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Healthcare resource use and associated costs of hypoglycemia in patients with type 2 diabetes prescribed sulfonylureas
Journal of Diabetes and Its Complications 31 (2017) 1620–1623
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Healthcare resource use and associated costs of hypoglycemia in patients with type 2 diabetes prescribed sulfonylureas Berhanu Alemayehu ⁎, Jinan Liu, Swapnil Rajpathak, Samuel S. Engel Merck & Co., Inc., Kenilworth, NJ, USA
a r t i c l e
i n f o
Article history: Received 23 May 2017 Received in revised form 21 July 2017 Accepted 24 July 2017 Available online 28 July 2017 Keywords: Type 2 diabetes Hypoglycemia Healthcare resource use Costs Sulfonylurea
a b s t r a c t Aims: The objective of this study was to evaluate diabetes-related healthcare resource use and associated costs in patients with type 2 diabetes (T2DM) treated with a sulfonylurea (SU), with and without hypoglycemia. Methods: In this retrospective cohort study, patients 18 years or older receiving SU monotherapy or as add-on to metformin were identified from a US healthcare claims database (MarketScan®). Of 113,743 patients (56.8% male, average age 62.6 years), 61.6% were on SU/metformin dual therapy and 38.4% were on SU monotherapy, and 5% had one or more episodes of hypoglycemia during the 12-month follow-up period. Results: Adjusted for baseline characteristics, patients with hypoglycemia were three times more likely than those without to use emergency room services (OR 3.04, 95% CI: 2.82, 3.25), almost four times more likely to have inpatient admissions (OR 3.84, 95% CI: 3.58, 4.12), and had more frequent physician office visits (4.3 vs 3.0 visits, p b 0.01) in the 12-month follow-up period. The adjusted annual diabetes-related medical expenditure was three times higher in patients with hypoglycemia compared with those without ($6884 vs $2392, p b 0.001). Conclusions: This study demonstrated the higher healthcare utilization and costs associated with hypoglycemia in patients with T2DM treated with an SU. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Based on American Diabetes Association (ADA) 1 and international treatment guidelines,2 the recommended first-line agent for the treatment of type 2 diabetes mellitus (T2DM) is generally metformin (MET). Sulfonylureas (SUs) as add-on therapy are often recommended as the second-line agent after MET failure due to their efficacy profile and generally lower drug acquisition cost, despite some adverse effects, such as weight gain, hypoglycemia and a potentially increased risk for ischemic complications.3 SUs reduce blood glucose levels primarily by blocking ATP-sensitive potassium channels in the pancreatic beta-cells, which stimulates insulin secretion in a glucose-independent manner, and can result in a hypoglycemic episode. During mild episodes, patients can develop symptoms such as sweating, tremors, and dizziness, which can typically be managed without requiring assistance. However, severe hypoglycemic events may cause serious harm to the patient, resulting in symptoms such as confusion, loss of consciousness, seizures, or even death.4
Disclosure statement: B. Alemayehu is a current employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. ⁎ Corresponding author. E-mail address: [email protected] (B. Alemayehu). https://doi.org/10.1016/j.jdiacomp.2017.07.012 1056-8727/© 2017 Elsevier Inc. All rights reserved.
Approximately 35% of adults in the United States (US) with T2DM receive SUs either as monotherapy or in combination with other agents.5 While SUs have a low acquisition cost, there are wider cost implications to consider when used for the management of T2DM,5 since the clinical consequences of hypoglycemia and the difficulty in achieving and maintaining glycemic control can lead to increased morbidity and require considerable healthcare resources, such as emergency room (ER) visits, emergency ambulance services, and hospitalizations, with the risk of hospitalization more pronounced among elderly patients with T2DM.6–8 In the elderly, there is also a strong association between hypoglycemia and fall-related events (e.g. fractures and head injuries), which in turn increase the likelihood of ER visit, hospital admission, and long-term care placement.9 In a recent observational study, hypoglycemia was found to be a clear driver of total costs for patients with T2D and found a 59.4% increase in total 1-year costs for patients who had a hospitalization/ER visit for a hypoglycemic event.10 According to the National Hospital Ambulatory Medical Care Survey, in 2005, annual expenditure of hospitalization for hypoglycemia from ER visits was estimated at $2.9 billion.11 A retrospective case study in the US has shown that the use of different classes of antidiabetic treatments is associated with varying risks of experiencing hypoglycemic events.12 Specifically, the use of insulin and SUs significantly increased the risk of hypoglycemia over the six month study period, while the use of dipeptidyl peptidase-4 (DPP-4) inhibitors was associated with a significantly decreased risk. Patients with
B. Alemayehu et al. / Journal of Diabetes and Its Complications 31 (2017) 1620–1623
hypoglycemia were significantly more likely to discontinue treatment and showed significantly higher annual all-cause and diabetes-related healthcare costs than patients without hypoglycemia. 12,13 Moreover, hypoglycemia has been shown to be associated with higher risks of incident vascular events,14 while fear of hypoglycemia has been independently associated with lower overall health status and mental and physical health.15 The objective of this study was to evaluate diabetes-related healthcare resource use (HCRU) and associated costs in those patients with T2DM who were treated with SUs, who may or may not have reported a hypoglycemic event, and to quantify the magnitude of the difference in HCRU between the two groups. 