Hypoglycemia is a common complication of

Original Research Incidence and Cost of Hypoglycemia Among Patients with Type 2 Diabetes in the United States: Analysis of a Health Insurance Databas...
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Original Research

Incidence and Cost of Hypoglycemia Among Patients with Type 2 Diabetes in the United States: Analysis of a Health Insurance Database Suellen M. Curkendall, PhD, Bin Zhang, MD, MSc, Kelly S. Oh, MA, Setareh A. Williams, PhD, Michael F. Pollack, MS, and John Graham, PharmD ABSTRACT • Objective: To evaluate the incidence and economic impact of hypoglycemia in a cohort of patients with type 2 diabetes mellitus (T2DM). • Methods: Patients > 18 years diagnosed during the period 2003 to 2008 were selected from the Thomson Reuters MarketScan databases and followed from their first diabetes diagnosis in the study period until the end of continuous coverage or 31 Dec 2008, whichever came first. All hypoglycemia events identified by a claim (ICD-9-CM 250.3, 250.8, 251.0, 251.1, 251.2) on a unique date were counted. Incidence rates were calculated overall and by treatment setting and diabetes drug regimen. Direct costs were computed per hypoglycemia event. • Results: A total of 2.4 million patients with T2DM were identified, with 4.9 million patient-years (PY). Overall incidence of hypoglycemia was 3.46/100 PY (rates of 0.18, 0.05, 0.69, and 2.54 for emergency room [ER]-to-inpatient, inpatient, ER, and outpatient treatment settings, respectively). Within noninsulin antidiabetic drug (NIAD) regimens, incidence of hypoglycemia across all treatment settings was twice as high in patients prescribed regimens containing sulfonylureas (4.00 events/100 PY) than those prescribed nonsulfonylurea regimens (1.88 events/100 PY). Costs were highest for ER-to-inpatient hypoglycemia events ($10,362/event, all drug regimens) and lowest for outpatient events ($285/ event, all drug regimens). Estimated hypoglycemia costs for patients on sulfonylureas were $3.87 per patient per month and $0.84 for other NIADs. • Conclusion: Hypoglycemia incidence and costs among patients with T2DM varied by drug regimen and treatment setting. Within noninsulin regimens, patients on sulfonylureas had higher incidence and costs than those on nonsulfonylurea NIADs.

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ypoglycemia is a common complication of diabetes treatment. While well documented in insulin-treated type 1 diabetes mellitus (T1DM), it has not been as extensively studied in patients with type 2 diabetes mellitus (T2DM), particularly with regard to oral antidiabetic drugs. A retrospective study of patients attending an outpatient specialty diabetes clinic in the United States found that the prevalence of hypoglycemic symptoms for patients with T2DM varied from 12% to 30%, depending on the treatment received. In this study, 0.5% of patients treated with insulin alone or in combination with oral medications experienced severe hypoglycemia, defined as a loss of consciousness or other significant change in mental status requiring assistance or treatment [1]. A study in Scotland of hypoglycemia requiring emergency treatment found that 7.3% of patients with T2DM treated with insulin had at least 1 episode of severe hypoglycemia, corresponding with an incidence of 11.8 per 100 patient-years. Incidence rates for patients with T2DM treated with sulfonylureas and metformin or diet were 0.9 and 0.05 per 100 patient-years, respectively [2]. Most of the available studies have focused on comparing hypoglycemia incidence in specific treatments rather than the population with T2DM as a whole [3–6]. Differences in study design and data collection methodologies across studies make it difficult to compare findings across studies and often result in a wide range of possible outcomes.

