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. Author manuscript; available in PMC: 2018 May 1.
Published in final edited form as: J Diabetes Complications. 2017 Feb 21;31(5):869–873. doi: 10.1016/j.jdiacomp.2017.02.009

High Rates of Severe Hypoglycemia among African American Patients with Diabetes: The Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) Network

Andrew J Karter a, Kasia J Lipska b, Patrick J O’Connor c, Jennifer Y Liu a, Howard H Moffet a, Emily B Schroeder d, Jean M Lawrence e, Gregory A Nichols f, Katherine M Newton g, Ram D Pathak h, Jay Desai c, Beth Waitzfelder i, Melissa G Butler j, Abraham Thomas k, John F Steiner d, on behalf of the SUPREME-DM Study Group
PMCID: PMC5491095  NIHMSID: NIHMS870108  PMID: 28319006

Abstract

Aims

Seven-year surveillance study (2005–2011) to evaluate race/ethnic differences in the trends in rates of severe hypoglycemia (SH) in a population of insured, at-risk adults with diabetes.

Methods

SH events were identified via any primary or principal diagnosis from emergency department or inpatient encounters among African American, Asian, Latino and White adult diabetes patients treated with insulin or secretagogues (Sulfonylureas or Meglitinides), receiving care from integrated healthcare delivery systems across the United States. We calculated age- and sex-standardized annual SH rates and average annual percent change (AAPC) in SH rates.

Results

Annual SH rates ranged from 1.8% to 2.1% during this 7-year observation period (2,200,471 person-years). African Americans had consistently higher SH rates compared with Whites, while Latinos and Asians had consistently lower rates compared with Whites in each of the 7 years (all p<0.01). The trend increased significantly only among African Americans (AAPC = +4.3%; 95% CI: +2.1, +6.5%); in the other groups, the AAPC was not significantly different from zero.

Conclusions

Surveillance efforts should monitor the racial/ethnic-specific rates. The factors underlying substantially higher rates of hypoglycemia in African Americans should be evaluated. Clinically and culturally-appropriate strategies to reduce the risk of SH need to be developed and tested.

Keywords: hypoglycemia, racial differences, complications, insulin, sulfonylureas, insulin secretagogues

1. INTRODUCTION

1.1

There is a growing public health concern regarding the occurrence of severe hypoglycemia (SH) among diabetes patients, particularly those treated with insulin or secretagogues that stimulate endogenous insulin production.(Lipska, 2014) Severe hypoglycemia (SH) is a well-recognized adverse effect of glucose-lowering therapy. SH is associated with a tripling of the risk of mortality(Bonds et al., 2010; McCoy et al., 2012; Zoungas et al., 2010) and substantial increases in risk of dementia(Whitmer, Karter, Yaffe, Quesenberry, & Selby, 2009), stroke(Yu, Lin, Chang, Sung, & Kao, 2014), falls(Schwartz et al., 2008), fall-related fractures(Johnston, Conner, Aagren, Ruiz, & Bouchard, 2012), motor vehicle accidents(Signorovitch et al., 2012), and cardiovascular events,(Goto, Arah, Goto, Terauchi, & Noda, 2013), poorer quality of life(Laiteerapong et al., 2011) and emotional challenges.(Trief, Sandberg, Dimmock, Forken, & Weinstock, 2013) Recent randomized controlled trials have reported average annual SH rates of 0.3 to 1.0 events per 100 person-years,(Gerstein et al., 2008b; Patel et al., 2008a) which is considerably lower than rates of clinically recognized SH observed in real-world, usual care settings(Lipska et al., 2013) and national surveillance.(Prevention, 2014) We previously reported rates of SH among patients receiving care in integrated health care delivery systems ranging from 1.4 to 1.6 events per 100 person-years.(Pathak et al., 2015)

1.2

Prior studies have documented racial/ethnic disparities in the quality of diabetes care and outcomes, but less is known about racial/ethnic differences in rates of SH. National surveillance of hypoglycemic events recorded in the emergency department (ED) have recorded recent trends in hypoglycemia nationwide, however lacked data on race/ethnicity, as well as type of diabetes and medication use.(Prevention, 2014) Racial/ethnic minorities with diabetes are less likely to achieve recommended glycemic targets(Ali, McKeever Bullard, Imperatore, Barker, & Gregg, 2012; Kirk et al., 2006) and more likely to experience long-term diabetic complications(Karter et al., 2002; Wang et al., 2012) compared with whites with diabetes. Prior studies were not specifically designed to examine racial/ethnic differences in SH rates, but several reported higher risk of hypoglycemia in minority populations compared with white patients.(Ginde, Espinola, & Camargo, 2008; Lipska et al., 2014; Shen & Washington, 2008; Shorr, Ray, Daugherty, & Griffin, 1997) Racial/ethnic health inequalities in population-based studies are likely in part attributable to differential access to care. No recent epidemiologic study has comprehensively characterized racial/ethnic differences in the rates and trends of SH from emergency department or inpatient encounters in a diabetes population with uniform access to care.

