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Adding Glucose-Lowering Agents Delays Insulin Initiation and Prolongs Hyperglycemia
Courtney Hugie, PharmD, BCPS; Nancee V. Waterbury, PharmD, BCACP; Bruce Alexander, PharmD; Robert F. Shaw, PharmD, MPH, BCPS, BCNSP; and Jason A. Egge, PharmD, MS, BCPS
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Adding Glucose-Lowering Agents Delays Insulin Initiation and Prolongs Hyperglycemia

Courtney Hugie, PharmD, BCPS; Nancee V. Waterbury, PharmD, BCACP; Bruce Alexander, PharmD; Robert F. Shaw, PharmD, MPH, BCPS, BCNSP; and Jason A. Egge, PharmD, MS, BCPS
A review of national Veterans Health Administration data has identified how the number of glucose-lowering agents used prior to insulin initiation impacts glycemic control.
Analysis found the use of multiple GLAs did not clinically impact A1C at insulin initiation. On average, veterans delayed starting insulin for 65 months while A1C remained above treatment goals. Two-thirds of patients started insulin after receiving a trial of 1 or 2 GLAs, whereas the addition of 3 or more GLAs further delayed insulin initiation. When compared with the overall mean, patients who received >3 GLAs delayed their use of insulin by an additional 29 months and were exposed to 15 consecutive months of poor glycemic control. In accordance with the VA/DoD practice guidelines, the most common 2-class combination of GLAs, prior to starting insulin, was metformin with a sulfonylurea. The newer agents, dipeptidyl peptidase-4 inhibitors and GLP-1 receptor agonists, were most commonly prescribed for those veterans in the >3-GLA cohort. It was more common for older veterans (aged >60 years) to receive a trial on 3 or more GLAs compared with younger veterans. This finding may reflect implementation of recommendations from the ADA/AGS consensus statement.

Previous large-scale studies have shown similar findings on delaying insulin therapy. Kostev and colleagues examined data in the United Kingdom and Germany to determine whether time to insulin therapy had changed from 2005 to 20109; they found that the median time to insulin initiation significantly increased in both countries. In addition, there was a significant increase in the A1C measured prior to insulin initiation in 2010 compared with in 2005 (8.4% [68 mmol/mol] vs 8.2% [66 mmol/mol]; P <.001 in Germany; and 9.8% [84 mmol/mol] vs 9.5% [80 mmol/mol]; P <.001 in the United Kingdom). The authors speculated that the decision to use new diabetes medications instead of starting insulin may have contributed to these higher A1Cs and delayed insulin initiation.9

Khanti and colleagues studied the time to treatment intensification in individuals with T2D treated with 1, 2, or 3 oral antidiabetes drugs, and the associated levels of glycemic control. For patients taking 1, 2, or 3 oral antidiabetic agents, median time to intensification with insulin was 7.1, 6.1, or 6.0 years, respectively.10 A retrospective study involving 14,824 people with T2D between 1995 and 2005 observed that the median time to insulin initiation for people prescribed multiple oral antidiabetic agents was 7.7 years, and the mean A1C before insulin was 9.85% (84 mmol/mol).11

The costs associated with T2D are significant, as several studies have reported a strong association between costs and diabetes control.3,12 Between 1998 and 2003, annual diabetes costs increased 24% when comparing patients with an A1C ≤7% with patients with an A1C >9%.12 More recently, a trial reported by Aagren and Luo of 34,469 patients with T2D found that a 1 percentage point increase in A1C corresponded to a 4.4% increase in diabetes-related costs, whereas a 1 percentage point drop in A1C was associated with a 4.2% reduction in costs.13 Levin and colleagues reviewed 51,771 patients to examine both efficacy and costs when patients added a third agent to their regimen of 2 oral antidiabetic drugs.14 They found that patients who added insulin had the greatest reduction in A1C, and after 2 years, they saw an 11% reduction in their diabetes-related healthcare costs. Costs increased for patients who delayed insulin initiation by adding a noninsulin agent (oral agent or GLP-1). After 2 years, patients on 3 oral agents saw their diabetes-related healthcare costs increase by 46%, whereas the costs for patients who added a GLP-1 increased 72%.14

This study did not report on the cost burden associated with T2D in the VAHCS; however, there is a known association between improved diabetes control and lower healthcare costs. In this study, patients who started insulin after 2 GLAs experienced a 2.5 percentage point drop in A1C over an average of 14 months. The report from Aagren and Luo indicates this improvement in A1C would result in substantial cost savings.13 Delaying insulin for a third GLA resulted in 3 more consecutive months of poorer glucose control, a 24-month delay in insulin initiation, and a 15-month lapse before patients achieved their lowest A1C post insulin initiation. This duration of prolonged hyperglycemia would be expected to increase diabetes-related healthcare costs for the VAHCS.

Limitations

This study has several limitations. First, poor glycemic control was defined as an A1C >8% (64 mmol/mol), but providers could have established higher glycemic targets for their patients. This may especially be true for the 21% of veterans 70 years or older in the analysis. Second, the date of first GLA trial was determined by provider entry of VA electronic prescription. Veterans may have started therapy prior to entering the VAHCS. To control for this, only veterans with a documented A1C in the VAHCS lab package 60 days prior to the date of first GLA prescription were included. Third, the ability of veterans to receive prescriptions outside the VAHCS might have influenced the analysis in multiple ways. A veteran may have requested to purchase a GLA outside the VA system, especially if the non-VA cost was less expensive. In addition, the accuracy of the date of insulin initiation and corresponding A1C level were dependent on VA prescription data. To overcome this, the study population was limited to those veterans who received a prescription for a GLA within 6 months prior to first VA insulin prescription. Fourth, the analysis did not report duration of diabetes because of concerns with timely ICD-9-CM coding in relation to ADA diagnostic criteria for T2D. Despite these limitations, the veterans with T2D in the analysis comprise a good representation of clinical practice and diabetes control within a closed formulary system.

