Pharmacist-Led Review of Empagliflozin and Ertugliflozin Following Formulary Update

ABSTRACT

Objectives: To evaluate the appropriateness of the medication management for anyone who might have been affected by the Horizon New Jersey Health Medicaid Health Maintenance Organization (HNJH Medicaid HMO) formulary update from empagliflozin to ertugliflozin and to then optimize drug selection and monitoring.

Study Design: This is a single-center, 2-phase, pilot project led by 2 pharmacy students and the lead clinical pharmacist at a federally qualified health center in Trenton, New Jersey.

Methods: The primary outcome of the study is the number and percentage of patients whose prescription was changed inappropriately from empagliflozin to ertugliflozin. Secondary outcomes include the number and percentage of patients whose prescription was changed inappropriately because of failure to consider cardiovascular history and/or missed renal function checks and whether pharmacists were able to optimize therapy. Data were generated from electronic health record reports and analyzed in Microsoft Excel.

Results: A total of 126 unique patients were identified as receiving empagliflozin and/or ertugliflozin and 16 patients were switched from empagliflozin to ertugliflozin, all of whom had HNJH Medicaid HMO. Thirteen of the 16 (81.3%) patients were managed inappropriately based on their history of cardiovascular disease or inappropriate renal monitoring. Pharmacists recommended 22 interventions for patients who received empagliflozin and/or ertugliflozin, and all recommendations were accepted by providers.

Conclusions: Following the HNJH Medicaid HMO’s coverage update from empagliflozin to ertugliflozin, some patients received inappropriate therapy and providers accepted clinical pharmacists’ recommendations to optimize therapy.

Am J Manag Care. 2023;29(8):424-428. https://doi.org/10.37765/ajmc.2023.89408

Takeaway Points

Drugs within the sodium-glucose cotransporter 2 (SGLT2) inhibitor class have different evidence for cardiovascular protection and recommendations for renal monitoring. Changes to an insurance carrier’s drug formularies lead to changes in SGLT2 inhibitor therapy for patients, and these patients’ cardiovascular health and renal function may not be considered when primary care providers shift them from one drug to another.

• Missed opportunities to utilize an SGLT2 inhibitor with cardioprotective effects or to monitor renal function were observed.
• Pharmacists, in collaboration with pharmacy students, can work in federally qualified health centers to optimize the use of these drugs.

Study findings have shown that diabetes management by pharmacists, in addition to the care provided by primary care providers (PCPs), can improve diabetes outcomes.^1-6 Pharmacists have also demonstrated an ability to improve glycemic outcomes and cardiovascular management, but this has historically looked at hypertension, lipid, and/or aspirin management.^7,8 There are new opportunities for pharmacists to optimize antidiabetic agents that improve glycemic management and improve cardiovascular protective effects in certain populations.

Diabetes management has experienced a paradigm shift with the advent of new classes of antidiabetic medications, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are now one of the preferred medication classes according to the American Diabetes Association.⁹ SGLT2 inhibitors block the renal reabsorption of glucose rather than depending on increasing insulin secretion or increasing insulin sensitivity, and they have been shown to reduce blood pressure and body weight in addition to their glycemic benefits.^9,10 These combined benefits make SGLT2 inhibitors favorable antidiabetic options; however, not all SGLT2 inhibitors carry the same FDA-approved indications and therefore there is some nuance to choosing SGLT2 inhibitor therapy. For example, empagliflozin has proven benefits of hemoglobin A_1c reduction, cardiovascular protection in those with heart disease, and improved outcomes for those with heart failure,^11-18 whereas ertugliflozin failed to achieve superiority over placebo in reducing death from cardiovascular causes or hospitalization for heart failure.¹⁹ Although renal function should be assessed before initiating any SGLT2 inhibitor, and as clinically indicated after initiation, empagliflozin can be used in patients with diabetes who have an estimated glomerular filtration rate (eGFR) as low as 30 mL/min/1.73 m², whereas ertugliflozin must be avoided in those who have an eGFR less than 45 mL/min/1.73 m² per current manufacturer recommendations.^11,20