1.3

Centers for Disease Control and Prevention conducts national surveillance on hypoglycemia events using the National Emergency Department Sample (NEDS)(Prevention, 2014), however limitations in the source data preclude evaluations by race/ethnicity. We conducted 7-year surveillance study (2005–2011) to evaluate differences in trends of hypoglycemia among insured, at-risk adults with diabetes. These included African American, Asian, Latino and White diabetes patients treated with insulin or secretagogues (Sulfonylureas or Meglitinides), age 18 years and older, receiving care from integrated health care delivery systems participating in the multi-institutional SUPREME-DM network across the United States (2,200,471 person-years).

1.4

We examined temporal trends in the annual SH rates during 2005 – 2011 by race/ethnicity using data from the SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) network(Nichols et al., 2012), a multi-institutional, observational cohort including almost a million adults with diabetes receiving care from integrated health care delivery systems across the US.(Orandi et al., 2016) This study was approved by the Kaiser Permanente Colorado (KPCO) Institutional Review Board (IRB) and each participating site’s IRB either ceded oversight to the KPCO IRB or gave its approval.

2. MATERIAL AND METHODS

2.1 Study Setting and Data Sources

SUPREME-DM is a consortium of 11 integrated, healthcare systems: Geisinger Health System (Pennsylvania), Group Health (Washington), HealthPartners (Minnesota), Henry Ford Health System (Michigan), Marshfield Clinic (Wisconsin), and Kaiser Permanente regions in Colorado, Northern California, Southern California, Hawaii, Georgia, Oregon and Washington state. Research institutions embedded in these organizations developed a distributed virtual data warehouse that incorporates patient information from electronic medical records (EMR) and includes demographics, pharmacy dispensing and claims, laboratory tests results, and diagnostic codes from emergency department, outpatient and inpatient care encounters.(Hornbrook et al., 2005) Members in these healthcare systems receive insurance primarily through group plans, or Medicare, Medicaid or other publicly-supported programs. These data were used to construct the SUPREME-DM DataLink, the largest clinically-detailed, private-sector diabetes population in the US.(Nichols, et al., 2012) The SUPREME-DM methods have been detailed previously.(Basu, Rehkopf, Siddiqi, Glymour, & Kawachi, 2016; Nichols, et al., 2012; Orandi, et al., 2016)

2.2 Study Population

Using the SUPREME-DM cohort, we examined annual SH rates among African American, Asian, Latino and white adult health plan members ≥18 years of age with diabetes mellitus dispensed either insulin or secretagogues (Sulfonylureas or Meglitinides) during a 7-year study observation period: 2005 – 2011. We utilized a retrospective panel study design (series of cross-sectional assessments) to calculate annual SH rates for each year of observation. Eligibility among members enrolled in the health plan was determined for each calendar year separately based on the following criteria: diagnosed with diabetes in a prior year and dispensed any insulin or secretagogues in that calendar year.

2.3 Study Exposures

Self-reported race/ethnicity (African American, Asian, Latino or white) was obtained from the SUPREME-DM DataLink. Subjects reporting Latino ethnicity were categorized as Latino and the other racial/ethnic categories (African American, Asian and whites) were categorized as non-Latino. Approximately 14% of the individuals in the sample were of unknown race/ethnicity and were excluded from the race-stratified analysis; 3.5% of the sample were of mixed or other racial/ethnic categories and were also excluded as there were insufficient numbers to support stable annual SH rates over time.