2. Material and methods This was a retrospective, cohort study of patients identified from the MarketScan® database, a healthcare claims database in the US. The study was conducted in patients with T2DM who were over 18 years of age and had initiated an SU either as monotherapy or as add-on dual therapy to MET, between 1 January 2012 and 31 December 2012 (index date period). Patients were identified based on ICD-9-CM and prescription codes, and were required to have continuous enrollment in a health plan for 12 months prior to and 12 months following the index date. Thus, the baseline period was defined as the 12 months prior to the index date, and patients were then followed up for a further 12 months after receipt of an SU. 2.1. Data source The MarketScan® databases (‘MarketScan®’, Truven Health Analytics, Ann Arbor, MI) are derived from outpatient and inpatient healthcare claims for employees and their beneficiaries in the US. Data include commercial claims and healthcare encounters, including information on demographics, health plan membership, ICD-9-CM codes, and CPT2 Study Population codes from over 100 employers and N12 health plans. The databases also include data on retirees with supplemental insurance, thus including data on the elderly with continuity of care across those aged 65 and over. Although not nationally representative, the MarketScan® database features a geographically diverse population from all 50 US states. Overall and diabetes-specific annual HCRU and associated costs (inpatient, ER, office visit, and prescriptions) were collated for analysis. Documented hypoglycemic events were identified using a validated algorithm,16 while diabetes-specific HCRU and costs were estimated from claims associated with primary or secondary diagnosis of T2DM based on ICD-9CM codes 250.x0 and 250.x2, and NDC codes for antidiabetic agents were used for diabetes-specific costs for prescriptions. 2.2. Statistical methods Univariate descriptive statistics were generated for relevant patient characteristics. The average annual number of services/costs, standard deviation, and range were reported for overall and diabetes-associated services and costs. Multiple regression analyses were conducted to estimate HCRU and costs in both the hypoglycemic and non-hypoglycemic cohorts adjusted for baseline characteristics. Logistic regression was used to determine factors associated with the likelihood of hospitalization and/or ER visits in the hypoglycemic and non-hypoglycemic cohorts adjusted for patients' baseline characteristics. The following independent variables were considered: age, sex, Charlson Comorbidity Index (CCI), Diabetes Complications Severity Index (DCSI), diabetic retinopathy, nephropathy, neuropathy, chronic pulmonary disease, heart failure, peripheral arterial disease, peripheral vascular disease, stroke/TIA, acute renal failure, renal disease, liver disease/hepatic insufficiency, cancer, dementia, depression, hypoglycemia,
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hypertension, as well as baseline office visits, ER visits, and hospitalization. Results of a reduced model are reported here based on statistical significance and clinical relevance. 3. Results Of 113,743 eligible patients (56.8% male, average age 62.6 years), 61.6% were on SU/MET dual therapy and 38.4% were on SU monotherapy (Table 1); 5% of patients had at least one episode of documented hypoglycemia (ICD-9-CM 251.2) during the 12-month follow-up. Important factors associated with hypoglycemia included age (mean 65.5 years in those with hypoglycemia vs 62.5 years in those without), Diabetes Complications Severity Index [DCSI] score (mean 2.39 vs 1.90, respectively), and CCI (mean 1.83 vs 1.08, respectively) (Table 1).17,18 The logistic regression analysis demonstrated that, when adjusted for baseline characteristics, the main factors associated with the likelihood of ER visits and hospitalizations while receiving SUs included incidents of hypoglycemia and numbers of ER visits or hospitalizations during the baseline period (Table 2). Patients with documented hypoglycemia were three times more likely than those without hypoglycemia to use diabetes-related ER services, and almost four times more likely to have diabetes-related inpatient admissions (Table 2). This corresponds with 24.8% vs 8.5% of patients with at least one ER visit and 26.3% vs 7.9% of patients with more than one hospitalization, respectively (Table 3). Patients with hypoglycemia were also more likely to have more frequent physician office visits (4.3 vs 3.0; Table 3). Consequently, both the overall and diabetes-related HCRU and costs were substantially higher in patients with hypoglycemic events than in those with no events (Table 3). Moreover, the annual diabetes-related medical expenditure, adjusted for baseline characteristics, was over three times higher in patients with hypoglycemia compared with those without [$9556 vs $2934, p b 0.001], while the adjusted annual diabetes-related cost of prescriptions was $449 for patients with hypoglycemia compared with $506 in patients without (p b 0.001; Fig. 1). Further, the adjusted annual overall medical expenditure was twice as high in patients with hypoglycemia compared with patients with no hypoglycemia ($23,412 vs $11,485, p b 0.001; Fig. 1), while the adjusted annual overall cost of prescriptions was also significantly higher in patients with hypoglycemia than in those without ($3028 vs $2801, respectively, p b 0.001). 4. Discussion In patients with T2DM, hypoglycemia is the result of the interplay of relative or absolute insulin excess and compromised physiological defenses against falling plasma glucose concentrations.19 While the optimization of glycemic control to prevent diabetes-associated complications has received much attention, the associated risk of hypoglycemia, however, remains and can have a significant impact on health, particularly in the elderly patient.4 A recent meta-analysis of 22 studies of patients with any SU treatment reported hypoglycemic events in 5.9% (95% CI 2.5-13.4%). 20 Our study confirmed a similar proportion of patients with T2DM who were treated with SUs, and who experienced hypoglycemia, with Table 1 Baseline patient demographics. Characteristics
Overall
Hypoglycemia
No hypoglycemia
Patient number (%) Mean age at index (SD) Male (%) CCI score, mean (SD) DCSI score, mean (SD)
113,743 (100) 62.6 (12.9) 56.8 1.92 (1.44) 1.12 (1.88)
5585 (4.9) 65.5 (13.1) 57.7 2.39 (1.71) 1.83 (2.5)
108,158 (95.1) 62.5 (12.9) 56.7 1.90 (1.4) 1.08 (1.8)
CCI, Charlson Comorbidity Index; DCSI, Diabetes Complications Severity Index; SD, standard deviation.
