Hospitalizations Due to Severe Hypoglycemia in Patients with Type 1 Diabetes Mellitus: US National Perspective Singh G, Mithal A, Mannalithara A, Sehgal A, Bron M, Dabbous O, Peng X ICORE Stanford University Takeda Pharmaceuticals

Disclosures Supported by a grant from Takeda Pharmaceuticals Drs. Bron and Peng are employees of Takeda Pharmaceuticals Dr. Dabbous is a former employee of Takeda Pharmaceuticals

Type 1 Diabetes Mellitus in US Type 1 Diabetes Mellitus (T1DM) affects >1 million Americans In adults, T1DM constitutes approximately 5% of all diagnosed cases of diabetes Tight glycemic control using intensive insulin therapy significantly reduces long-term microvascular and macrovascular complications in T1DM (The Diabetes Control and Complications Trial (DCCT)) U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed August 29,2012.

Pathophysiology of Hypoglycemia Hyper-insulinemia Compromised response to falling glucose level Hypoglycemia

Objective To examine the prevalence and costs and payer status of severe hypoglycemia hospitalizations in T1DM patients in the US

Methods and Data Nationwide Inpatient Sample (NIS) Largest publicly available all-payer inpatient care database 20% stratified sample of all U.S. hospitalizations (1988 – 2011) ~5 to 8 million records of inpatient stays per year from about 1,000 hospitals representing ~85 – 96 % of all non–federal hospitals Complex survey design with multistage strata and clustering Strict quality-control and extensive validation

2009 NIS: Represents 96% of US Population Year Data Sources Number of Hospitals Number of Discharges in the NIS, Unweighted Weighted for National Estimates 2009 AR AZ CA CO CT FL GA HI IL IN IA KS LA KY MD MA ME MI MN MO MT NC NE NH NJ NM NY NV OH OK OR PA RI SC SD TN TX UT VA VT WA WI WV WY (Added NM and MT) 1,050 7,810,762 39,434,956 NIS 2009

NIS: Data Characteristics Over 100 clinical and non-clinical variables for each hospital stay, for example: Primary and secondary diagnoses Primary and secondary procedures. Admission and discharge status Patient demographics (e.g., gender, age, race, median income for ZIP Code). Expected payment source Length of stay and total charges Hospital characteristics (e.g., ownership, size, teaching status)

Calculating National Estimates The NIS is drawn from those states participating in Healthcare Cost and Utilization Project (HCUP) These states comprised over 96% of the US population in 2009 Weights are provided to calculate national estimates

NIS Sample Weights (Details) Sample weights calculated as ratio of discharges in community hospitals to discharges in the sample Sample weights constant for all discharges within each stratum, with the exception of adjustments for hospitals with missing quarters of data. Number of discharges in the universe calculated from total number of discharges reported in the American Hospital Association (AHA) hospital survey data Sum of the sample weights in each stratum represents total number of discharges reported in the AHA survey

Study Cohort All inpatient hospitalizations in 2009 with primary or secondary diagnosis of: T1DM (ICD9 codes 250.x1, 250.x3), and Hypoglycemia (ICD9 codes 250.8x, 251.0x, 251.1x, 251.2x) in patients aged ≥18 years. Denominator: 2009 US resident population (over 18 years): 232,637,3621 1 Estimated from US Census Bureau Data, 2010 census

Statistics SAS ( Statistical Analysis System) version 9.3 procedure PROC SURVEYMEANS used for calculating sample statistics and appropriate variances based on data from complex sampling designs All estimates reported with 95% Confidence Intervals (CI)

Results

Total All-Cause US Hospitalizations (18 years or older, 2009) 33.1 million in 232.6 million person-years 14,226 per 100,000 person-years T1DM 326,395 All-Cause Hospitalizations (1%) 140 per 100,000 US population Hypoglycemia in T1DM 20,839 hospitalizations (9 per 100,000 US pop) 6.4% of all T1DM hospitalizations