Henry J. Austin Health Center (HJAHC), the only federally qualified health center in Mercer County, New Jersey, is the largest ambulatory care provider in the city of Trenton and served 17,800 unique patients in 2021. Horizon New Jersey Health (HNJH) Medicaid Health Maintenance Organization (HMO) is the leading insurance payer for patients at HJAHC, and of the 12,227 (68.7%) patients with insurance, 7998 (65.4%) had HNJH Medicaid HMO. Empagliflozin was initially approved as the covered SGLT2 inhibitor under the HNJH Medicaid HMO medication formulary, but empagliflozin was removed from the formulary in 2019 and replaced by ertugliflozin, a cheaper drug of the same class.^21,22 As 13,777 (77.4%) HJAHC patients are known to live at or below the poverty line and it is known that those with lower income levels are at higher risk for experiencing cost-related medication nonadherence, HJAHC PCPs recognize the importance of choosing therapy that is affordable and accessible to their patients.²³ This formulary change makes ertugliflozin the most accessible SGLT2 inhibitor to patients with HNJH Medicaid HMO, and PCPs may change patients from empagliflozin to ertugliflozin to avoid a lapse in treatment. Although there are data to suggest that cardiorenal protective effects are a classwide benefit of SGLT2 inhibitors, choice in therapy should be guided by FDA indications in addition to consideration of insurance formularies and access.^24,25 We hypothesize that because of updates in SGLT2 inhibitor coverage on the HNJH Medicaid HMO medication formulary, PCPs would inevitably switch patients from empagliflozin to ertugliflozin and that, although this may be an acceptable change for many, some patients would lose out on empagliflozin’s cardiovascular benefits and some with impaired or unknown renal function would be inappropriately switched to ertugliflozin.

Objectives

The objectives of the study are to evaluate the appropriateness of the medication management for anyone who might have been affected by the HNJH Medicaid HMO formulary update from empagliflozin to ertugliflozin and to then optimize drug selection and monitoring.

METHODS

This is a single-center, 2-phase, pilot project led by 2 pharmacy students (R.N. and A.B.N.) and the lead clinical pharmacist of HJAHC (M.T.B.). Phase 1 of the study was a retrospective analysis, whereas phase 2 of the study was a modified retrospective analysis that allowed for a longer data collection period and a prospective portion that allowed the pharmacist to contact PCPs and patients to address any medication therapy problems (MTPs) that were identified. This project was approved by the institutional review boards at HJAHC and Rutgers University.

The primary outcome of the study is the number and percentage of patients whose prescription was changed inappropriately from empagliflozin to ertugliflozin by failing to account for cardioprotective properties or ensure appropriate renal monitoring. Secondary outcomes include the number and percentage of patients whose prescription was changed inappropriately because of failure to consider cardiovascular history and/or missed renal function checks. We also evaluate acceptance rates of the pharmacist’s interventions on MTPs and whether the pharmacist was able to speak to the patient.

Data reports were generated from the electronic health record (EHR), Athenahealth, which included patient age at time of service, insurance status, and prescription history for empagliflozin or ertugliflozin at any strength. Reports were downloaded into Microsoft Excel files and stored in a network folder with protections that allowed only study authors to access the reports. Inclusion criteria for the reports included any patient of HJAHC who received a prescription for empagliflozin or ertugliflozin from April 2016 through September 2020. No exclusions were made based on patient age, insurance status, or comorbidities.

Students filtered the report to identify any patient who switched between the SGTL2 inhibitors. Students conducted chart reviews in the EHR for those patients identified in the data download to document history of established atherosclerotic cardiovascular disease (ASCVD) and to record eGFR (mL/min/1.73 m²) values with dates. Inappropriate cardiovascular consideration was defined as treatment with ertugliflozin despite documented history of ASCVD. Inappropriate renal monitoring was defined as having no baseline and/or follow-up renal function check within 6 months of initiation of empagliflozin or ertugliflozin or a switch between them.