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B. Alemayehu et al. / Journal of Diabetes and Its Complications 31 (2017) 1620–1623
Table 2 Factors associated with the likelihood of overall and diabetes-related ER or hospital admissions. Baseline characteristics
Overall utilization ER visits
Age Female CCI/DCSI Hypoglycemia Number of physician office visits at baseline ER visit at baseline Hospitalization visit at baseline SU monotherapy (vs SU/MET)
Diabetes-related utilization Hospitalizations
ER visits
Hospitalizations
OR
95% CI
OR
95% CI
OR
95% CI
OR
95% CI
1.00 1.23 1.06 2.32 1.01 2.76 1.40 1.18
(1.00, 1.00) (1.19, 1.27) (1.05, 1.07) (2.18, 2.47) (1.01, 1.01) (2.66, 2.86) (1.34, 1.47) (1.14, 1.22)
1.03 1.03 1.12 3.34 1.01 1.52 2.01 1.21
(1.03, 1.03) (0.99, 1.06) (1.11, 1.13) (3.12, 3.57) (1.01, 1.01) (1.45, 1.59) (1.91, 2.11) (1.17, 1.26)
1.00 1.27 1.07 3.03 1.01 3.33 1.50 1.18
(0.997, 1.00) (1.22, 1.32) (1.06, 1.08) (2.82, 3.25) (1.00, 1.02) (3.16, 3.51) (1.40, 1.60) (1.13, 1.23)
1.02 1.08 1.11 3.84 1.01 1.66 2.03 1.17
(1.02, 1.03) (1.04, 1.13) (1.10, 1.12) (3.58, 4.12) (1.00, 1.02) (1.56, 1.77) (1.90, 2.17) (1.12, 1.23)
CCI, Charlson Comorbidity Index; DCSI, Diabetes Complications Severity Index; ER, emergency room; MET, metformin; SD, standard deviation; SU, sulfonylurea.
documented hypoglycemic events leading to the utilization of significantly more healthcare resources. These findings were consistent with those reported by Bron et al., who investigated the healthcare costs incurred by patients with T2DM who were receiving various classes of antidiabetic treatment. 12 The study found that patients with at least one hypoglycemic event per year incurred $18,273 per year in all-cause healthcare costs, which was significantly higher than those without hypoglycemic events ($8908; p b 0.0001). Moreover, the diabetes-related healthcare cost was also significantly higher among patients with hypoglycemic events than in those without ($8969 and $3220, respectively, p b 0.0001). Similarly, in a recent study in patients with T2DM treated with basal insulin, compared with patients with no hypoglycemic events during the first year of follow up, those patients with a hypoglycemic event had a greater burden of complications and comorbidity associated with significantly higher healthcare utilization and cost. 21 Further, a lower risk of hypoglycemia and lower healthcare resource use and costs have been identified in patients treated with a DPP-4 inhibitor than for those treated with an SU, primarily due to costs associated with hospitalizations.22 It is also important to acknowledge the impact of hypoglycemia on clinical outcomes in patients with T2DM. Retrospective analysis of data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that severe symptomatic hypoglycemia was
associated with an increased risk of mortality.23 Although cardiovascular outcomes data from the Veterans Affairs Diabetes Trial (VDAT) did not show a clear relationship between major cardiovascular events (e.g. myocardial infarction, stroke, and congestive heart failure) and the intensity of glucose control undertaken by the patient with T2DM,24 the occurrence of hypoglycemic events was higher in those patients with intensive glycemic control. Moreover, in a substudy of VADT, serious hypoglycemia was associated with coronary artery calcium progression, as an indicator of atherosclerosis.25 There are some limitations in this study, in that the non-randomized observational nature of the data allows only for the assessment of associations as opposed to causal relationships. Moreover, the database has no laboratory test measures, such as HbA1C, and potentially important patient characteristics (e.g. body weight) are not available. Additionally, the database captures only prescriptions that are filled and does not record patient compliance. There is also the possibility of misclassification due to the inability to verify comorbidities, and there is the likelihood that the incidence of hypoglycemic events is underestimated and that only severe events may be captured. Due to sample sizes issues (relatively small proportion of patients with hypoglycemia compared to those without), we did not use propensity score matching to balance the baseline differences between the two groups. Instead, we relied on a multiple regression model to control for confounders. 5. Conclusions
Table 3 Overall and diabetes-specific HCRU and associated costs post index date. Overall utilization and costs
Diabetes-related utilization and costs
Hypoglycemia No Hypoglycemia No hypoglycemia hypoglycemia Mean physician office visits Proportion with any ER visit None 1–2 3+ Proportion with any hospitalization None 1–2 3+ Costs Inpatient cost Outpatient cost ER cost Medical cost Prescription cost Total cost
13
10.5
4.3
3.0
66.5% 27.4% 6.2%
83.1% 15.3% 1.7%
75.1% 22.1% 2.7%
91.5% 8.0% 0.5%
69.6% 27.5% 3.0%
88.5% 10.9% 0.6%
73.7% 26.3% 0.0%
92.1% 7.9% 0.0%
$10,154 $9764
$3016 $5469
$5518 $3292
$1184 $1165
$465 $20,384 $3028
$198 $8683 $2801
$295 $9106 $449
$78 $2427 $506
$23,412
$11,485
$9556
$2934
25,000
ER, emergency room; HCRU, healthcare resource use.
