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Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus
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Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus Kate L. Lapane a,*, Bill M. Jesdale a, Catherine E. Dube´ a, Camilla B. Pimentel b, Swapnil N. Rajpathak c a
Department of Quantitative Health Sciences, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA b Clinical and Population Health Research Program, Graduate School of Biomedical Sciences, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA c US Outcomes Research, Merck & Co., Inc., 1 Merck Drive, Whitehouse Station, NJ 08889, USA
article info
abstract
Article history:
Aims: Although sulfonylureas increase the risk of hypoglycemia which may lead to fall-
Received 25 September 2014
associated fractures, studies quantifying the association between sulfonylureas and falls
Received in revised form
and/or fractures are sparse and existing studies have yielded inconsistent results. Our
11 February 2015
objective is to evaluate the extent to which sulfonylurea use was associated with fractures
Accepted 2 May 2015
and falls among nursing home residents with type 2 diabetes mellitus.
Available online xxx
Methods: We performed a propensity-matched retrospective new user cohort study of
Keywords:
information on sulfonylurea and biguanide use initiated as monotherapy (nsulfonylurea = 5807
12,327 Medicare Parts A/B/D eligible long-stay NH residents. Medicare Part D data provided Nursing home
and nbiguanide = 6151) after NH entry. Medicare hospitalizations were used to identify hypo-
Diabetes
glycemic events (ICD-9-CM codes 250.8, 251.1, 251.2) and fall-associated fractures (ICD-9-CM
Sulfonylurea
codes 800, 804, 812–817, 820, 823, 824). Minimum Data Set 2.0 (2008–2010) provided infor-
Falls
mation on falls and potential confounders. Cox models conducted on propensity-matched
Fractures
samples provided adjusted hazard ratio (aHR) estimates and 95% confidence intervals (CI). Results: Falls were common (37.4 per 100 person-years). Fractures were not associated with initiation of sulfonylureas. Sulfonylurea initiation was associated with an excess risk of falls among residents with moderate activities of daily living limitations (aHR: 1.13; 95% CI: 1.00–1.26), but not among those with minimal limitations or dependence in activities of daily living. Conclusions: Nursing home residents with moderate limitations in activities of daily living are at increased risk of falls upon initiation of sulfonylureas. Initiating sulfonylurea use in NH residents must be done with caution. # 2015 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +1 508 856 8965; fax: +1 508 856 8993. E-mail address: [email protected] (K.L. Lapane). http://dx.doi.org/10.1016/j.diabres.2015.05.009 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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1.
Introduction
Falls are a leading cause of injury, disability, and death among older adults [1]. Nursing home residents fall at three times the rate of community dwelling older adults [2], and 50–75% of nursing home residents fall each year. The physical, psychological, and social consequences of falls are considerable [3,4]. Nursing home residents take an average of eight medications per day [5]. Thus, understanding the fall and fracture-related risk of commonly used medications in this setting is important. Sulfonylureas are often used in diabetes management [6,7], despite the known complication of hypoglycemia which occurs in 11–18% of users [8]. Because of the association between sulfonylurea use and hypoglycemia, a causal link between sulfonylurea use and falls and fractures is reasonable. Our recent systematic review revealed that few studies attempted to estimate the association between sulfonylureas and falls and fall-associated fractures [9]. Those studies conducted to date did not show an increased risk of falls/ fractures with sulfonylurea use. These studies may have been biased by the inclusion in the comparator group of use of thiazolidinediones, which are known to increase fracture risk. Furthermore, frail older adults, like nursing homes residents, were often excluded despite their increased risk of hypoglycemia, falls, and fractures. The purpose of this study was to evaluate the extent to which sulfonylurea use was associated with fractures and falls among nursing homes residents with type 2 diabetes mellitus. The importance of this study is underscored by the increasing prevalence of diabetes [10], with 35% of people with type 2 diabetes using sulfonylureas alone or in combination with biguanide and/or thiazolidinediones [11]. In US nursing homes, one quarter of residents have diabetes and 30% use sulfonylurea alone or in combination with other antidiabetic agents [12].
2.
Subjects, materials and methods
This study was approved by the University of Massachusetts Medical School Institutional Review Board.
2.1.
Data sources
We obtained the Medicare Beneficiary Summary Files, including the Chronic Condition Summary File, Minimum Data Set (MDS) version 2.0 data, and Medicare Parts A and D data. Medicare Part D is the prescription drug insurance benefit to improve access to essential medications to Medicare beneficiaries. The MDS captures resident-level information on an extensive array of variables including sociodemographics, comorbidities, and physical and cognitive functioning on admission, quarterly, annually, or following a significant change in the resident’s status [13]. The MDS has been shown to be a reliable [14], valid [15,16], and comprehensive assessment of residents’ medical, cognitive [17], functional [18], and psychological status.