CONCLUSIONS
In this study, the decision to use multiple GLAs delayed the escalation to insulin and resulted in prolonged months of hyperglycemia. Reluctance to start insulin (“clinical inertia”) is influenced by both patient and provider factors.10 Patients may be reluctant to start insulin due to fears of hypoglycemia, weight gain, and the pain of self-injections. Conflicting literature on the benefits of insulin treatment may contribute to a provider’s inertia surrounding insulin initiation. The landmark United Kingdom Prospective Diabetes Study (UKPDS) trial showed a reduced risk of microvascular complications and nonfatal myocardial infarction in patients with T2D receiving metformin, a sulfonylurea, or insulin to achieve A1C goals early in the disease process.15 This trial clearly demonstrates the benefit in achieving glycemic control prior to prolonged periods of hyperglycemia.

More recently, large-scale studies—including Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and the Veterans Affairs Diabetes Trial—showed reduced benefit with intensification in patients with longstanding T2D and poor glycemic control. The ADVANCE trial reported that tight glucose control in T2D resulted in no significant reduction in the incidence of retinopathy or macrovascular complications. In the ACCORD trial, the glycemic control arm was halted early after an increased mortality rate in the intensive group was observed. The difference in benefits between UKPDS and the more recent large-scale trials suggests maximal benefit results when glycemic control is achieved prior to prolonged periods of hyperglycemia.15

The use of multiple glucose-lowering drug classes was associated with a numerical, but not a clinical, difference in A1C at insulin initiation. This delay in initiating insulin in veterans with T2D results in prolonged periods of poor glycemic control, which may lead to increased negative health and economic outcomes. 

Author Affiliations: The Iowa City Veteran Affairs Health Care System (CH, NVW, BA, RFS, JAE), Iowa City, IA.

Source of Funding: None.

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 (CH, NVW, BA, JAE); acquisition of data (CH, BA, RFS); analysis and interpretation of data (CH, NVW, BA, RFS, JAE); drafting of the manuscript (CH, NVW, BA); critical revision of the manuscript for important intellectual content (CH, NVW, BA); statistical analysis (RFS); provision of patients or study materials (CH); administrative, technical, or logistic support (JAE); and supervision (NVW, JAE).

Address correspondence to: Courtney Hugie, PharmD, BCPS, Ambulatory Care Pharmacist, Kaiser Permanente, 20700 Ventura Blvd, Woodland Hills, CA 91364. E-mail: courtney.hugie@kp.org.
REFERENCES

1. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. CDC website. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.  Accessed March 16, 2016.

2. Close to 25 percent of VA Patients have diabetes. Veterans Health Administration website. http://www.va.gov/health/NewsFeatures/20111115a.asp. Accessed March 16, 2016.

3. The cost of diabetes. American Diabetes Association website. http://www.diabetes.org/advocacy/news-events/cost-of-diabetes.html. Published October 2013. Updated June 22, 2015. Accessed March 16, 2016.

4. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80.

5. VA/DoD clinical practice guideline for the management of diabetes mellitus. US Department of Veterans Affairs website.  http://www.healthquality.va.gov/guidelines/CD/diabetes/DM2010_FUL-v4e.pdf. Published 2010. Accessed March 16, 2016.

6. Kirkman MS, Briscoe VJ, Clark N, et al; Consensus Development Conference on Diabetes and Older Adults. Diabetes in older adults: a consensus report. J Am Geriatr Soc. 2012;60(12):2342-2356. doi: 10.1111/jgs.12035.

7. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379. doi: 10.2337/dc12-0413. 

8. American Indian and Alaska Native servicemembers and veterans. Department of Veteran Affairs website. http://www.va.gov/TRIBALGOVERNMENT/docs/AIAN_Report_FINAL_v2_7.pdf. Published September 2012. Accessed March 13, 2016.

9. Kostev K, Rathmann W. Changes in time to insulin initiation in type 2 diabetes patients: a retrospective database analysis in Germany and UK (2005-2010). Prim Care Diabetes. 2013;7(3):229-233. doi: 10.1016/j.pcd.2013.03.003.

10. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36(11):3411-3417. doi: 10.2337/dc13-0331.

11. Calvert MJ, McManus RJ, Freemantle N. Management of type 2 diabetes with multiple oral hypoglycaemic agents or insulin in primary care: retrospective cohort study. Br J Gen Pract. 2007;57(539):455-460.

12. Banerji MA, Dunn JD. Impact of glycemic control on healthcare resource utilization and costs of type 2 diabetes: current and future pharmacologic approaches to improving outcomes. Am Health Drug Benefits. 2013;6(7):382-392.

13. Aagren M, Luo W. Association between glycemic control and short-term healthcare costs among commercially insured diabetes patients in the United States. J Med Econ. 2011;14(1):108-114. doi: 10.3111/13696998.2010.548432.

14. Levin PA, Wei W, Zhou S, Xie L, Baser O. Outcomes and treatment patterns of adding a third agent to 2 OADs in patients with type 2 diabetes. J Manag Care Spec Pharm. 2014;20(5):501-512.

15. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187-192. doi: 10.2337/dc08-9026. 
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