From Thomson Reuters Healthcare, Washington, DC (Dr. Curkendall, Ms. Oh), Bristol-Myers Squibb, Health Outcomes and Economic Research, Princeton, NJ (Dr. Zhang, Dr. Graham), and AstraZeneca, Health Economics and Outcomes Research, Wilmington, DE (Dr. Williams, Mr. Pollack). Vol. 18, No. 10 October 2011 JCOM 455

Hypoglycemia in T2DM Hypoglycemia has a considerable economic impact [7–9]. US studies of the cost of hypoglycemia focus mainly on insulin-treated patients and/or include both T1DM and T2DM, providing little insight into hypoglycemia costs associated with noninsulin antidiabetic drug (NIAD) treatment in T2DM [3–7,10]. One study of insulin treatment of T1DM and T2DM found a mean cost per hypoglycemia episode of $1186 or $7.04 per patient per month [7]. Another US study of insulin treatment of T1DM and T2DM found $3241 in annualized costs of hypoglycemia-related medical encounters. Patients with hypoglycemia also experienced 8.7 more shortterm disability days per year compared with those not affected by hypoglycemia [10]. Leese et al in Scotland found that the annual cost associated with severe hypoglycemia events in T1DM and T2DM was approximately £13 million ($21.5 million) when extrapolated to the entire UK population [2]. A UK study identified hypoglycemia as the most common reason for ER visits among patients with diabetes [11]. The objective of this study was to help fill the void in evidence regarding the incidence and cost of hypoglycemia in T2DM overall. A retrospective, observational study was conducted using US insurance claims data to select patients with T2DM and to identify all occurrences of hypoglycemia that required medical intervention. Incidence and costs were determined for different hypoglycemia treatment settings, such as inpatient, emergency room and physician’s office, and for diabetes treatment regimens. Methods Data Source Data were derived from the Thomson Reuters MarketScan commercial and Medicare supplemental databases, which contain health care claims for over 30 million privately insured individuals annually covered under a variety of commercial and Medicare supplemental health plans. Detailed cost, use, and outcomes data are available, covering inpatient services, outpatient services and prescription drug claims. Patients Patients meeting the criteria for T2DM from 2003 through 2008 were selected. T2DM was determined by the presence of 2 claims with different dates of service containing ICD-9-CM diagnosis codes 250.x0 or 250.x2 or 1 claim with the specified codes and a pre456 JCOM October 2011 Vol. 18, No. 10

scription claim for insulin or a NIAD. Patients were excluded if they were younger than 18 years at the index date or had claims for T1DM (250.x1 or 250.x3) or gestational diabetes (648.8x) during the study period. Incidence of Hypoglycemia Eligible patients were followed from their first T2DM claim in the study window (index date) until the end of continuous drug and medical coverage or 31 Dec 2008, whichever came first. All hypoglycemia events in this time period that resulted in a visit to a health care provider were identified and used for analysis. A hypoglycemia event was identified by a claim on a unique date for an inpatient stay or an ER or physician visit containing any of the following ICD-9-CM diagnosis codes: 250.3x (diabetes with other coma), 250.8x (diabetes with other specified manifestations), 251.0x (hypoglycemic coma), 251.1x (other specified hypoglycemia), or 251.2x (hypoglycemia, unspecified). Because code 250.8x can be used for hypoglycemia as well as other complications associated with diabetes, claims containing this code were further screened and excluded if an accompanying diagnosis was specific to another condition (eg, 707.x, chronic skin ulcers, and 731.8, other bone involvement) [12]. Hypoglycemia incidence rates were evaluated by treatment settings and treatment regimens. Treatment settings included ER-to-inpatient, inpatient, ER, and outpatient. ER-to-inpatient included patients treated in the ER and subsequently admitted to the hospital, as identified by a primary or secondary diagnosis of hypoglycemia on an ER claim and a principal diagnosis of hypoglycemia on a hospital claim. Inpatient included patients admitted directly to the hospital, as determined by the absence of an ER claim or a principal diagnosis of hypoglycemia on a hospital claim. ER included patients treated in the ER and released, as evidenced by an ER claim with a primary or secondary diagnosis of hypoglycemia and no hospital claim. Outpatient included patients who had a primary or secondary diagnosis of hypoglycemia on an outpatient claim and no ER or hospital claims. Regarding treatment regimens, a descriptive analysis was conducted among a subgroup of patients who had at least 6 months of follow-up data available for use in determining their diabetes regimen. Diabetes treatments were categorized into 5 types of regimens: insulin only, insulin and a sulfonylurea (other NIADs are allowed but not required), insulin and a non-sulfonylurea NIAD www.jcomjournal.com