2.4 Outcomes

SH events were identified via any primary or principal diagnosis from an ED or inpatient encounter using a validated coding algorithm with estimated positive predictive value of 89%.(Ginde, Blanc, Lieberman, & Camargo, 2008)

2.5 Analyses

Annual SH rates were calculated separately for each calendar year using the eligible population for that year as the denominator and the number of patients experiencing at least one SH event in that same calendar year as the numerator. Event rates were standardized to the age and sex distribution of the 2010 United States Census. We specified log-linear models to estimate average annual percent change (AAPC) by race/ethnicity to quantify the rate of change and identify those trends which differed significantly from zero.(Kim, Fay, Feuer, & Midthune, 2000) Analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC) and Joinpoint Regression Program version 4.1.0.(Fenwick et al., 2016)

3. RESULTS

3.1

The denominator was based on the number of eligible patients with diabetes treated with insulin or secretagogues varied over the course of the 7-year study: 275,201 patients in 2005; 290,887 in 2006; 307,150 in 2007; 314,724 in 2008; 324,090 in 2009; 336,833 in 2010; and 351,586 in 2011 (a total of 2,200,471 person-years). The demographic distributions remained relatively stable over time and so, for simplicity, we report the characteristics of subjects only in the final year of observation (2011) (Table 1). Mean age of the sample was 61.4 years (SD=13.7) and more than half were over age 60. There were roughly similar numbers of men and women, and minorities (i.e., Latinos, African Americans and Asians) comprised approximately half the cohort.

Table 1.

Characteristics of the Health Plan members with diabetes treated with insulin or sulfonylureas or Meglitinides, the SUPREME-DM DataLink, 2011.

Number of individuals, N (%)
Full sample* African American Asian Latino White
44,580 (12.3) 43,792 (12) 91,219 (25.1) 171,995 (47.3)
Age group, years
 18–29 6,409 (1.8) 754 (1.7) 454 (1) 1,846 (2) 3,355 (2)
 30–44 31,404 (8.9) 4,109 (9.2) 3,903 (8.9) 12,405 (13.6) 10,987 (6.4)
 45–59 112,562 (32) 15,240 (34.2) 15,114 (34.5) 35,027 (38.4) 47,181 (27.4)
 60–74 138,704 (39.5) 17,753 (39.8) 17,644 (40.3) 30,809 (33.8) 72,498 (42.2)
 75+ 62,507 (17.8) 6,724 (15.1) 6,677 (15.3) 11,132 (12.2) 37,974 (22.1)
Sex
 Women 166,030 (47.2) 23,816 (53.4) 20,352 (46.5) 44,406 (48.7) 77,456 (45)
 Men 185,556 (52.8) 20,764 (46.6) 23,440 (53.5) 46,813 (51.3) 94,539 (55)
Drug treatment:
 Secretagogues only (Sulfonylurea or Metaglitinides) 189,540 (53.9) 22,500 (50.5) 29,332 (67) 51,755 (56.7) 85,953 (50)
 Insulin only 99,281 (28.2) 14,290 (32.1) 7,646 (17.5) 21,638 (23.7) 55,707 (32.4)
 Both secretagogues and insulin 62,765 (17.9) 7,790 (17.5) 6,814 (15.6) 17,826 (19.5) 30,335 (17.6)
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*

We excluded the 3.4% (n=12,292) that were classified as “other” race

3.2

The overall, age- and sex-standardized annual SH rates ranged from 1.8% to 2.1% for the total population during this 7-year observation period. There were significant racial/ethnic differences in annual SH rates (Table 2). African Americans had consistently higher rates compared with whites, while Latinos and Asians had consistently lower rates compared with whites in each year of observation (Figure). As an example, the annual SH rates among African Americans in 2011 was 66% (1.3 percentage points) higher than the rate among Whites (3.26% vs. 1.96%; p<0.0001), while SH rates among Latinos (1.66%) and Asians (1.01%) were 0.3 and 0.9 percentage points lower than among whites (both differences p<0.0001)

Table 2.

Trends (2005–2011) in severe hypoglycemia (SH) diagnosed during emergency department (ED) or inpatient encounters among African Americans, Asians, Latinos and white individuals with diabetes treated with insulin or secretagogues (sulfonylureas or meglitinides) who were members in eleven U.S. healthcare systems (the SUPREME-DM DataLink).