Per patient cost ($)
Variable
It is well documented that the management of hypoglycemic events in patients with T2DM imposes a significant burden on healthcare resources, and that hypoglycemia is commonly attributed to lack of glycemic control from antidiabetic treatments. This study in patients with T2DM who are treated with SUs confirmed that those patients who experience hypoglycemic events consume a disproportionally higher cost of care than patients without hypoglycemia. Hypo
No hypo
20,000 15,000 10,000 5000 0
Medical cost
Rx cost
Diabetes-related expenditure
Medical cost
Rx cost
Overall expenditure
Fig. 1. Diabetes-related and overall expenditure in patients with and without hypoglycemic events.
B. Alemayehu et al. / Journal of Diabetes and Its Complications 31 (2017) 1620–1623
Acknowledgements Medical writing assistance was provided by K Ian Johnson, BSc, of McCann Health, Macclesfield, UK. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. Disclosures This research was funded by Merck & Co., Inc., Kenilworth, NJ, USA. BA, JL, SR, and SSE are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. Funding This work was supported by Merck & Co., Inc., Kenilworth, NJ, USA. References 1. American Diabetes Association. Standards of medical care in diabetes-2017: summary of revisions. Diabetes Care. 2017;40:S4-5. 2. McGuire H, Longson D, Adler A, Farmer A, Lewin I. Management of type 2 diabetes in adults: summary of updated NICE guidance. BMJ. 2016;353:i1575. 3. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429-42. 4. Wong CW. Avoiding hypoglycaemia: a new target of care for elderly diabetic patients. Hong Kong Med J. 2015;21:444-54. 5. Dodd AH, Colby MS, Boye KS, Fahlman C, Kim S, Briefel RR. Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999–2004. Curr Med Res Opin. 2009;25:1605-13. 6. Geller AI, Shehab N, Lovegrove MC, Kegler SR, Weidenbach KN, Ryan GJ, et al. National estimates of insulin-related hypoglycemia and errors leading to emergency department visits and hospitalizations. JAMA Intern Med. 2014;174:678-86. 7. Jha AK, Aubert RE, Yao J, Teagarden JR, Epstein RS. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. Health Aff (Millwood). 2012;31:1836-46. 8. Veronese G, Marchesini G, Forlani G, Saragoni S, Degli EL, Centis E, et al. Costs associated with emergency care and hospitalization for severe hypoglycemia. Nutr Metab Cardiovasc Dis. 2016;26:345-51.