Original Research (no sulfonylureas), a sulfonylurea drug and no insulin (other NIADs are allowed but not required), and a nonsulfonylurea NIAD and no insulin (no sulfonylureas). NIAD included alpha-glucosidase inhibitors, metformin, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1), and pramlintide. A hypoglycemia incidence rate was calculated as 100*(total hypoglycemia events)/(total patient-years [PY] of follow-up), using the number of hypoglycemia events and the sum of each patient’s follow-up time from index diagnosis of diabetes through end of eligibility or study window. When the hypoglycemia incidence rates were computed for each regimen, the numerator was 100*(hypoglycemia events assigned to the regimen) and the denominator was total patient-years (PY) of follow-up on the same regimen. In order to determine the total follow-up time for use in the denominator of the incidence computation, each patient’s prescriptions dispensed during 6-month periods starting with the diabetes index date were evaluated. For example, if a patient had 2 prescriptions for metformin during the first 6 months of follow-up and 2 prescriptions for a metformin/glyburide combination in the second 6 months of follow-up, that patient would contribute 6 months of person-time to the non-sulfonylurea NIAD regimen and 6 months to the sulfonylurea NIAD regimen because glyburide is a sulfonylurea. For the numerator of incidence, each hypoglycemia event was assigned a diabetes regimen by reviewing the prescriptions dispensed during the 6 months prior to the event. Hypoglycemia Costs Hypoglycemia costs were also assessed by treatment setting and treatment regimen. Direct costs were computed at the hypoglycemia event level using the paid insurance claims for that event. For an inpatient hypoglycemia event, costs included the total cost of the inpatient stay and any other charges paid to providers for services delivered during the stay (eg, physician consultations). For an ER hypoglycemia event, costs included the total cost of the ER visit. For an outpatient hypoglycemia event, the costs included the total cost of the physician visit. The costs for claims processed under a fee-for-service arrangement were the allowed charges (ie, the actual amounts paid by primary and secondary insurers plus patient cost share amounts [ie, copayments and deductibles]). The costs for claims processed under www.jcomjournal.com

a capitated arrangement were estimated using the average cost of non-capitated claims, by geographic region and by year. In addition to per-event cost, the monthly cost of hypoglycemia per patient was estimated. All costs were standardized to 2008 using the Medical Care Consumer Price Index (CPI). Results A total of 2.4 million eligible patients were identified. These patients accumulated 4.9 million PY of follow-up. During follow-up, 91,595 of these patients experienced 169,248 hypoglycemia events for an overall incidence rate of 3.46 per 100 PY (95% confidence interval [CI], 3.44–3.48). The highest incidence was observed for events treated in the outpatient setting (2.54), followed by ER (0.69) and ER-to-inpatient (0.18) (Table 1). The lowest rate was observed for events that resulted in direct admissions to the hospital (0.05). The overall hypoglycemia incidence rate was significantly higher in the elderly (5.01 for > 65 years vs. 2.74 for < 65 years); p < 0.001, results not shown in table). Incidence rates varied widely by drug regimen, with the highest rates found among patients who were prescribed insulin alone (9.20) (Table 1). Among patients prescribed only NIADs, the rates were higher among patients prescribed regimens containing sulfonylureas than those prescribed nonsulfonylurea NIAD (4.00 vs. 1.88). Among these patients on NIADs without insulin, 9.3% of hypoglycemia events (0.37 out of a total of 4.00 events per 100 PY) experienced by patients whose regimens contained sulfonylureas were treated in inpatient settings (ER-to-inpatient and inpatient combined), compared with 2.5% (0.05 out of a total of 1.88 events per 100 PY) among patients on NIAD not containing sulfonylureas. Among insulin-treated patients, the proportion of hypoglycemia events treated in the inpatient setting was 6.7% on insulin alone, 7.2% on insulin with sulfonylureas, and 4.3% on insulin combined with other NIAD. A subgroup of hypoglycemia events was selected for which the patient had continuous eligibility for prescription drug and medical insurance during the 6 months prior to the hypoglycemia event, resulting in a total of 78,533 patients and 144,416 hypoglycemia events. Cost analyses were performed on this subset. The mean age of a patient in this group experiencing a hypoglycemia event was 64.3 years (Table 2). Among patients with hypoglycemia events, those treated with sulfonylurea regimens Vol. 18, No. 10 October 2011 JCOM 457