African American Asian Latino White
2005
 Patients experiencing SH 859 274 956 2,510
 At risk population 38,322 30,726 64,199 141,954
 Standardized SH rate* (95% CI) 2.7%
(2.2−3.1%)		 0.7%
(0.5−0.9%)		 1.7%
(1.4−1.9%)		 2.0%
(1.8−2.1%)
 Absolute difference (ref: White) +0.7%† −1.2%† −0.3% † ref
2006
 Patients experiencing SH 1,013 393 1,220 2,839
 At risk population 39,746 32,940 69,863 148,338
 Standardized SH rate* (95% CI) 2.5%
(2.1−2.8%)		 1.0%
(0.7−1.3%)		 1.7%
(1.5−1.9%)		 2.2%
(2.0−2.4%)
 Absolute difference (ref: White) +0.3% (ns) −1.2% † −0.5% † ref
2007
 Patients experiencing SH 1,108 466 1,255 2,997
 At risk population 41,035 35,820 75,550 154,745
 Standardized SH rate* (95% CI) 2.8%
(2.4−3.2%)		 1.1%
(0.8−1.4%)		 1.8%
(1.6−2.0%)		 2.2%
(2.0−2.4%)
 Absolute difference (ref: White) +0.6%† −1.1% † −0.4%† ref
2008
 Patients experiencing SH 1,188 457 1,501 3,108
 At risk population 41,579 37,335 79,011 156,802
 Standardized SH rate* (95% CI) 2.8%
(2.4−3.2%)		 0.9%
(07−1.1%)		 1.9%
(1.7−2.1%)		 2.2%
(2.0−2.4%)
 Absolute difference (ref: White) +0.6%† −1.3%† −0.3%† ref
2009
 Patients experiencing SH 1,167 501 1,524 3,201
 At risk population 42,319 39,321 82,227 160,223
 Standardized SH rate* (95% CI) 2.8%
(2.5−3.2%)		 1.3%
(0.9−1.7%)		 1.9%
(1.7−2.1%)		 2.3%
(2.1−2.4%)
 Absolute difference (ref: White) +0.6%† −0.9%† −0.3%† ref
2010
 Patients experiencing SH 1,259 518 1,536 3,228
 At risk population 43,530 41,253 86,018 166,032
 Standardized SH rate* (95% CI) 3.1%
(2.7−3.5%)		 1.1%
(0.8−1.3%)		 1.9%
(1.7−2.1%)		 2.0%
(1.9−2.2%)
 Absolute difference (ref: White) +1.1%† −1.0%† −0.1% (ns) ref
2011
 Patients experiencing SH 1,321 518 1,566 3,297
 At risk population 44,580 43,792 91,219 171,995
 Standardized SH rate* (95% CI) 3.3%
(2.9−3.7%)		 1.0%
(0.8−1.1%)		 1.7%
(1.5−1.8%)		 2.0%
(1.8−2.1%)
 Absolute difference (ref: White) +1.3%† −1.0%† −0.3%† ref
Trend analysis
Average annual percent change (AAPC) in standardized rate (95%CI) +4.3%
(2.1−6.5%)†
 +3.9
(−3.6−12.0%)
ns		 +0.5%
(−0.6−1.7%) ns		 −0.9%
(−4.4−2.8%)
ns
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*

Age- and sex-standardized to the 2010 US Census population

†

p-value<0.05; ns=non-significant

Figure. Annual SH rates* among patients with diabetes treated with insulin or a secretagogue (Sulfonylureas or Meglitinides) in the SUPREME-DM DataLink. (2005–2011).

Figure

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*Age & sex standardized to the 2010 U.S. population; solid lines for race-specific trends, dashed line for total population trend

3.3

The overall AAPC in SH rates during 2005 – 2011 was not significantly different from zero (+0.6%; 95% CI: −1.8, +3.1%). However there was a significant increase in annual SH rates (AAPC = +4.3%; 95% CI: +2.1, +6.5%) among African Americans during the 7 year observation period. The AAPC in annual SH rates in Latinos (+0.5%; 95% CI: −0.6, +1.7%), Asians (+3.9%; 95% CI: −3.6, +12.0%), and Whites (−0.9%; 95% CI: −4.4, +2.8%) were not significantly different from zero.

4. DISCUSSION

4.1

Among insured patients with diabetes treated with insulin or secretagogues in integrated health care delivery systems during 2005–2011, annual rates of SH events diagnosed in the emergency department (ED) or inpatient setting differed by race/ethnicity. Relative to whites, African Americans had ~1.7 -fold higher rates of SH, while Asians and Latinos had lower rates. Moreover, annual SH rates among African Americans increased significantly during the window of observation, but did not change among Asians, Latinos and whites.

