non-standard in their definitions of intermediary CKD endpoints and use different eGFR cutoffs in their definitions. Synchronization of kidney disease outcomes in trials would greatly improve the field and allow for future modeling work to include more intermediate outcomes.

In regards to Aziz et al, it is possible that higher levels of weight loss could translate to lower rates of some complications. However, data from the SUSTAIN clinical trials have not yet show these benefits.  Additionally, regarding their comment about quality of life and long-acting GLP1-RAs, it is unlikely these would lead to important changes in our outcomes.   We already included a sensitivity analysis where there was no decrease in quality of life due to injections and found that using GLP1-RAs as first-line was still not cost-effective by a large margin (>$300,000/QALY).  We also do appreciate that we did not include the cost of clinic utilization; however, this issue was not accounted for in any of the simulations, and so the results would cancel out and be nominal compared to the high costs of complications.

Disclosures:

Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-2941.

Choi et al. (2024) examined the cost-effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists as initial treatments for type 2 diabetes in the U.S. Their model predicted significant reductions in macrovascular complications with these newer medications, but found they were not cost-effective compared to metformin, mainly because of their high prices. This has important implications for patient access and healthcare policy. The authors concluded that SGLT2 inhibitors and GLP-1 receptor agonists would need substantial price reductions (70% and 90%, respectively) to be cost-effective. This highlights a serious problem. As Choi et al. noted, even though some GLP-1 receptor agonists are now available as generics, their prices remain high. This suggests that market exclusivity and generic versions alone may not lower prices enough to make these drugs cost-effective for first-line use. The high cost of these medications has several consequences. First, it may limit their use, especially among patients with limited financial resources or those relying on public insurance programs with restricted drug coverage (2,3). This could lead to unequal access to treatments that have been shown to reduce cardiovascular events and mortality. Second, it puts a significant burden on the healthcare system, contributing to rising healthcare costs (4). It is crucial for policymakers to address this issue. Without changes to the current system, limited access to these drug classes will likely continue and may worsen existing disparities in diabetes care. Potential strategies include: 1. Negotiating drug prices: Allowing government payers (e.g., Medicare) to negotiate drug prices with manufacturers. 2. Importation: Facilitating the importation of lower-cost medications from other countries. 3. Value-based pricing: Linking drug prices to their clinical value and health outcomes (5). By addressing the high cost of SGLT2 inhibitors and GLP-1 receptor agonists, we can improve access to effective treatments for type 2 diabetes, reduce healthcare costs, and lessen health disparities.

References

1. Choi JG, Winn AN, Skandari MR, et al. First-Line Therapy for Type 2 Diabetes With Sodium–Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: A Cost-Effectiveness Study. Ann Intern Med. 2024;177(9):1167-1175. doi:10.7326/M23-2974

2. Raymond B, Valentine WJ, Secnik M, et al. Impact of Type 2 Diabetes Medication Cost Sharing on Patient Outcomes and Health Plan Costs. The American Journal of Managed Care. 2016;22(6):433-440.

3. Poon T, Ng C, Fisher A. Novel Type 2 Diabetes Medication Access and Effect of Patient Cost Sharing. Journal of Managed Care & Specialty Pharmacy. 2018;24(9):847-853.

4. AHA. Costs of Caring | AHA - American Hospital Association. American Hospital Association; 5. CBO. Alternative Approaches to Reducing Prescription Drug Prices. Congressional Budget Office; 2021.