7.39 3.97 1.86

7.54

6.51

4.00

1.88

Insulin + sulfonylurea

Insulin + nonsulfonylurea NIAD

Sulfonylurea + no insulin

Nonsulfonylurea NIAD + no insulin

458 JCOM October 2011 Vol. 18, No. 10 1.91

4.03

6.65

7.70

9.39

3.48

0.04

0.28

0.21

0.41

0.45

0.18

0.03

0.27

0.18

0.38

0.41

0.17

0.04

0.29

0.23

0.45

0.49

0.18

0.01

0.09

0.07

0.13

0.16

0.05

0.01

0.08

0.06

0.11

0.14

0.05

0.01

0.09

0.09

0.15

0.19

0.06

Events per 100 95% CI PY Lower Upper

Admitted Directly to Hospital

0.20

0.93

1.41

1.72

2.40

0.69

0.20

0.92

1.34

1.65

2.31

0.69

0.21

0.95

1.48

1.79

2.49

0.70

Events per 100 95% CI PY Lower Upper

Treated in ER and Released

1.63

2.69

4.82

5.29

6.19

2.54

1.61 1.65

2.67 2.72

4.69 4.94

5.16 5.41

6.04 6.34

2.52 2.55

Events per 100 95% CI PY Lower Upper

Treated as Outpatients

$11,122 (16,554) $9746 (11,770) $9408 (22,082)

501

244

3826

456

Insulin + sulfonylurea

Insulin + nonsulfonylurea NIAD

Sulfonylurea + no insulin

Nonsulfonylurea NIAD + no insulin

$6250

$5582

$6209

$6735

$6796

$5852

155

1241

86

159

170

2240

$7872 (11,101)

$6269 (10,564)

$7690 (10,817)

$9587 (14,096)

$10,040 (14,744)

$7317 (11,318)

$4563

$4441

$5019

$5002

$5083

$4630

Median

2619

12,646

1637

2072

2450

27,895

N

$715 (1228)

$690 (1252)

$627 (967)

$615 (1021)

$610 (1038)

$701 (1252)

Mean (SD)

$389

$309

$364

$317

$338

$351

Median

Treated in ER and Released

20,335

34,383

5468

6189

6033

99,116

N

$230 (1171)

$288 (1380)

$242 (845)

$313 (1529)

$380 (1866)

$285 (1415)

Mean (SD)

Treated as Outpatients

$93

$91

$97

$94

$101

$93

Median

*Overall includes patients who were treated with one of the regimens listed as well as untreated and those whose treatment regimen was unknown. Uncapitated health care claims with total charge ≤ $0 were not included in the N, mean, or medians. ER = emergency room; NIAD = noninsulin antidiabetic drug; SD = standard devitation.

$11,183 (16,416)

$13,179 (23,340)

464

Insulin only

$10,362 (21,016)

7064

Overall*

N

Mean (SD)

Median

Mean (SD)

N

Admitted Directly to Hospital

Treated in ER and Then Admitted as Inpatients

Table 3. Average Cost per Hypoglycemia Event (N = 144,416 events)

*Overall rate includes patients who were treated with one of the regimens as well as those who were not treated with oral antidiabetic agents or insulin and those who did not have enough follow-up time to determine the drug regimen. CI = confidence interval; ER = emergency room; NIAD = noninsulin antidiabetic drug; PY = patient-years.

