Severe Hypoglycemia Requiring Medical Intervention in a Large Cohort of Adults With Diabetes Receiving Care in U.S. Integrated Health Care Delivery Systems: 2005–2011

Ram D. Pathak; Emily B. Schroeder; Elizabeth R. Seaquist; Chan Zeng; Jennifer Elston Lafata; Abraham Thomas; Jay Desai; Beth Waitzfelder; Gregory A. Nichols; Jean M. Lawrence; Andrew J. Karter; John F. Steiner; Jodi Segal; Patrick J. O'Connor

Disclosures

Diabetes Care. 2016;39(3):363-370.

Abstract and Introduction

Abstract

Objective Appropriate glycemic control is fundamental to diabetes care, but aggressive glucose targets and intensive therapy may unintentionally increase episodes of hypoglycemia. We quantified the burden of severe hypoglycemia requiring medical intervention in a well-defined population of insured individuals with diabetes receiving care in integrated health care delivery systems across the U.S.

Research Design and Methods This observational cohort study included 917,440 adults with diabetes receiving care during 2005 to 2011 at participating SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) network sites. Severe hypoglycemia rates were based on any occurrence of hypoglycemia-related ICD-9 codes from emergency department or inpatient medical encounters and reported overall and by age, sex, comorbidity status, antecedent A1C level, and medication use.

Results Annual rates of severe hypoglycemia ranged from 1.4 to 1.6 events per 100 person-years. Rates of severe hypoglycemia were higher among those with older age, chronic kidney disease, congestive heart failure, cardiovascular disease, depression, and higher A1C levels, and in users of insulin, insulin secretagogues, or β-blockers (P < 0.001 for all). Changes in severe hypoglycemia occurrence over time were not clinically significant in the cohort as a whole but were observed in subgroups of individuals with chronic kidney disease, congestive heart failure, and cardiovascular disease.

Conclusions Risk of severe hypoglycemia in clinical settings is considerably higher in identifiable patient subgroups than in randomized controlled trials. Strategies that reduce the risk of hypoglycemia in high-risk patients are needed.

Introduction

Appropriate glycemic control is a cornerstone of diabetes care.^[1] The value of good glycemic control in reducing microvascular complications of diabetes was demonstrated for type 1 diabetes in 1993 by the Diabetes Control and Complications Trial^[2] and for type 2 diabetes in 1998 by the United Kingdom Prospective Diabetes Study (UKPDS).^[3–5] In response to these findings, early national standards of diabetes care defined the acceptable level of glycated hemoglobin (A1C) as <8% for most patients with diabetes.^[6] In 2002, the American Diabetes Association decreased the target A1C for adults to <7%.^[7] Changes in national guidelines and the addition of new glucose-lowering medications resulted in a dramatic decrease in A1C levels in the U.S. from a mean A1C of 8.2% in 1996^[8] to 7.2% in 2006.^[9] In 2008, results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD),^[10] Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE),^[11] and Veterans Affairs Diabetes Trial (VADT)^[12] trials, follow-up from the Steno-2^[13] and UKPDS^[14] trials, and multiple epidemiological studies of A1C level and treatment intensification^[15,16] began to raise concerns about the risks of aggressive treatment and suggested that A1C goals should be individually customized^[10,17] based on anticipated benefits and risk of therapy, including increased risk of severe hypoglycemia with more aggressive glucose and A1C goals.^[18–20]

Hypoglycemia can be a life-threatening complication of diabetes as well as a major source of anxiety and a threat to quality of life.^[21,22] A recent study of 33 million Medicare patients demonstrated that although hospital admission for hyperglycemia events declined ~39% from 1999 to 2011, the admission rates for hypoglycemia increased ~12%, and hypoglycemia is now the most common acute metabolic event leading to hospitalization.^[23] Most estimates of severe hypoglycemia risk are derived from clinical trials, in which event rates range from 0.3 to 1 per 100 person-years of observation.^[11,18,24] However, the Medicare data described above and other observational studies suggest that severe hypoglycemia in community-treated patients is much more common than indicated by clinical trial data.^[25–27] Additional evidence from clinical trials suggests that the increased risk of hypoglycemia in the absence of the strict oversight present in clinical trials may also be related to a variety of other factors, including age, cardiovascular and kidney function, cognition, body weight, diabetes duration, and glucose-lowering agent use.^[28,29]

Having established the SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) DataLink, which represents the largest insured diabetes patient cohort with data from electronic health records in the U.S. outside of the Veterans Administration,^[30] we sought to quantify the burden of severe hypoglycemia requiring medical intervention in a well-defined community population. Specific goals of the current study were to quantify the occurrence of severe hypoglycemia among insured, community-treated adults with diabetes; to identify subgroups of individuals at high risk of severe hypoglycemia; and to report trends in hypoglycemia over time as a whole and among different subgroups. On the basis of experiences in clinical practice and the clinical trial findings described above, we hypothesized that rates of severe hypoglycemia would be higher among patients treated with insulin who are elderly and have multiple comorbid conditions.