2.2.
Study cohort
We conducted a retrospective cohort study. We used a new user study design [19] to improve the validity of the study by allowing adjustment for pre-treatment disease severity [20]. We identified 173,095 residents with a diagnosis of type 2 diabetes mellitus (ICD-9 code: 250) on an annual or quarterly MDS 2.0 assessment, 6 months of continuous co-enrollment in Medicare Parts A, B, and D, and 1 prescription for a sulfonylurea and/or biguanide between 2008 and 2010. Of these, 48,389 had 1 full MDS assessment (admission, quarterly, annual, or significant change in status) preceding the index date of oral antidiabetic therapy initiation. The full assessment is conducted annually. We excluded residents <50 years of age (n = 876), comatose/paralyzed (n = 6566), receiving hospice care (n = 717), had bone cancer/infection (n = 396), had a hip fracture before 180 days of initiation of sulfonylurea or biguanide (n = 2865), or were missing data on key variables (n = 223). Of the remaining 36,746 residents, 12,327 were classified as ‘‘new users’’ if they used Part D 90 days before the first observed oral antidiabetic prescription fill, and no evidence of prior antidiabetic use including insulin. The median follow-up time was 683 days (range: 1–1002 days).
2.3.
Hypoglycemia, falls, and fractures
We considered three endpoints: (1) severe hypoglycemia; (2) fall; and (3) fractures occurring in parts of the body typically associated with falling. We identified hospitalizations due to hypoglycemia using ICD-9-CM codes (250.8, 251.1, 251.2). Residents were categorized as having a fall (incident or recurrent) prior to hospitalization if there was a discharge diagnosis of an accidental fall (ICD-9-CM E880–E888) or an MDS documentation of a fall in the past 30 days. For fractures, we included hospitalizations coded as: (1) hip fracture (ICD-9-CM 820), (2) radius/ulna fracture (ICD-9-CM 813), (3) humerus fracture (ICD-9-CM 812); (4) hand (ICD-9-CM 814–817), (5) tibia/ fibula (ICD-9-CM 823), (6) ankle (ICD-9-CM 824), or (7) skull/face (ICD-9-CM 800, 804). Use of administrative data to identify fracture is valid [21–23]. All outcome measures were calculated as time to event. Using an intention-to-treat approach [24], person time was calculated from initiation of oral antidiabetic medication to the date of the first occurrence of the event of interest, loss of eligibility for Medicare Parts A, B, or D, death, or December 31, 2010, which was the end of the follow-up period.
2.4.
Diabetes medication use
We were interested in constructing two primary comparisons. The first compared monotherapy sulfonylurea use and monotherapy biguanide use. Second, we identified residents initiating combination therapy (sulfonylurea and biguanide) compared to biguanide use alone. Using Medicare Part D pharmacy claims, we identified new users as residents initiating one of the target treatments 90 days after the first evidence of Part D utilization for any medication, and the absence of any antidiabetic medication use (including insulin)
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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before that date. The first prescription fill date was considered the index date.
2.5.
Confounders
We considered the following variables as confounders: age, race/ethnicity, sex, body mass index, concomitant medications (e.g., benzodiazepines, antidepressants, antipsychotics, bisphosphonates and other drugs that may strengthen or weaken bones), comorbid conditions (e.g., osteoporosis, dementia, stroke), sensory, cognitive, or physical functioning impairments, and diabetic retinopathy. Cognitive impairment was assessed using the Cognitive Performance Scale [25,26], ranging from 0 (intact) to 6 (very severe impairment). Activities of daily living (ADLs) were assessed using the MDS ADL scale [27], a five-point scale used to rate each resident’s ability to perform each ADL (dressing, eating, toilet use, bathing, locomotion, transfer, and continence) [25].
2.6.