For the prospective portion, we included any patient who received either drug, regardless of insurance status or whether their therapy was changed, to screen for anyone who would benefit from a corrective intervention. Students then compiled a listing of patients who required action items as of February 6, 2021, including changes in pharmacotherapy and/or laboratory monitoring. Patients who missed baseline renal function checks were excluded from the prospective portion of the study as the opportunity to check baseline renal function was already missed. The pharmacist (M.T.B.) contacted PCPs of HJAHC via electronic messaging within the EHR to recommend interventions. If a PCP approved of the pharmacist’s recommendation, the pharmacist called the patient to implement the recommendation along with the provision of medication counseling. If the patient could not be reached, the pharmacist documented the recommendation within the EHR for the PCP to follow up with the intervention during a subsequent encounter with the patient. The pharmacist implemented interventions, such as laboratory monitoring or medication orders, on behalf of the PCP under their credentialing privileges as approved by HJAHC.

Descriptive statistics were conducted after completion of chart reviews to identify the number and percentages of patients whose therapy was appropriately switched between empagliflozin and ertugliflozin. MTPs were categorized according to the Pharmacy Quality Alliance Framework.²⁶ A Fisher exact test was conducted to check for statistical significance in whether the patient was spoken to directly by the pharmacist.

RESULTS

Retrospective

A total of 126 unique patients were identified from the data download as receiving empagliflozin and/or ertugliflozin within the study window; 51 (40.5%) of these patients were enrolled in HNJH Medicaid HMO and 29 (23.0%) patients were uninsured.

Twenty-four total patients, regardless of insurance status, changed SGLT2 inhibitor therapy. Sixteen patients, all of whom had HNJH Medicaid HMO, were switched from empagliflozin to ertugliflozin. Chart reviews demonstrated that the switch from empagliflozin to ertugliflozin was managed appropriately in only 3 of these 16 (18.8%) occurrences (Table 1 [A]).

The remaining 13 of 16 (81.3%) patients were inappropriately switched from empagliflozin to ertugliflozin. Failure to monitor renal function before or after making the SGLT2 inhibitor switch was the most common reason to designate the shift as inappropriate, which accounted for 9 of the 13 (56.3%) inappropriate occurrences. One (6.25%) patient was inappropriately switched because of a lack of cardiovascular consideration and 3 (18.8%) patients were switched inappropriately based on a lack of cardiovascular consideration and inappropriate renal monitoring. A further breakdown of the HNJH Medicaid HMO patients who were switched between the 2 SGLT2 inhibitor therapies can be observed in Table 1 (B).

Prospective

Of the 126 patients identified, 22 patients with actionable interventions were identified, half of whom had HNJH Medicaid HMO. PCPs accepted 100% of the pharmacist’s recommendations. For the MTPs identified by the pharmacist, the majority of monitoring recommendations were implemented through documentation in the patient’s chart after the patient could not be reached compared with speaking directly with the patient (45.5% vs 36.4%; P < .001). The single patient who was recommended to change from ertugliflozin to empagliflozin because of ASCVD history was spoken to by the pharmacist (4.5% vs 0%; P = .045). Of 3 patients who were recommended to complete renal function monitoring and change to empagliflozin, the majority were spoken to directly by the pharmacist compared with those who received a documented recommendation (9.1% vs 4.5%; P = .001). It should be noted that these 2 patients spoken to by the pharmacist refused the change from ertugliflozin to empagliflozin. Further details of the pharmacist’s interventions can be found in Table 2.

DISCUSSION

Updates to the HNJH Medicaid HMO medication formulary led to changes in SGLT2 inhibitor therapy, particularly switches from empagliflozin to ertugliflozin. ASCVD history and renal function were not always appropriately considered when adjusting SGLT2 inhibitor therapy. Although empagliflozin has proven to be beneficial in those with chronic kidney disease, it is still recommended and necessary to monitor the renal function. Results of this study show that all patients who were changed from empagliflozin to ertugliflozin had HNJH Medicaid HMO and that most of these patients were managed inappropriately.