Total All-Cause US Hospitalizations (18 years or older, 2009) 33.1 million in 232.6 million person-years 14,226 per 100,000 person-years T2DM 7.2 million All-Cause Hospitalizations (21.7%) 3,100 per 100,000 US population Hypoglycemia in T2DM 248,422 hospitalizations (107 per 100,000) 3.4% of all T1DM hospitalizations

Prevalence (US, 2009) (18 years of older) All-cause hospitalizations: 14,226 per 100,000 person years T1DM hospitalizations: 1 % of all-cause hospitalizations 140 per 100,000 US population Hypoglycemia in T1DM hospitalizations: 6.38% of all T1DM hospitalizations (95%CI= 6.30-6.47) 9 per 100,000 US population

T2DM Hospitalizations1 T2DM Hospitalizations in 18 years and older in 2009 : 7.2 million hospitalizations 21.7% of all-cause hospitalizations 3,100 per 100,000 US population Hypoglycemia in T2DM Hospitalizations: 248,422 hospitalizations with Hypoglycemia in T2DM 3.44% of all T2DM hospitalizations (CI = 3.43-3.46) 107 per 100,000 US population 1 Data Previously Presented at EASD, 2012:Hospitalizations due to severe hypoglycemia in patients with type 2 diabetes: a US national perspective – Singh, G. et.al. EASD, 3-7th Nov, 2012, Berlin, Germany.

Hypoglycemia Hospitalizations as % of All-Cause T1DM and T2DM Hospitalizations

Hypoglycemia Hospitalizations as a % of All-Cause T1DM hospitalizations by Gender CI female 5.9% to 6.1% CI male 6.7% - 7%

Mean Age at Admission with Diagnosis of Hypoglycemia with T1DM

Hospitalization Type in T1DM Hypoglycemia Most Hospitalizations are Non-Elective

Length of Stay T1DM patients with hypoglycemia stayed longer compared to those with all-cause hospitalizations

Charges for Hospitalizations with Hypoglycemia in T1DM (US$ per admission)

National Bill : Total Charges for Hypoglycemia Hospitalizations in T1DM Total hospitalizations = 20,839 (95% CI = 19,233 - 22,445) Charge per hospitalization = $46,039 (CI = $42,144-$49,934) Total charges = $ 959,406,721 As a comparison, hypoglycemia hospitalizations in T2DM : Total hospitalizations = 248,422 (CI = 234,321-262,523) Charges per hospitalization = $48,569 (CI = $45,781-$51,357) Total charges = $ 12.07 billion Average Charge of US All-Cause Hospitalization: $33,232

Who is paying for T1DM Hypoglycemia Hospitalizations Who is paying for T1DM Hypoglycemia Hospitalizations ? Medicare and Medicaid are responsible for 64% of Payment

Inpatient Case Fatality Rate in T1DM Hypoglycemia Hospitalizations Case-fatality in T1DM Hypoglycemia 284 deaths Case-fatality = 1.36% (CI = 0.98-1.74%) Case Fatality rate for all-cause T1DM hospitalizations 1.4% (CI = 1.3-1.51%) Case Fatality rate for all-cause hospitalizations 2.2%

Limitations and Strengths No unique patient identifiers. Dependence on ICD9 codes. No information on lifestyle factors or medications. Charges vs. Costs Study limited to adults 18 years or older Nationwide sample of over 96% of all US population – robust data. Stratified, randomized sample from US hospitals - not a “convenience” sample.

Can we predict hypoglycemia? Future Work Can we predict hypoglycemia?

Conclusions Hypoglycemia in T1DM was associated with 20,839 hospitalizations and 284 deaths in 2009, and a total cost of about $1 billion, most of which is paid by Medicare and Medicaid. While aggressive glycemic control remains important for patients, the significant clinical and financial implications of severe hypoglycemia should also be noted. Careful selection of anti-diabetic drugs and close monitoring should be considered to reduce the risk of severe hypoglycemia. Development of novel anti-diabetics to reduce hypoglycemia while maintaining glycemic control would be highly desirable.