Statistical analysis
To understand the extent of imbalance in a long list of potential confounders, we conducted cross-tabulations of baseline characteristics by exposure category. We then developed a propensity score [28]. Covariates strongly associated with exposure but unrelated to outcome were not included [29,30]. We used the greedy matching algorithm to identify two separate matched groups for each comparison group of interest, matching both on subject sex and propensity score [31]. Because of the roughly equivalent numbers of monotherapy users, we performed a 1:1 match (without replacement), with a 0.01 propensity match threshold. We matched as many as 10 biguanide monotherapy users to each combination therapy user. We used the c-statistic to assess the degree of overlap between exposure groups (c-statisticmonotherapy = 0.67; c-statisticcombination therapy = 0.70) [32] and noted that none of the potential confounders differed by greater than
Table 1 – Characteristics of nursing home residents by initiation of sulfonylureas, biguanides or both (n = 12,327). Total sample
Sociodemographics Age (Years) 50–64 65–74 75–84 85 Women Race/ethnicitya White Black Other Severe cognitive impairment Dependent in activities of daily living Body mass indexa Overweight Obese Comorbid conditionsa Osteoporosis Hypothyroidism Atherosclerotic heart disease Congestive heart failure Hypertension Hypotension Nephropathy Chronic kidney diseaseb Dementia, including Alzheimer’s diseaseb Stroke or transient ischemic attack Diabetic retinopathy Glaucoma Cataracts Macular degeneration
Propensity matched sample
Sulfonylureas (n = 5807)
Biguanide (n = 6151)
Sulfonylureas (n = 4436)
Biguanide (n = 4436)
11.7 21.4 35.5 31.4 69.1
5.9 15.1 35.5 43.5 67.0
7.3 18.0 37.1 37.6 69.5
7.0 18.3 37.4 37.4 69.5
79.9 13.4 6.5 8.7 38.9
80.7 13.2 5.9 9.4 43.1
80.6 13.6 6.0 9.5 41.6
81.0 13.0 6.3 9.2 41.7
29.5 42.4
31.1 35.1
30.4 38.5
30.2 38.5
18.9 21.1 15.5 25.3 78.0 4.1 7.5 24.1 65.6 19.2 0.8 7.9 8.3 4.3
17.5 23.2 19.1 35.3 80.6 3.9 17.5 38.5 64.8 20.3 1.0 8.8 8.5 5.8
18.5 21.8 17.4 30.9 79.3 3.9 9.7 28.7 65.2 19.9 1.0 8.3 8.6 5.0
18.5 21.4 16.7 27.3 79.4 3.6 9.4 29.3 67.4 20.0 0.9 8.4 8.6 4.9
a
Missing data for total sample: race/ethnicity (n = 30), body mass index (n = 365), osteoporosis (n = 1440), hypothyroidism (n = 1434), atherosclerotic heart disease (n = 912), heart failure (n = 887), hypertension (n = 1337), hypotension (n = 1445), nephropathy (n = 1425), stroke or transient ischemic attack (n = 268), cataracts, diabetic retinopathy, glaucoma, and macular degeneration (n = 1456). Missing data for sulfonylurea v. biguanide match: race/ethnicity (n = 26), body mass index (n = 273), osteoporosis (n = 1072), hypothyroidism (n = 1071), atherosclerotic heart disease (n = 690), heart failure (n = 674), hypertension (n = 994), hypotension (n = 1075), nephropathy (n = 1068), stroke or transient ischemic attack (n = 205), cataracts, diabetic retinopathy, glaucoma, and macular degeneration (n = 1084). b From the Chronic Condition Summary File.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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3.6% absolute difference between the comparator groups. Cox models accounting for the propensity-matched design were used to estimate adjusted hazards ratios (aHR) and 95% confidence intervals (CI). These estimates were adjusted for potential confounders. We also performed three sensitivity analyses. We first imposed additional censoring at the time of discontinuation of the index medication or at the date of initiation of insulin or any oral antidiabetic medication. Then, we censored sulfonylurea users if they discontinued sulfonylurea or if they initiated insulin. Biguanide users were censored if they switched to a treatment thought to induce hypoglycemia (e.g., sulfonylurea, meglitinide), discontinued biguanide, or initiated insulin. Lastly, we restricted the analysis to residents with no evidence of insulin use subsequent to the index date, matching on propensity score as described above, restricted to never users of insulin.
3.
Results
Among those initiating biguanides, 43.5% were 85 years of age whereas 31.4% of sulfonylurea initiators were 85 years, respectively (Table 1). Dependency in ADLs was common (38.9% sulfonylurea initiators, 43.1% biguanides). Obesity and co-morbid conditions were prevalent. Oral glucocorticoid use was similar across sulfonylurea initiators (19.3%) and biguanide initiators (20.9%). Bisphosphonates were used in 9.4% of sulfonylurea initiators and 7.7% of biguanide initiators. Parathyroid hormone use was rare (<0.2%). Calcitonin use and estrogen replacement therapy was uncommon (calcitonin: 1.9% sulfonylurea and 2.6% biguanide; estrogen: 2.8% sulfonylurea and 1.8% biguanide). Before the propensity matching, chronic kidney disease and chronic heart failure appeared to be more common in biguanide initiators relative to SU initiators. After propensity matching, the prevalence estimates are very similar for those initiating sulfonylureas and biguanides. Few residents initiated sulfonylureas and biguanides. For those identified, distributions of potential confounders were similar (within 2%) in the propensity matched samples (data not shown). Five percent experienced a hospitalization for hypoglycemia during the follow-up period (Table 2). Falls documented on the MDS were more common than hospitalizations for falls (41.0% versus 5.0%, respectively). During the follow-up period, 4.2% experienced a fall-associated fracture, with hip being the most common fracture site. Overall, the rate of hospitalization for hypoglycemia was highest among the residents initiating combination therapy (sulfonylurea and biguanides) at 6.9 per 100 person-years, and lowest among biguanide initiators at 2.0 per 100 person-years (Fig. 1, Table 3). The rate of hospitalizations for hypoglycemia was higher in sulfonylurea initiators relative to residents initiating biguanides (aHR: 2.37; 95% CI: 1.86–3.01) (Panel A, Fig. 1). Analyses by gender revealed comparable effects in men and women (Table 3). The propensity-matched analysis comparing the rate of hospitalization with hypoglycemia among nursing home residents initiating combined sulfonylurea and biguanides to those initiating sulfonylureas alone suggested an excess rate with combination therapy (aHR: 1.41;
Table 2 – Proportion of hypoglycemia, fall, and fracture related events among the total eligible population using an intention-to-treat analysis (n = 12,327)a.