PCPs accepted all 22 of the pharmacist’s recommendations, which indicates appropriate recommendations by the pharmacist and demonstrates the high level of trust and collaboration between pharmacists and PCPs at HJAHC. The majority of renal monitoring recommendations were made through documentation in the chart, because in many cases the patient could not be reached. Of the 4 patients with history of clinical ASCVD, 2 patients refused the recommended change in therapy.

Limitations

A limitation of this study is the sample size, which is too small to accurately represent the greater population of patients in New Jersey who were affected by this formulary change. Another limitation of this study was the feasibility of laboratory work during the COVID-19 pandemic. Inappropriate renal monitoring was defined as lacking renal function check within 6 months pre- or post change in empagliflozin or ertugliflozin therapy to account for concerns about patients’ limited access to outpatient laboratories throughout the COVID-19 pandemic. Although it can be assumed that PCPs changed therapy from empagliflozin to ertugliflozin as a result of formulary change, it is possible that PCPs might have chosen to change therapy for another reason, without providing documentation in the chart explicitly describing their rationale. Interventions were delivered by calling patients for brief, unscheduled discussions, rather than intervening during visits with the established care team, therefore limiting the development of patient-pharmacist rapport. This study looked at those with defined cardiovascular history (secondary prevention) and did not consider whether patients had cardiovascular risk without history of event (primary prevention); therefore, it may underrepresent the number of patients who would benefit from empagliflozin over ertugliflozin.

CONCLUSIONS

Medication formulary changes are directed to allow patients to receive therapy while controlling costs, but they may lead to inappropriate changes in pharmacotherapy. This project demonstrated that after a change in HNJH Medicaid HMO’s coverage from empagliflozin to ertugliflozin, some patients received unideal therapy by missing opportunities to either receive cardiovascular protection or monitor renal function. This study introduces a replicable project for pharmacy students to make interventions in diabetes pharmacotherapy and for increased pharmacist collaboration with providers to manage SGLT2 inhibitors following formulary changes.

Acknowledgments

The authors gratefully acknowledge Rebecca Klege, PhD, director of research at Henry J. Austin Health Center, for completing the statistical analysis of the data included in this article.

Author Affiliations: Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey (MTB, RN, ABN, CM), Piscataway, NJ; Henry J. Austin Health Center (MTB, CM), Trenton, NJ.

Source of Funding: Funding for salary support was provided by the Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, and Henry J. Austin Health Center.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (MTB, ABN); acquisition of data (MTB, RN); analysis and interpretation of data (MTB, RN, ABN, CM); drafting of the manuscript (MTB, CM); critical revision of the manuscript for important intellectual content (MTB, RN, ABN, CM); statistical analysis (MTB); administrative, technical, or logistic support (MTB); and supervision (MTB).

Address Correspondence to: M. Thomas Bateman Jr, PharmD, BCACP, Henry J. Austin Pharmacy Department, 321 N Warren St, Trenton, NJ 08618. Email: mtb163@pharmacy.rutgers.edu.

REFERENCES

1. Wagner ML, McCarthy C, Bateman MT, Simmons D, Prioli KM. Pharmacists improve diabetes outcomes: a randomized controlled trial. J Am Pharm Assoc (2003). 2022;62(3):775-782.e3. doi:10.1016/j.japh.2021.12.015

2. Leal S, Glover JJ, Herrier RN, Felix A. Improving quality of care in diabetes through a comprehensive pharmacist-based disease management program. Diabetes Care. 2004;27(12):2983-2984. doi:10.2337/diacare.27.12.2983

3. Ray S, Lokken J, Whyte C, Baumann A, Oldani M. The impact of a pharmacist-driven, collaborative practice on diabetes management in an urban underserved population: a mixed method assessment. J Interprof Care. 2020;34(1):27-35. doi:10.1080/13561820.2019.1633289