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9. Zhao Y, Kachroo S, Kawabata H, Colilla S, Mukherjee J, Fonseca V, et al. Association between hypoglycemia and fall-related fractures and health care utilization in older veterans with type 2 diabetes. Endocr Pract. 2016;22:196-204. 10. Meng J, Casciano R, Lee YC, Stern L, Gultyaev D, Tong L, et al. Effect of diabetes treatment-related attributes on costs to type 2 diabetes patients in a real-world population. J Manag Care Spec Pharm. 2017;23:446-52. 11. Zhao Y, Shi Q, Wang Y, Fonseca V, Shi L. Economic burden of hypoglycemia: Utilization of emergency department and outpatient services in the United States (2005–2009). J Med Econ. 2016;19:852-7. 12. Bron M, Marynchenko M, Yang H, Yu AP, Wu EQ. Hypoglycemia, treatment discontinuation, and costs in patients with type 2 diabetes mellitus on oral antidiabetic drugs. Postgrad Med. 2012;124:124-32. 13. Liu S, Zhao Y, Hempe JM, Fonseca V, Shi L. Economic burden of hypoglycemia in patients with type 2 diabetes. Expert Rev Pharmacoecon Outcomes Res. 2012;12:47-51. 14. Zhao Y, Campbell CR, Fonseca V, Shi L. Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care. 2012;35:1126-32. 15. Shi L, Shao H, Zhao Y, Thomas NA. Is hypoglycemia fear independently associated with health-related quality of life? Health Qual Life Outcomes. 2014;12:167. 16. Ginde AA, Blanc PG, Lieberman RM, Camargo Jr CA. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4. 17. Charlson ME, Charlson RE, Peterson JC, Marinopoulos SS, Briggs WM, Hollenberg JP. The Charlson comorbidity index is adapted to predict costs of chronic disease in primary care patients. J Clin Epidemiol. 2008;61:1234-40. 18. Williams SA, Pollack MF, Dibonaventura M. Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2011;91:363-70. 19. American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28:1245-9. 20. Schopman JE, Simon AC, Hoefnagel SJ, Hoekstra JB, Scholten RJ, Holleman F. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014;30:11-22. 21. Fonseca V, Chou E, Chung HW, Gerrits C. Economic burden of hypoglycemia with basal insulin in type 2 diabetes. Am J Manag Care. 2017;23:114-22. 22. Raju A, Shetty S, Cai B, D'Souza AO. Hypoglycemia incidence rates and associated health care costs in patients with type 2 diabetes mellitus treated with second-line linagliptin or sulfonylurea after metformin monotherapy. J Manag Care Spec Pharm. 2016;22:483-92. 23. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909. 24. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-39. 25. Saremi A, Bahn GD, Reaven PD. A link between hypoglycemia and progression of atherosclerosis in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2016;39:448-54.
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Healthcare resource use and associated costs of hypoglycemia in patients with type 2 diabetes prescribed sulfonylureas Berhanu Alemayehu ⁎, Jinan Liu, Swapnil Rajpathak, Samuel S. Engel Merck & Co., Inc., Kenilworth, NJ, USA
a r t i c l e
i n f o
Article history: Received 23 May 2017 Received in revised form 21 July 2017 Accepted 24 July 2017 Available online 28 July 2017 Keywords: Type 2 diabetes Hypoglycemia Healthcare resource use Costs Sulfonylurea
a b s t r a c t Aims: The objective of this study was to evaluate diabetes-related healthcare resource use and associated costs in patients with type 2 diabetes (T2DM) treated with a sulfonylurea (SU), with and without hypoglycemia. Methods: In this retrospective cohort study, patients 18 years or older receiving SU monotherapy or as add-on to metformin were identified from a US healthcare claims database (MarketScan®). Of 113,743 patients (56.8% male, average age 62.6 years), 61.6% were on SU/metformin dual therapy and 38.4% were on SU monotherapy, and 5% had one or more episodes of hypoglycemia during the 12-month follow-up period. Results: Adjusted for baseline characteristics, patients with hypoglycemia were three times more likely than those without to use emergency room services (OR 3.04, 95% CI: 2.82, 3.25), almost four times more likely to have inpatient admissions (OR 3.84, 95% CI: 3.58, 4.12), and had more frequent physician office visits (4.3 vs 3.0 visits, p b 0.01) in the 12-month follow-up period. The adjusted annual diabetes-related medical expenditure was three times higher in patients with hypoglycemia compared with those without ($6884 vs $2392, p b 0.001). Conclusions: This study demonstrated the higher healthcare utilization and costs associated with hypoglycemia in patients with T2DM treated with an SU. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Based on American Diabetes Association (ADA) 1 and international treatment guidelines,2 the recommended first-line agent for the treatment of type 2 diabetes mellitus (T2DM) is generally metformin (MET). Sulfonylureas (SUs) as add-on therapy are often recommended as the second-line agent after MET failure due to their efficacy profile and generally lower drug acquisition cost, despite some adverse effects, such as weight gain, hypoglycemia and a potentially increased risk for ischemic complications.3 SUs reduce blood glucose levels primarily by blocking ATP-sensitive potassium channels in the pancreatic beta-cells, which stimulates insulin secretion in a glucose-independent manner, and can result in a hypoglycemic episode. During mild episodes, patients can develop symptoms such as sweating, tremors, and dizziness, which can typically be managed without requiring assistance. However, severe hypoglycemic events may cause serious harm to the patient, resulting in symptoms such as confusion, loss of consciousness, seizures, or even death.4
Disclosure statement: B. Alemayehu is a current employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. ⁎ Corresponding author. E-mail address: [email protected] (B. Alemayehu). https://doi.org/10.1016/j.jdiacomp.2017.07.012 1056-8727/© 2017 Elsevier Inc. All rights reserved.