Hospitalized for hypoglycemia Any fall Fall documented on Minimum Data Set Hospitalization for fall Any fall-associated fractureb Hip fracture Humerus fracture Radius/ulna fracture Tibia/fibula fracture Ankle fracture Hand fracture Skull/face fracture
Percent
Number of events
5.1 41.0 40.1
626 5060 4939
5.0 4.2 2.7 0.4 0.2 0.4 0.4 0.1 0.3
621 497 333 55 24 49 50 14 39
a As propensity score development and matching was conducted per specific outcome of interest, we show data from the total sample for the hip fracture outcome intention-to-treat analysis. b Including hip, humerus, radius/ulna, tibia/fibula, ankle, radius/ ulna, hand, and/or skull/face.
95% CI: 0.98–2.05). The rate of falls by monotherapy treatment type was high among all groups (Panel B, Fig. 1), approximately 40 per 100 residents per year. Fractures at fall-associated sites were similar among sulfonylurea and biguanide initiators (3.1 and 2.9 per 100 person-years, respectively) (Panel C, Fig. 1). For combination therapy, a similar estimate of effect as observed for falls was observed for hospitalizations associated with falls (aHR: 0.65; 95% CI: 0.34–1.22). To provide comparisons to previous research, we also separated out hip fractures and evaluated them as a separate outcome. The rate of hip fractures was 2.0 per 100 resident years in both the sulfonylurea and biguanide groups (aHR: 1.20; 95% CI: 0.90–1.60). Regardless of age of residents or level of dependency in ADLs, sulfonylurea initiation was associated with excess rate of severe hypoglycemia (Table 4). Falls tended to be more common in those initiating sulfonylureas relative to biguanide initiators among aged 75 to 84 years (aHR: 1.11; 95% CI: 0.98– 1.26), but not in the younger or older age groups. The association between sulfonylurea initiation and falls was apparent only in those with moderate limitations in ADLs (aHR: 1.13; 95% CI: 1.01–1.26). The results of the analyses of fallassociated fractures mirrored what was observed for falls. The association between initiation of sulfonylureas and severe hypoglycemia in the as-treated analyses censoring on date of initiation of insulin or oral antidiabetic agent or discontinuation of initial medication was greater than in the intention-to-treat analyses (aHR 4.94; 95% CI: 2.98–8.20). No effect was observed for falls (aHR 1.01; 95% CI: 0.90–1.13) or fallassociated fractures (aHR 1.02; 95% CI: 0.70–1.49). In the second sensitivity analysis, the association between sulfonylureas initiation and severe hypoglycemia was also more pronounced than in the intention-to-treat analysis (aHR 4.17; 95% CI: 2.65–6.58). No effect was observed for falls (aHR 1.02; 95% CI: 0.91–1.14) or fall-associated fractures (aHR 1.03; 95% CI: 0.72–1.48). Among residents for whom we did not find any evidence of insulin use, sulfonylurea initiation was associated with an increased rate of severe hypoglycemic events (aHR:
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Fig. 1 – Kaplan–Meier estimates of the cumulative incidence of hospitalization for hypoglycemia (A), falls (B), and hospitalization for fractures (C) by sulfonylurea and biguanide initiation. Fractures included those where the clinical site may be suggestive of fall-associated fracture.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Table 3 – Sulfonylurea initiation and hypoglycemia, fall, and fall-associated fracture among propensity-matched samples using an intention-to-treat analysis. Hospitalization for hypoglycemia Events Person- Rateb years Overall Initiation of monotherapy Sulfonylureas
289
6307
4.6
Biguanides Women Sulfonylureas
132
6518
2.0
179
4471
4.0
Biguanides Men Sulfonylureas
86
4605
1.9
110
1835
6.0
Biguanides
46
1913
2.4
34
522
6.5
99
4800
2.1
Overall Combined versus monotherapy Sulfonylureas/ biguanides Biguanide
Events
2.37 (1.86–3.01) Referent 2.28 (1.69–3.08) Referent 2.53 (1.73–3.81) Referent
2.96 (1.94–4.51) Referent
Falls Person- Rateb Events years
1864
4560
40.9
1844
4546
1282
Hospitalization for fractures at sites associated with fallsa Personyears
Rateb Events Personyears
194
6174
3.1
40.6
0.98 (0.90–1.06) Referent
180
6305
2.9
3216
39.9
1.01 (0.92–1.11)
157
4319
3.6
1244
3251
38.3
Referent
134
4418
3.0
582
1345
43.3
0.91 (0.79–1.04)
37
1855
2.0
600
1295
46.3
Referent
46
1886
2.4
143
406
35.2
0.91 (0.76–1.10)
11
516
2.1
1312
3325
39.5
Referent
121
4533
2.7
Rateb