6.36

9.02

9.20

3.44

3.46

Insulin only

Events per 100 95% CI PY Lower Upper

Events per 100 95% CI PY Lower Upper

Overall*

Treated in ER and Then Admitted as Inpatients

All Treatment Settings

Table 1. Incidence of Hypoglycemia Events (N = 2.4 million patients with T2DM, 4.9 patient-years of follow-up, 91,595 patients with 169,248 hypoglycemia events)

Hypoglycemia in T2DM

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Original Research Table 2. Demographic Characteristics of Patients with T2DM Who Had Hypoglycemia Events (N = 144,416 events)

Events, n Mean age, yr

Insulin and Nonsulfonylurea NIAD

Sulfonylurea and No Insulin

Nonsulfonylurea NIAD and No Insulin

Overall*

Insulin Only

Insulin and Sulfonylurea

144,416

9594

9339

7726

55,713

24,663

64.3

65.9

66.2

62.4

68.0

59.8

Age groups 18–34 yr

2.5%

1.6%

0.4%

1.3%

0.7%

3.5%

35–44 yr

6.4%

4.6%

3.9%

5.6%

3.5%

9.1%

45–54 yr

16.2%

13.8%

13.6%

18.3%

12.2%

22.3%

55–64 yr

27.6%

29.0%

31.4%

35.7%

25.2%

31.8%

65–79 yr

30.3%

32.8%

32.3%

29.8%

36.2%

23.8%

80+ yr

17.2%

18.4%

18.4%

9.4%

22.2%

9.4%

Female

48.7%

46.4%

44.5%

45.3%

46.6%

52.7%

Urban residence

84.1%

84.9%

84.9%

82.0%

84.9%

83.5%

Overall includes patients who were treated with one of the regimens listed as well as those who were not treated with oral antidiabetic agents or insulin. NIAD = noninsulin antidiabetic drug.

tended to be older compared with those on insulin only or on non-sulfonylurea NIADs. Costs were highest for hypoglycemia events in the ER-to-inpatient setting ($10,362), followed by inpatient ($7317), ER ($701), and outpatient ($285) settings (Table 3). Similar results were found in comparing costs across treatment setting for specific drug regimens. The monthly cost of hypoglycemia varied by drug regimen and was primarily driven by differences in the incidence of hypoglycemia. The Figure presents the monthly cost of hypoglycemia events for patients with T2DM treated with each drug regimen, based on incidence rates from Table 1 and cost figures from Table 3. Patients treated with an insulin-only regimen had the highest direct medical costs of hypoglycemia ($9.49 per patient per month). Among patients treated with NIADs only, the hypoglycemia costs for patients on a NIAD regimen containing sulfonylureas were between 4 and 5 times as high as costs for patients on a nonsulfonylurea NIAD regimen ($3.87 vs. $0.84 per patient per month, respectively). Discussion This study found the highest incidence in the outpatient treatment setting while the highest costs were in the ER-to-inpatient and inpatient treatment www.jcomjournal.com

settings, respectively. Within noninsulin regimens, incidence across all treatment settings was twice as high in patients on sulfonylureas (4.00 events per 100 PY) versus nonsulfonylurea NIADs (1.88 events per 100 PY). Patients treated with sulfonylureas were more likely to experience hypoglycemia events that were treated in inpatient settings, as evidenced by an incidence rate involving an inpatient stay of 0.37 events per 100 PY, compared to only 0.05 events per 100 PY in patients on non-sulfonylurea NIAD. The higher incidence overall and within the inpatient treatment settings contributed to the higher overall cost per 1000 patients within the sulfonylurea group ($3.87 per patient-month) versus the nonsulfonylurea group ($0.84 per patient-month). Findings from this study suggest that hypoglycemia may have considerable economic implications. If the distribution of antidiabetic drug regimens for a health plan was similar to that of the current study, in which 46% of the follow-up time consisted of oral-only sulfonylurea regimens, the expected number of hypoglycemia events annually for a group of 1000 treated patients would be 35 with a cost of $34,702 ($2.89 per patient per month). If the patients treated with oral-only sulfonylurea regimens were instead treated with oral-only nonsulfonylurea regimens, the expected Vol. 18, No. 10 October 2011 JCOM 459