Approximately 35% of adults in the United States (US) with T2DM receive SUs either as monotherapy or in combination with other agents.5 While SUs have a low acquisition cost, there are wider cost implications to consider when used for the management of T2DM,5 since the clinical consequences of hypoglycemia and the difficulty in achieving and maintaining glycemic control can lead to increased morbidity and require considerable healthcare resources, such as emergency room (ER) visits, emergency ambulance services, and hospitalizations, with the risk of hospitalization more pronounced among elderly patients with T2DM.6–8 In the elderly, there is also a strong association between hypoglycemia and fall-related events (e.g. fractures and head injuries), which in turn increase the likelihood of ER visit, hospital admission, and long-term care placement.9 In a recent observational study, hypoglycemia was found to be a clear driver of total costs for patients with T2D and found a 59.4% increase in total 1-year costs for patients who had a hospitalization/ER visit for a hypoglycemic event.10 According to the National Hospital Ambulatory Medical Care Survey, in 2005, annual expenditure of hospitalization for hypoglycemia from ER visits was estimated at $2.9 billion.11 A retrospective case study in the US has shown that the use of different classes of antidiabetic treatments is associated with varying risks of experiencing hypoglycemic events.12 Specifically, the use of insulin and SUs significantly increased the risk of hypoglycemia over the six month study period, while the use of dipeptidyl peptidase-4 (DPP-4) inhibitors was associated with a significantly decreased risk. Patients with
B. Alemayehu et al. / Journal of Diabetes and Its Complications 31 (2017) 1620–1623
hypoglycemia were significantly more likely to discontinue treatment and showed significantly higher annual all-cause and diabetes-related healthcare costs than patients without hypoglycemia. 12,13 Moreover, hypoglycemia has been shown to be associated with higher risks of incident vascular events,14 while fear of hypoglycemia has been independently associated with lower overall health status and mental and physical health.15 The objective of this study was to evaluate diabetes-related healthcare resource use (HCRU) and associated costs in those patients with T2DM who were treated with SUs, who may or may not have reported a hypoglycemic event, and to quantify the magnitude of the difference in HCRU between the two groups. 2. Material and methods This was a retrospective, cohort study of patients identified from the MarketScan® database, a healthcare claims database in the US. The study was conducted in patients with T2DM who were over 18 years of age and had initiated an SU either as monotherapy or as add-on dual therapy to MET, between 1 January 2012 and 31 December 2012 (index date period). Patients were identified based on ICD-9-CM and prescription codes, and were required to have continuous enrollment in a health plan for 12 months prior to and 12 months following the index date. Thus, the baseline period was defined as the 12 months prior to the index date, and patients were then followed up for a further 12 months after receipt of an SU. 2.1. Data source The MarketScan® databases (‘MarketScan®’, Truven Health Analytics, Ann Arbor, MI) are derived from outpatient and inpatient healthcare claims for employees and their beneficiaries in the US. Data include commercial claims and healthcare encounters, including information on demographics, health plan membership, ICD-9-CM codes, and CPT2 Study Population codes from over 100 employers and N12 health plans. The databases also include data on retirees with supplemental insurance, thus including data on the elderly with continuity of care across those aged 65 and over. Although not nationally representative, the MarketScan® database features a geographically diverse population from all 50 US states. Overall and diabetes-specific annual HCRU and associated costs (inpatient, ER, office visit, and prescriptions) were collated for analysis. Documented hypoglycemic events were identified using a validated algorithm,16 while diabetes-specific HCRU and costs were estimated from claims associated with primary or secondary diagnosis of T2DM based on ICD-9CM codes 250.x0 and 250.x2, and NDC codes for antidiabetic agents were used for diabetes-specific costs for prescriptions. 2.2. Statistical methods Univariate descriptive statistics were generated for relevant patient characteristics. The average annual number of services/costs, standard deviation, and range were reported for overall and diabetes-associated services and costs. Multiple regression analyses were conducted to estimate HCRU and costs in both the hypoglycemic and non-hypoglycemic cohorts adjusted for baseline characteristics. Logistic regression was used to determine factors associated with the likelihood of hospitalization and/or ER visits in the hypoglycemic and non-hypoglycemic cohorts adjusted for patients' baseline characteristics. The following independent variables were considered: age, sex, Charlson Comorbidity Index (CCI), Diabetes Complications Severity Index (DCSI), diabetic retinopathy, nephropathy, neuropathy, chronic pulmonary disease, heart failure, peripheral arterial disease, peripheral vascular disease, stroke/TIA, acute renal failure, renal disease, liver disease/hepatic insufficiency, cancer, dementia, depression, hypoglycemia,