1.13 (0.89–1.44) Referent 1.25 (0.96–1.63) Referent 0.77 (0.45–1.32) Referent
0.82 (0.43–1.54) Referent
CI: confidence interval. a Including hip fracture (ICD-9-CM 820), radius/ulna fracture (ICD-9-CM 813), humerus fracture (ICD-9-CM 812), 4) hand (ICD-9-CM 814-817), tibia/fibula (ICD-9-CM 823), ankle (ICD-9-CM 824), or skull/face: (ICD-9-CM 800, 804). b Per 100 person-years.
3.20; 95% CI: 2.12–4.82), but not falls (aHR: 1.04; 95% CI: 0.94– 1.15) or fall-associated fractures (aHR: 1.14; 95% CI: 0.83–1.56).
4.
Discussion
Despite the biologically plausible chain of events that may link sulfonylurea use to increased risk of fractures (e.g., sulfonylurea use leads to hypoglycemia which leads to falls and fractures) and the concern of aging-related changes in pharmacokinetics and pharmacodynamics, the few studies attempting to quantify the association between sulfonylureas and fall-associated fractures have yielded contradictory results [9] and rarely included elderly nursing home residents. Sulfonylurea initiation was associated with severe hypoglycemia, with the association with falls apparent only in NH residents with moderate limitations in activities of daily living. No association between initiation of sulfonylureas and fractures was observed in this study. Our study extends previous research by documenting the rate of severe hypoglycemia in the nursing home. In a clinical trial population, 1.2% of patients randomized to receive sulfonylureas experienced serious hypoglycemic events in a year. In our population, the rate of hospitalization for hypoglycemia is markedly higher (4.6 per 100 person-years). Our study demonstrated that sulfonylurea initiation was associated with an excess risk of severe hypoglycemia among a medically complex nursing home population. Among geriatric patients, the excess risk of severe hypoglycemia
associated with sulfonylurea use has been attributed to prescribing of sulfonylureas despite the presence of critical contraindications (e.g., renal insufficiency) [33]. Compromised renal function is typical of many nursing home residents and may interfere with the clearance of sulfonylureas, placing residents at risk for life-threatening hypoglycemia. We were unable to determine the appropriateness of sulfonylurea initiation. Estimating the impact of sulfonylurea use on hypoglycemic events not requiring hospitalizations was beyond the capabilities of the administrative data used. Hypoglycemia as a result of sulfonylurea use is often subclinical [8]. As such, it is likely that the extent of hypoglycemia in the nursing home population is greater than we were able to document using administrative data sources. Age, multiple co-morbidity, renal insufficiency, and sulfonylurea use are known risk factors of hypoglycemia. In the nursing home setting, educating staff to recognize and treat hypoglycemia would be prudent. Despite the confirmation of the association between sulfonylurea and hypoglycemic events, we did not show an association between initiation of sulfonylureas and fractures. Our study confirms previous work showing that over three years of follow-up, 80% of residents experienced at least one fall. We found that the association between sulfonylurea initiation and rate of falls was confined to those with moderate limitations in activities of daily living. Causes of falls are multifactorial in the nursing home setting. The fraction of falls actually attributable to sulfonylurea use may be relatively small compared to other more commonly used medications,
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Table 4 – Sulfonylurea initiation and hypoglycemia, fall, and fall-associated fractures among propensity-matched samples stratified by age and ADLs. Severe hypoglycemia
Falls
Hospitalization for fractures at sites associated with fallsa
Events
Personyears
Rateb
Events
Personyears
Rateb
Events
Personyears
Rateb
Events
Personyears
Rateb
Age 50–74 years Sulfonylureas
91
1658
5.5
406
1299
31.3
1662
2.5
40
1710
2.3
421
1243
33.9
0.93 (0.79–1.09) Referent
41
Biguanides
2.67 (1.71–4.15) Referent
35
1665
2.1
1.00 (0.59–1.69) Referent
104
2455
4.2
756
1693
44.7
86
2375
3.6
55
2524
2.2
703
1785
39.4
1.11 (0.98–1.26) Referent
70
2478
2.8
100
2167
4.6
691
1547
44.7
65
2114
3.1
39
2248
1.7
697
1519
45.9
1.02 (0.89–1.16) Referent
74
2142
3.5
Minimal limitations in ADLs (0–2) 100 2180 Sulfonylureas
4.6
681
1537
44.3
75