4.2

Intensive glucose-lowering strategies in clinical trial populations have been associated with an increase in the risk of hypoglycemia.(Duckworth et al., 2009; Gerstein et al., 2008a; Patel et al., 2008b) Identifying and avoiding overly intensive treatment strategies (or overtreatment) in patients at risk for SH has become a clinical priority.(Lee, 2014; Lipska, 2014; Lipska & Montori, 2013; Lipska, et al., 2014; McCoy et al., 2016; Pogach & Aron, 2010, 2012) However people experiencing hypoglycemia are not necessarily over-treated. Given the harms associated with SH, recent guidelines suggest that avoiding hypoglycemia should be prioritized over aggressive glycemic targets, particularly in older patients,(Seaquist et al., 2013) and measuring rates of SH as a diabetes care quality measure has been suggested.(Clarke et al., 1999) It is unknown to what extent these potential changes in models of care will reduce the risk of SH among different racial/ethnic subgroups. Given the national focus on identifying and eliminating health inequalities, SH surveillance with a focus on vulnerable subgroups should be given greater attention.

4.3

Some study limitations should be noted. Our sample was limited to the 4 largest U.S. racial/ethnic groups, and thus we were unable calculate rates of SH in other racial/ethnic subgroups. This was a surveillance study based on panel data, and thus we did not study nor do we have the appropriate data to investigate the causes of race/ethnic differences in hypoglycemia. Similarly, we lack the ability to stratify our sample by type of diabetes. The SUPREME-DM DataLink discontinued data capture at the end of the 7-year observation window, and it unclear whether observed racial/ethnic patterns persisted after 2011. By limiting our study of racial/ethnic differences in SH to episodes diagnosed in an ED or inpatient encounter, we did not include the vast majority of SH episodes that receive assistance from others outside of ED or hospital settings. In the DISTANCE Study, ~11% of surveyed diabetes patients reported an SH event in the previous 12 months, while only ~0.5% of that cohort received an ED or inpatient diagnosis of SH.(Sarkar et al., 2010) Since it is unclear what factors led persons experiencing an SH event to receive medical attention in the ED or hospital, racial/ethnic patterns of self-reported SH(Berkowitz et al., 2014; Lipska, et al., 2013) may differ from SH diagnosed at a medical facility. Moreover, since we based findings on SH identified via primary or principal diagnoses, findings cannot be generalized to SH events that were secondary to other diagnoses. We studied the proportion of patients that experienced at least one episode in a given year, but did not study the reoccurrence of events (e.g., multiple episodes per year per patient).

4.4

In conclusion, among insured patients across the US, African Americans had persistently higher annual SH rates compared with whites, while Asians and Latinos had lower rates. Moreover, rates increased significantly in African Americans during 2005 – 2011, while none of the other racial/ethnic groups experienced significant changes in their rates. It is unknown whether these differences are due to factors such as racial/ethnic variation in quality of care (despite being insured); differences in utilization of ED services; contextual factors beyond being insured such as lower socioeconomic status(Berkowitz, et al., 2014) or food insufficiency(Seligman, Bolger, Guzman, Lopez, & Bibbins-Domingo, 2014); different rates of beta cell failure and predisposition to more frequent or severe hypoglycemia; or differential distribution of other clinical risk factors (e.g., renal disease, congestive heart failure(Pathak, et al., 2015)). A recent review of racial differences in HbA1c(Herman, 2016) described data showing that, at a given HbA1c level, glucose levels are substantively lower in African Americans compared with whites.(Wolffenbuttel et al., 2013) It was suggested that the risk of SH may be elevated in African Americans when efforts are made to treat African Americans and whites to the same target HbA1c levels.(Herman, 2016) Thus a “one size fits all” target for HbA1c may cause harm. More research is needed to understand to what extent racial differences in the association between HbA1c and glucose, other clinical risk factors, and environmental factors explain the elevated risk of SH in African Americans. Future studies should assess avenues for addressing these potential causes of elevated SH in African Americans and implement interventions to reduce rates of SH in all racial/ethnic groups, with a particular emphasis on African-Americans. SH is a serious side-effect of glucose lowering therapy and continued surveillance, a better understanding of the causes for racial/ethnic inequalities, and development of clinically and culturally-appropriate strategies to reduce the risk of hypoglycemia are needed.

Acknowledgments

We gratefully acknowledge Geisinger Health System for their efforts at developing and refining the SUPREME-DM data sets that informed this work.

Funding sources: The SUPREME-DM project was supported by the Agency for Healthcare Research and Quality [grant number R01HS019859]. Dr Karter was also supported by hypoglycemia-related research grants from NIDDK (R01DK103721, R01DK081796, P30DK092924) and the U.S. Food and Drug Administration (BAA-13-00119).

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