Hypoglycemia in T2DM ER then admitted

Admitted directly

ER then released

Outpatient

$10.00

Cost PPPM for treatment of hypoglycemia

$9.00 $8.00 $7.00 $6.00 $5.00 $4.00 $3.00 $2.00 $1.00 $0.00 Insulin only

Insulin + sulfonylurea

Insulin + non-sulfonylurea NIAD

Sulfonylurea + no insulin

Non-sulfonylurea NIAD + no insulin

Figure. Cost per patient per month (PPPM) for treatment of hypoglycemia in patients with T2DM by treatment regimen and treatment setting.

number of hypoglycemia events would decrease to 17 with an annual cost of $13,507 ($1.13 per patient per month). That is, for patients treated with NIAD only, shifting treatment from a sulfonylurea to a nonsulfonylurea NIAD has the potential to decrease the number of hypoglycemia events and associated costs. Incidence rates of hypoglycemia from this study appear to be similar to published literature. The population-based study of Leese et al [2] found an incidence of severe hypoglycemia requiring emergency treatment by health care personnel of 11.8 and 0.9 events per 100 PY for insulin and sulfonylureas, respectively, in T2DM. Although the ability to ascertain hypoglycemia events might be impacted by differences in medical care delivery in the United States and Scotland, if we combine the hypoglycemia events that were treated in the ER or inpatient settings in the current study for sulfonylurea without insulin, the incidence is 1.30 events per 100 PY (0.28 + 0.09 + 0.93), closer to that found in Leese et al [2]. Regardless of the mag460 JCOM October 2011 Vol. 18, No. 10

nitude of the differences, both studies found higher rates of hypoglycemia with insulin compared with sulfonylureas. Several studies have analyzed hypoglycemia costs on a per-event or annualized basis. Inconsistencies in findings relative to the current study are likely the result of a number of factors, including difference in methodology for cost calculations and in approach to identification of hypoglycemia events. Nevertheless, the trend, if not the magnitude, of higher hospital and ER event costs is consistent with the current study. For instance, Heaton et al [7] evaluated hypoglycemia in patients with T1DM or T2DM using insulin, finding (adjusting to 2008 dollars) an overall mean cost per episode of $1958 and costs by setting of $8130 for hospital, $1341 for ER, and $299 for physician office visit. The per-event costs in the current study were generally higher versus Heaton et al and may in part be due to definition of costs. We calculated costs based on actual amounts paid, including copayments www.jcomjournal.com

Original Research and deductibles, whereas Heaton el al used only costs paid from payers to providers. ER event costs in the current study were lower, likely due to the fact that the current study analyzed ER-to-inpatient separately. The current study annual per-patient costs across treatment settings ranged from $10.12 to $113.88, depending on drug regimen. This study was subject to several limitations. First, this analysis captured only events for which patients sought medical treatment (events with claims). Therefore, it is likely that we underestimated the clinical burden of hypoglycemia (eg, symptomatic events). One recent clinical trial found 36.3% of patients treated with a glipizide and metformin reported experiencing a hypoglycemia event (symptomatic or severe) [13]. Second, whereas pharmacy data indicate that medications were prescribed, they do not necessarily indicate how the medications were used by the patients. Third, assignment of drug regimen was based on presence of 1 or more prescription claims for insulin or NIADs. Insulin and metformin can be obtained inexpensively from discount sources, and we would not have captured medications purchased by patients and not claimed on insurance. Fourth, hypoglycemia incidence rates were descriptive and were not adjusted for the nonrandom nature of treatment. However, our findings regarding the higher rates of hypoglycemia associated with sulfonylureas compared with other NIADs are consistent with findings from clinical trials. A recent literature review of randomized controlled trials of NIAD added to metformin included 7 trials in which hypoglycemia rates for sulfonylureas were directly compared with other NIADs [14]. In 6 of these trials, the rates of hypoglycemia (number of events/number of patients) in the sulfonylurea arms were much higher than the comparator drug (DPP-4 inhibitors, thiazolidinediones, GLP-1 analogs), ranging from 5 times to 29 times as high [14]. Fifth, these results are based on a commercially-insured population and may not be the same as in other populations. Lastly, the burden of lost work productivity was not included. Conclusion Based on this claims data analysis, hypoglycemia incidence and costs among patients with T2DM varied by drug regimen and treatment setting. Patients treated with insulin had the highest incidence and highest estimated costs. Within noninsulin regimens, patients on sulfonylurea NIADs had higher incidence and costs than those on nonsulfonylurea NIADs. The potential www.jcomjournal.com