2143
3.5
746
1490
50.1
0.91 (0.80–1.04) Referent
81
2222
3.6
942
1951
48.3
99
2771
3.6
879
2012
43.7
1.13 (1.01–1.26) Referent
73
2844
2.6
220
1038
21.2
23
1215
1.9
203
1026
19.8
1.03 (0.82–1.30) Referent
23
1207
1.9
Age 75–84 years Sulfonylureas Biguanides Age 85+ years Sulfonylureas Biguanides
2318
2.1
Moderate limitations in ADLs (3–4) Sulfonylureas 124 2873
4.3
Biguanides
Biguanides
48
48
Dependent in ADLs (5–6) 63 Sulfonylureas Biguanides
34
2948
1.6
1215
5.2
1229
2.8
2.00 (1.37–2.91) Referent
2.64 (1.71–4.08) Referent
2.21 (1.47–3.34) Referent
2.73 (1.83–4.06) Referent
2.50 (1.49–4.20) Referent
1.37 (0.95–1.99) Referent
0.95 (0.63–1.46) Referent
0.98 (0.69–1.41) Referent
1.29 (0.92–1.81) Referent
1.00 (0.49–2.05) Referent
ADL: activity of daily living; CI: confidence interval. a Including hip fracture (ICD-9-CM 820), radius/ulna fracture (ICD-9-CM 813), humerus fracture (ICD-9-CM 812), 4) hand (ICD-9-CM 814-817), tibia/fibula (ICD-9-CM 823), ankle (ICD-9-CM 824), or skull/face: (ICD-9-CM 800, 804). b Per 100 person-years.
independent effects of multiple co-morbidities, and environmental factors. Approximately 5% of falls result in fractures, 5% in serious soft-tissue injuries, and 2% in hospitalization or immobilization for an extended period, which may lead to further functional decline [34]. Nursing home residents have a disproportionate rate of hip fracture resulting from falls and higher mortality rates after hip fracture than communitydwelling older people [35]. Nevertheless, we did not find an association between sulfonylurea initiation and fractures. The clinical relevance of strategies to avoid falls and fractures in residents must not be minimized. Our study must be considered with a few caveats in mind. The data shown represent real world prescribing practice in a population often excluded from clinical trials by virtue of their age, institutionalization, or medical complexity. Confounding is reduced because we applied propensity score methods, although residual confounding by indication is possible. No measures of bone mineral density were available. If we had bone mineral density information, we would have been able to explore why we observed an association between sulfonylurea initiation and falls, but not fractures. We assumed that residents actually initiated the oral antidiabetic therapy which appeared in the Medicare Part D claims files. Although
differential effects of sulfonylureas have been documented [36], we could not estimate the effect of different sulfonylurea agents. Nondifferential misclassification is possible because we included fractures at sites typically associated with falls, whether or not the fracture co-occurred with a fall-associated ICD-9 injury code, and we did not limit codes to the primary code. The median length of follow-up time available in the current study limited our ability to evaluate the long-term effects of sulfonylurea on risk of falls and fractures. If sulfonylureas were thought to influence bone metabolism, a longer period of study would be necessary. Relative to biguanides, sulfonylureas confer an increased rate of serious hypoglycemia, which is markedly higher than in community-dwelling older adults. The rate of falls and fractures associated with sulfonylurea initiation were not consistently statistically higher than biguanides. An excess rate of falls associated with sulfonylurea initiation was observed in residents with moderate limitations in activities of daily living. Falls and fractures may be occurring at such a high rate in this setting that the additional risk from sulfonylurea-induced hypoglycemia was not apparent. Initiating diabetes medication in elderly nursing home residents must be done with care.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Author contributions Dr. Lapane had full access to the data used in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Lapane, Jesdale, Rajpathak, and Ms. Pimentel. Acquisition of data: Dr. Dube´, Lapane. Analysis and interpretation of data: Drs. Lapane, Jesdale. Drafting of manuscript: Dr. Lapane, Jesdale. Critical revision of manuscript for important intellectual content: Ms. Pimentel, Drs. Lapane, Jesdale, Dube´, and Rajpathak. Obtained funding: Dr. Lapane. Study supervision: Dr. Lapane. Final approval of the manuscript to be submitted: Ms. Pimentel, Drs. Lapane, Jesdale, Dube´, and Rajpathak.