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hypertension, as well as baseline office visits, ER visits, and hospitalization. Results of a reduced model are reported here based on statistical significance and clinical relevance. 3. Results Of 113,743 eligible patients (56.8% male, average age 62.6 years), 61.6% were on SU/MET dual therapy and 38.4% were on SU monotherapy (Table 1); 5% of patients had at least one episode of documented hypoglycemia (ICD-9-CM 251.2) during the 12-month follow-up. Important factors associated with hypoglycemia included age (mean 65.5 years in those with hypoglycemia vs 62.5 years in those without), Diabetes Complications Severity Index [DCSI] score (mean 2.39 vs 1.90, respectively), and CCI (mean 1.83 vs 1.08, respectively) (Table 1).17,18 The logistic regression analysis demonstrated that, when adjusted for baseline characteristics, the main factors associated with the likelihood of ER visits and hospitalizations while receiving SUs included incidents of hypoglycemia and numbers of ER visits or hospitalizations during the baseline period (Table 2). Patients with documented hypoglycemia were three times more likely than those without hypoglycemia to use diabetes-related ER services, and almost four times more likely to have diabetes-related inpatient admissions (Table 2). This corresponds with 24.8% vs 8.5% of patients with at least one ER visit and 26.3% vs 7.9% of patients with more than one hospitalization, respectively (Table 3). Patients with hypoglycemia were also more likely to have more frequent physician office visits (4.3 vs 3.0; Table 3). Consequently, both the overall and diabetes-related HCRU and costs were substantially higher in patients with hypoglycemic events than in those with no events (Table 3). Moreover, the annual diabetes-related medical expenditure, adjusted for baseline characteristics, was over three times higher in patients with hypoglycemia compared with those without [$9556 vs $2934, p b 0.001], while the adjusted annual diabetes-related cost of prescriptions was $449 for patients with hypoglycemia compared with $506 in patients without (p b 0.001; Fig. 1). Further, the adjusted annual overall medical expenditure was twice as high in patients with hypoglycemia compared with patients with no hypoglycemia ($23,412 vs $11,485, p b 0.001; Fig. 1), while the adjusted annual overall cost of prescriptions was also significantly higher in patients with hypoglycemia than in those without ($3028 vs $2801, respectively, p b 0.001). 4. Discussion In patients with T2DM, hypoglycemia is the result of the interplay of relative or absolute insulin excess and compromised physiological defenses against falling plasma glucose concentrations.19 While the optimization of glycemic control to prevent diabetes-associated complications has received much attention, the associated risk of hypoglycemia, however, remains and can have a significant impact on health, particularly in the elderly patient.4 A recent meta-analysis of 22 studies of patients with any SU treatment reported hypoglycemic events in 5.9% (95% CI 2.5-13.4%). 20 Our study confirmed a similar proportion of patients with T2DM who were treated with SUs, and who experienced hypoglycemia, with Table 1 Baseline patient demographics. Characteristics
Overall
Hypoglycemia
No hypoglycemia
Patient number (%) Mean age at index (SD) Male (%) CCI score, mean (SD) DCSI score, mean (SD)
113,743 (100) 62.6 (12.9) 56.8 1.92 (1.44) 1.12 (1.88)
5585 (4.9) 65.5 (13.1) 57.7 2.39 (1.71) 1.83 (2.5)
108,158 (95.1) 62.5 (12.9) 56.7 1.90 (1.4) 1.08 (1.8)
CCI, Charlson Comorbidity Index; DCSI, Diabetes Complications Severity Index; SD, standard deviation.
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Table 2 Factors associated with the likelihood of overall and diabetes-related ER or hospital admissions. Baseline characteristics
Overall utilization ER visits
Age Female CCI/DCSI Hypoglycemia Number of physician office visits at baseline ER visit at baseline Hospitalization visit at baseline SU monotherapy (vs SU/MET)
Diabetes-related utilization Hospitalizations
ER visits
Hospitalizations
OR
95% CI
OR
95% CI
OR
95% CI
OR
95% CI
1.00 1.23 1.06 2.32 1.01 2.76 1.40 1.18
(1.00, 1.00) (1.19, 1.27) (1.05, 1.07) (2.18, 2.47) (1.01, 1.01) (2.66, 2.86) (1.34, 1.47) (1.14, 1.22)
1.03 1.03 1.12 3.34 1.01 1.52 2.01 1.21
(1.03, 1.03) (0.99, 1.06) (1.11, 1.13) (3.12, 3.57) (1.01, 1.01) (1.45, 1.59) (1.91, 2.11) (1.17, 1.26)
1.00 1.27 1.07 3.03 1.01 3.33 1.50 1.18
(0.997, 1.00) (1.22, 1.32) (1.06, 1.08) (2.82, 3.25) (1.00, 1.02) (3.16, 3.51) (1.40, 1.60) (1.13, 1.23)
1.02 1.08 1.11 3.84 1.01 1.66 2.03 1.17
(1.02, 1.03) (1.04, 1.13) (1.10, 1.12) (3.58, 4.12) (1.00, 1.02) (1.56, 1.77) (1.90, 2.17) (1.12, 1.23)
CCI, Charlson Comorbidity Index; DCSI, Diabetes Complications Severity Index; ER, emergency room; MET, metformin; SD, standard deviation; SU, sulfonylurea.