for hypoglycemia should be taken into consideration when considering treatment options for patients with T2DM.

Acknowledgments: The authors acknowledge Gregory Lenhart, Kimberly Ruiz, and Danielle Liffmann of Thomson Reuters for assistance with statistical analyses and Michele Shaw, an independent business owner, for editorial assistance. The authors acknowledge Girishanthy Krishnarajah and Bharvi Balar for contributions to the study concept and protocol. Corresponding author: Suellen Curkendall, 4301 Connecticut Ave NW, Suite 330, Washington, DC 20008. Funding/support: The study was funded by Bristol-Myers Squibb and AstraZeneca. Financial disclosures: None. Author contributions: conception and design, SMC, SAW, MFP; analysis and interpretation of data, SMC, BZ, KSO, SAW, MFP, JG; drafting of article, SMC, BZ; critical revision of the article, SMC, BZ, KSO, SAW, MFP, JG; statistical expertise, SMC, BZ, SAW, MFP, JG. REFERENCES 1. Miller CD, Phillips LS, Ziemer DC , et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 2001;161:1653–9. 2. Leese GP, Wang J, Broomhall J , et al. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and 2 diabetes. Diabetes Care 2003;26:1176–80. 3. Fabunmi R, Nielsen LL, Quimbo R , et al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Curr Med Res Opin 2009;25:777–86. 4. Bullano MF, Fisher MD, Grochulski WD, et al. Hypoglycemic events and glycosylated hemoglobin values in patients with type 2 diabetes mellitus newly initiated on insulin glargine or premixed insulin combination products. Am J Health-Syst Pharm 2006;63:2473–82. 5. Cobden D, Lee WC, Balu S, et al. Health outcomes and economic impact of therapy conversion to a biphasic insulin analog pen among privately insured patients with type 2 diabetes mellitus. Pharmacotherapy 2007;27:948–62. 6. Lee WC, Balu S, Cobden D, et al. Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther 2006;28:1712–25. 7. Heaton A, Martin S, Brelje T. The economic effect of hypoglycemia in a health plan. Manag Care Interface 2003;16:23–7.

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Hypoglycemia in T2DM 8. Lundkvist J, Berne C, Bolinder B, Jönsson L. The economic and quality of life impact of hypoglycemia. Eur J Health Econ 2005;6:197–202. 9. Curkendall SM, Natoli JL, Alexander CM, et al. Economic and clinical impact of inpatient diabetic hypoglycemia. Endocr Pract 2009;15:302–12. 10. Rhoads GG, Orsini LS, Crown W, et al. Contribution of hypoglycemia to medical care expenditures and short-term disability in employees with diabetes. J Occup Environ Med 2005;47:447–52. 11. Brackenridge A, Wallbank H, Lawrenson RA, Russell-Jones D. Emergency management of diabetes and hypoglycaemia. Emerg Med J 2006;23:183–5.

12. Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord 2008;8:4. 13. Göke B, Gallwitz B, Eriksson J, et al. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomized controlled trial. Int J Clin Pract 2010;64:1619–31. 14. Phung OJ, Scholle JM, Mehak T, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010;303:1410–8.

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462 JCOM October 2011 Vol. 18, No. 10

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