Sponsor’s role The funding source had no role in the collection, management, and analysis of the data. The study protocol underwent review at Merck prior to the initiation of the study.
Acknowledgments This study was funded by a contract to Dr. Lapane from US Outcomes Research, Merck & Co., Inc. Dr. Rajpathak is employed by Merck and Co., Inc. Conflict of interest statement We have no additional financial support or relationships that may pose a conflict of interest.
references
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Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus Kate L. Lapane a,*, Bill M. Jesdale a, Catherine E. Dube´ a, Camilla B. Pimentel b, Swapnil N. Rajpathak c a
Department of Quantitative Health Sciences, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA b Clinical and Population Health Research Program, Graduate School of Biomedical Sciences, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA c US Outcomes Research, Merck & Co., Inc., 1 Merck Drive, Whitehouse Station, NJ 08889, USA
article info
abstract
Article history:
Aims: Although sulfonylureas increase the risk of hypoglycemia which may lead to fall-
Received 25 September 2014
associated fractures, studies quantifying the association between sulfonylureas and falls
Received in revised form
and/or fractures are sparse and existing studies have yielded inconsistent results. Our
11 February 2015
objective is to evaluate the extent to which sulfonylurea use was associated with fractures
Accepted 2 May 2015
and falls among nursing home residents with type 2 diabetes mellitus.
Available online xxx
Methods: We performed a propensity-matched retrospective new user cohort study of
Keywords:
information on sulfonylurea and biguanide use initiated as monotherapy (nsulfonylurea = 5807
12,327 Medicare Parts A/B/D eligible long-stay NH residents. Medicare Part D data provided Nursing home
and nbiguanide = 6151) after NH entry. Medicare hospitalizations were used to identify hypo-
Diabetes
glycemic events (ICD-9-CM codes 250.8, 251.1, 251.2) and fall-associated fractures (ICD-9-CM
Sulfonylurea
codes 800, 804, 812–817, 820, 823, 824). Minimum Data Set 2.0 (2008–2010) provided infor-
Falls
mation on falls and potential confounders. Cox models conducted on propensity-matched
Fractures
samples provided adjusted hazard ratio (aHR) estimates and 95% confidence intervals (CI). Results: Falls were common (37.4 per 100 person-years). Fractures were not associated with initiation of sulfonylureas. Sulfonylurea initiation was associated with an excess risk of falls among residents with moderate activities of daily living limitations (aHR: 1.13; 95% CI: 1.00–1.26), but not among those with minimal limitations or dependence in activities of daily living. Conclusions: Nursing home residents with moderate limitations in activities of daily living are at increased risk of falls upon initiation of sulfonylureas. Initiating sulfonylurea use in NH residents must be done with caution. # 2015 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +1 508 856 8965; fax: +1 508 856 8993. E-mail address: [email protected] (K.L. Lapane). http://dx.doi.org/10.1016/j.diabres.2015.05.009 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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1.
Introduction
Falls are a leading cause of injury, disability, and death among older adults [1]. Nursing home residents fall at three times the rate of community dwelling older adults [2], and 50–75% of nursing home residents fall each year. The physical, psychological, and social consequences of falls are considerable [3,4]. Nursing home residents take an average of eight medications per day [5]. Thus, understanding the fall and fracture-related risk of commonly used medications in this setting is important. Sulfonylureas are often used in diabetes management [6,7], despite the known complication of hypoglycemia which occurs in 11–18% of users [8]. Because of the association between sulfonylurea use and hypoglycemia, a causal link between sulfonylurea use and falls and fractures is reasonable. Our recent systematic review revealed that few studies attempted to estimate the association between sulfonylureas and falls and fall-associated fractures [9]. Those studies conducted to date did not show an increased risk of falls/ fractures with sulfonylurea use. These studies may have been biased by the inclusion in the comparator group of use of thiazolidinediones, which are known to increase fracture risk. Furthermore, frail older adults, like nursing homes residents, were often excluded despite their increased risk of hypoglycemia, falls, and fractures. The purpose of this study was to evaluate the extent to which sulfonylurea use was associated with fractures and falls among nursing homes residents with type 2 diabetes mellitus. The importance of this study is underscored by the increasing prevalence of diabetes [10], with 35% of people with type 2 diabetes using sulfonylureas alone or in combination with biguanide and/or thiazolidinediones [11]. In US nursing homes, one quarter of residents have diabetes and 30% use sulfonylurea alone or in combination with other antidiabetic agents [12].