documented hypoglycemic events leading to the utilization of significantly more healthcare resources. These findings were consistent with those reported by Bron et al., who investigated the healthcare costs incurred by patients with T2DM who were receiving various classes of antidiabetic treatment. 12 The study found that patients with at least one hypoglycemic event per year incurred $18,273 per year in all-cause healthcare costs, which was significantly higher than those without hypoglycemic events ($8908; p b 0.0001). Moreover, the diabetes-related healthcare cost was also significantly higher among patients with hypoglycemic events than in those without ($8969 and $3220, respectively, p b 0.0001). Similarly, in a recent study in patients with T2DM treated with basal insulin, compared with patients with no hypoglycemic events during the first year of follow up, those patients with a hypoglycemic event had a greater burden of complications and comorbidity associated with significantly higher healthcare utilization and cost. 21 Further, a lower risk of hypoglycemia and lower healthcare resource use and costs have been identified in patients treated with a DPP-4 inhibitor than for those treated with an SU, primarily due to costs associated with hospitalizations.22 It is also important to acknowledge the impact of hypoglycemia on clinical outcomes in patients with T2DM. Retrospective analysis of data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that severe symptomatic hypoglycemia was
associated with an increased risk of mortality.23 Although cardiovascular outcomes data from the Veterans Affairs Diabetes Trial (VDAT) did not show a clear relationship between major cardiovascular events (e.g. myocardial infarction, stroke, and congestive heart failure) and the intensity of glucose control undertaken by the patient with T2DM,24 the occurrence of hypoglycemic events was higher in those patients with intensive glycemic control. Moreover, in a substudy of VADT, serious hypoglycemia was associated with coronary artery calcium progression, as an indicator of atherosclerosis.25 There are some limitations in this study, in that the non-randomized observational nature of the data allows only for the assessment of associations as opposed to causal relationships. Moreover, the database has no laboratory test measures, such as HbA1C, and potentially important patient characteristics (e.g. body weight) are not available. Additionally, the database captures only prescriptions that are filled and does not record patient compliance. There is also the possibility of misclassification due to the inability to verify comorbidities, and there is the likelihood that the incidence of hypoglycemic events is underestimated and that only severe events may be captured. Due to sample sizes issues (relatively small proportion of patients with hypoglycemia compared to those without), we did not use propensity score matching to balance the baseline differences between the two groups. Instead, we relied on a multiple regression model to control for confounders. 5. Conclusions
Table 3 Overall and diabetes-specific HCRU and associated costs post index date. Overall utilization and costs
Diabetes-related utilization and costs
Hypoglycemia No Hypoglycemia No hypoglycemia hypoglycemia Mean physician office visits Proportion with any ER visit None 1–2 3+ Proportion with any hospitalization None 1–2 3+ Costs Inpatient cost Outpatient cost ER cost Medical cost Prescription cost Total cost
13
10.5
4.3
3.0
66.5% 27.4% 6.2%
83.1% 15.3% 1.7%
75.1% 22.1% 2.7%
91.5% 8.0% 0.5%
69.6% 27.5% 3.0%
88.5% 10.9% 0.6%
73.7% 26.3% 0.0%
92.1% 7.9% 0.0%
$10,154 $9764
$3016 $5469
$5518 $3292
$1184 $1165
$465 $20,384 $3028
$198 $8683 $2801
$295 $9106 $449
$78 $2427 $506
$23,412
$11,485
$9556
$2934
25,000
ER, emergency room; HCRU, healthcare resource use.
Per patient cost ($)
Variable
It is well documented that the management of hypoglycemic events in patients with T2DM imposes a significant burden on healthcare resources, and that hypoglycemia is commonly attributed to lack of glycemic control from antidiabetic treatments. This study in patients with T2DM who are treated with SUs confirmed that those patients who experience hypoglycemic events consume a disproportionally higher cost of care than patients without hypoglycemia. Hypo
No hypo
20,000 15,000 10,000 5000 0
Medical cost
Rx cost
Diabetes-related expenditure
Medical cost
Rx cost
Overall expenditure
Fig. 1. Diabetes-related and overall expenditure in patients with and without hypoglycemic events.
B. Alemayehu et al. / Journal of Diabetes and Its Complications 31 (2017) 1620–1623
Acknowledgements Medical writing assistance was provided by K Ian Johnson, BSc, of McCann Health, Macclesfield, UK. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. Disclosures This research was funded by Merck & Co., Inc., Kenilworth, NJ, USA. BA, JL, SR, and SSE are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options. Funding This work was supported by Merck & Co., Inc., Kenilworth, NJ, USA. References 1. American Diabetes Association. Standards of medical care in diabetes-2017: summary of revisions. Diabetes Care. 2017;40:S4-5. 2. McGuire H, Longson D, Adler A, Farmer A, Lewin I. Management of type 2 diabetes in adults: summary of updated NICE guidance. BMJ. 2016;353:i1575. 3. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429-42. 4. Wong CW. Avoiding hypoglycaemia: a new target of care for elderly diabetic patients. Hong Kong Med J. 2015;21:444-54. 5. Dodd AH, Colby MS, Boye KS, Fahlman C, Kim S, Briefel RR. Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999–2004. Curr Med Res Opin. 2009;25:1605-13. 6. Geller AI, Shehab N, Lovegrove MC, Kegler SR, Weidenbach KN, Ryan GJ, et al. National estimates of insulin-related hypoglycemia and errors leading to emergency department visits and hospitalizations. JAMA Intern Med. 2014;174:678-86. 7. Jha AK, Aubert RE, Yao J, Teagarden JR, Epstein RS. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. Health Aff (Millwood). 2012;31:1836-46. 8. Veronese G, Marchesini G, Forlani G, Saragoni S, Degli EL, Centis E, et al. Costs associated with emergency care and hospitalization for severe hypoglycemia. Nutr Metab Cardiovasc Dis. 2016;26:345-51.
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