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Table 1. Baseline characteristics of the 917,440 patients with diabetes in the study sample by hypoglycemia status: the SUPREME-DM study ^a
	Total (N = 917,440)	Severe hypoglycemic events/year			P value^b
		None	1 severe	≥2 severe
		(n = 875,062)	(n = 41,063)	(n = 1,315)
Person-years of time at risk	4,322,786	4,085,965	232,747	4,075
Female (%)	47.9	47.8	49.0	47.5	<0.001
Age, mean (SD), years	57.9 (13.2)	57.7 (13.2)	61.0 (13.2)	60.5 (15.2)	<0.001
Comorbidities (%)
CKD	10.4	9.5	29.1	49.0	<0.001
CVD	18.7	18.0	34.2	49.0	<0.001
CHF	4.9	4.5	12.9	23.3	<0.001
Depression	11.1	11.1	11.0	16.0	<0.001
Comorbidity index, mean (SD)^c	2.70 (1.98)	2.70 (1.96)	2.96 (2.31)	3.98 (2.97)	<0.001
Follow-up, mean (SD), years	4.71 (2.18)	4.67 (2.18)	5.67 (1.81)	3.10 (1.97)	<0.001

^aStudy includes patients with a minimum of 1 year of follow-up after diabetes identification. ^bThree-way comparison between 0, 1, and ≥2 severe hypoglycemic events/year. ^cQuan modification of the Elixhauser comorbidity index (37).

Table 2. Rates of severe hypoglycemic events by year for adult participants in the SUPREME-DM
Study	Annual rate (per 100 person-years)							2005–2011 weighted rate	P value for time trend^f	P value across the groups^g
Study	2005	2006	2007	2008	2009	2010	2011	2005–2011 weighted rate	P value for time trend^f	P value across the groups^g
Total person-years	570,931	594,929	613,894	629,894	645,210	662,035	674,906
Overall
Unadjusted^a	1.44	1.58	1.55	1.55	1.50	1.48	1.46	1.51	0.448
Adjusted^b	1.47	1.59	1.51	1.49	1.36	1.37	1.47	1.47	0.011
Demographics^a
Age (years)										<0.001
20–44	1.35	1.26	1.32	1.15	1.22	1.06	1.15	1.22	0.016
45–54	0.96	1.03	0.99	0.99	1.02	0.93	0.93	0.98	0.357
55–64	1.09	1.15	1.11	1.14	1.06	1.11	1.11	1.11	0.852
65–74	1.58	1.81	1.76	1.71	1.63	1.60	1.52	1.66	0.034
75–84	2.34	2.72	2.64	2.70	2.57	2.51	2.39	2.55	0.393
≥85	2.90	2.80	2.89	3.09	2.72	2.68	2.70	2.81	0.314
Sex										0.154
Female	1.47	1.61	1.60	1.60	1.54	1.51	1.41	1.53	0.173
Male	1.42	1.55	1.50	1.51	1.47	1.45	1.51	1.49	0.970
Comorbidities^b
CKD (cohort year)										<0.001
Yes	7.16	6.20	4.95	5.77	5.04	4.48	4.51	5.26	<0.001
No	0.96	1.05	0.98	0.94	0.97	0.85	0.88	0.95	0.083
CHF (cohort year)										<0.001
Yes	8.30	7.32	7.64	7.54	6.45	6.73	6.52	7.19	0.002
No	1.28	1.40	1.32	1.33	1.33	1.19	1.22	1.29	0.021
CVD (cohort year)										<0.001
Yes	6.69	5.46	6.39	5.72	5.03	4.59	4.18	5.37	<0.001
No	1.03	1.15	1.04	1.04	1.07	0.95	0.97	1.03	0.190
Depression (baseline)										<0.001
Yes	2.25	2.24	2.38	2.12	2.13	1.76	2.03	2.12	0.041
No	1.39	1.49	1.40	1.44	1.39	1.29	1.28	1.38	0.003
Glycemic control^b
A1C										<0.001
<7%	1.00	1.20	1.06	0.92	0.86	0.92	0.79	0.96	<0.001
7–8%	1.57	1.56	1.73	1.69	1.61	1.58	1.49	1.60	0.492
8–9%	2.20	1.91	2.23	2.46	2.35	2.17	1.89	2.17	0.748
≥9%	2.44	2.53	2.54	2.60	2.77	2.48	2.69	2.58	0.442
Medication exposure^b
Diabetes medications										<0.001
Short-acting insulin^c	4.90	5.49	5.23	5.01	5.09	4.95	4.55	5.03	0.030
Long-acting insulin^c	3.79	3.30	3.54	2.99	3.28	3.03	2.72	3.18	<0.001
Secretagogues^d	0.97	0.88	0.91	0.97	0.87	0.88	1.01	0.93	0.764
Other drugs^e	0.42	0.39	0.42	0.41	0.44	0.42	0.39	0.41	0.999
β-Blockers										<0.001
Yes	2.46	2.47	2.38	3.29	2.99	2.04	1.65	2.46	0.173
No	1.36	1.45	1.38	1.36	1.35	1.23	1.25	1.34	0.417

^aUnadjusted. ^bAdjusted for age and sex. Categories are not mutually exclusive. ^cShort-acting insulin category includes patients additionally on long-acting insulin or on premixed insulin. Long-acting insulin category also includes patients on combination or premixed insulin. Includes NPH insulin. ^dInsulin secretagogues include sulfonylurea, combined sulfonylurea/biguanide, and meglitinides. ^eOther drugs include metformin, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, and GLP-1 agonists. ^fTest for monotonic trend across the years within each group from 2005 to 2011. ^gTest for whether average weighted rates differ between subgroups (e.g., female vs. male).