4. Wubben DP, Vivian EM. Effects of pharmacist outpatient interventions on adults with diabetes mellitus: a systematic review. Pharmacotherapy. 2008;28(4):421-436. doi:10.1592/phco.28.4.421

5. Chong MT. Pharmacist interventions in improving clinical outcomes in patients with type 2 diabetes mellitus among the underrepresented population: a collaborative ambulatory care pharmacy practice (CAPP) approach. J Res Pharm Pract. 2020;9(1):3-9. doi:10.4103/jrpp.JRPP_19_75

6. Farland MZ, Byrd DC, McFarland MS, et al. Pharmacist-physician collaboration for diabetes care: the diabetes initiative program. Ann Pharmacother. 2013;47(6):781-789. doi:10.1345/aph.1S079

7. Howard-Thompson A, Farland MZ, Byrd DC, et al. Pharmacist-physician collaboration for diabetes care: cardiovascular outcomes. Ann Pharmacother. 2013;47(11):1471-1477. doi:10.1177/1060028013504738

8. Rothman RL, Malone R, Bryant B, et al. A randomized trial of a primary care–based disease management program to improve cardiovascular risk factors and glycated hemoglobin levels in patients with diabetes. Am J Med. 2005;118(3):276-284. doi:10.1016/j.amjmed.2004.09.017

9. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S125-S143. doi:10.2337/dc22-S009

10. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783-794. doi:10.1111/dom.12670

11. Jardiance. Package insert. Boehringer Ingelheim Pharmaceuticals; 2023. Accessed July 9, 2023. https://content.boehringer-ingelheim.com/DAM/7d9c411c-ec33-4f82-886f-af1e011f35bb/jardiance-us-pi.pdf

12. Roden M, Weng J, Eilbracht J, et al; EMPA-REG MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208-219. doi:10.1016/S2213-8587(13)70084-6

13. Häring HU, Merker L, Seewaldt-Becker E, et al; EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014;37(6):1650-1659. doi:10.2337/dc13-2105

14. Häring HU, Merker L, Seewaldt-Becker E, et al; EMPA-REG METSU Trial Investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36(11):3396-3404. doi:10.2337/dc12-2673

15. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720

16. Fitchett D, Zinman B, Wanner C, et al; EMPA-REG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J. 2016;37(19):1526-1534. doi:10.1093/eurheartj/ehv728

17. Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190

18. Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038

19. Cannon CP, Pratley R, Dagogo-Jack S, et al; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi:10.1056/NEJMoa2004967

20. Steglatro. Package insert. Merck Sharp & Dohme Corp; 2022. Accessed July 9, 2023. https://www.merck.com/product/usa/pi_circulars/s/steglatro/steglatro_pi.pdf

21. Active ingredient: empagliflozin. RED BOOK Online. IBM Micromedex. Truven Health Analytics/IBM Watson Health; 2023. Accessed July 9, 2023. https://bit.ly/3Q6dmLG

22. Active ingredient: ertugliflozin. RED BOOK Online. IBM Micromedex. Truven Health Analytics/IBM Watson Health; 2023. Accessed July 9, 2023. https://bit.ly/3Q31p9N

23. Kang H, Lobo JM, Kim S, Sohn MW. Cost-related medication non-adherence among U.S. adults with diabetes. Diabetes Res Clin Pract. 2018;143:24-33. doi:10.1016/j.diabres.2018.06.016

24. Schmidt DW, Argyropoulos C, Singh N. Are the protective effects of SGLT2 inhibitors a “class-effect” or are there differences between agents? Kidney360. 2021;2(5):881-885. doi:10.34067/KID.0000622021

25. Johansen ME, Argyropoulos C. The cardiovascular outcomes, heart failure and kidney disease trials tell that the time to use sodium glucose cotransporter 2 inhibitors is now. Clin Cardiol. 2020;43(12):1376-1387. doi:10.1002/clc.23508

26. PQA medication therapy problem categories framework. Pharmacy Quality Alliance. August 2017. Accessed July 11, 2023. Available upon request at: https://www.pqaalliance.org/pqa-measures