2.
Subjects, materials and methods
This study was approved by the University of Massachusetts Medical School Institutional Review Board.
2.1.
Data sources
We obtained the Medicare Beneficiary Summary Files, including the Chronic Condition Summary File, Minimum Data Set (MDS) version 2.0 data, and Medicare Parts A and D data. Medicare Part D is the prescription drug insurance benefit to improve access to essential medications to Medicare beneficiaries. The MDS captures resident-level information on an extensive array of variables including sociodemographics, comorbidities, and physical and cognitive functioning on admission, quarterly, annually, or following a significant change in the resident’s status [13]. The MDS has been shown to be a reliable [14], valid [15,16], and comprehensive assessment of residents’ medical, cognitive [17], functional [18], and psychological status.
2.2.
Study cohort
We conducted a retrospective cohort study. We used a new user study design [19] to improve the validity of the study by allowing adjustment for pre-treatment disease severity [20]. We identified 173,095 residents with a diagnosis of type 2 diabetes mellitus (ICD-9 code: 250) on an annual or quarterly MDS 2.0 assessment, 6 months of continuous co-enrollment in Medicare Parts A, B, and D, and 1 prescription for a sulfonylurea and/or biguanide between 2008 and 2010. Of these, 48,389 had 1 full MDS assessment (admission, quarterly, annual, or significant change in status) preceding the index date of oral antidiabetic therapy initiation. The full assessment is conducted annually. We excluded residents <50 years of age (n = 876), comatose/paralyzed (n = 6566), receiving hospice care (n = 717), had bone cancer/infection (n = 396), had a hip fracture before 180 days of initiation of sulfonylurea or biguanide (n = 2865), or were missing data on key variables (n = 223). Of the remaining 36,746 residents, 12,327 were classified as ‘‘new users’’ if they used Part D 90 days before the first observed oral antidiabetic prescription fill, and no evidence of prior antidiabetic use including insulin. The median follow-up time was 683 days (range: 1–1002 days).
2.3.
Hypoglycemia, falls, and fractures
We considered three endpoints: (1) severe hypoglycemia; (2) fall; and (3) fractures occurring in parts of the body typically associated with falling. We identified hospitalizations due to hypoglycemia using ICD-9-CM codes (250.8, 251.1, 251.2). Residents were categorized as having a fall (incident or recurrent) prior to hospitalization if there was a discharge diagnosis of an accidental fall (ICD-9-CM E880–E888) or an MDS documentation of a fall in the past 30 days. For fractures, we included hospitalizations coded as: (1) hip fracture (ICD-9-CM 820), (2) radius/ulna fracture (ICD-9-CM 813), (3) humerus fracture (ICD-9-CM 812); (4) hand (ICD-9-CM 814–817), (5) tibia/ fibula (ICD-9-CM 823), (6) ankle (ICD-9-CM 824), or (7) skull/face (ICD-9-CM 800, 804). Use of administrative data to identify fracture is valid [21–23]. All outcome measures were calculated as time to event. Using an intention-to-treat approach [24], person time was calculated from initiation of oral antidiabetic medication to the date of the first occurrence of the event of interest, loss of eligibility for Medicare Parts A, B, or D, death, or December 31, 2010, which was the end of the follow-up period.
2.4.
Diabetes medication use
We were interested in constructing two primary comparisons. The first compared monotherapy sulfonylurea use and monotherapy biguanide use. Second, we identified residents initiating combination therapy (sulfonylurea and biguanide) compared to biguanide use alone. Using Medicare Part D pharmacy claims, we identified new users as residents initiating one of the target treatments 90 days after the first evidence of Part D utilization for any medication, and the absence of any antidiabetic medication use (including insulin)
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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before that date. The first prescription fill date was considered the index date.
2.5.
Confounders
We considered the following variables as confounders: age, race/ethnicity, sex, body mass index, concomitant medications (e.g., benzodiazepines, antidepressants, antipsychotics, bisphosphonates and other drugs that may strengthen or weaken bones), comorbid conditions (e.g., osteoporosis, dementia, stroke), sensory, cognitive, or physical functioning impairments, and diabetic retinopathy. Cognitive impairment was assessed using the Cognitive Performance Scale [25,26], ranging from 0 (intact) to 6 (very severe impairment). Activities of daily living (ADLs) were assessed using the MDS ADL scale [27], a five-point scale used to rate each resident’s ability to perform each ADL (dressing, eating, toilet use, bathing, locomotion, transfer, and continence) [25].
2.6.
Statistical analysis
To understand the extent of imbalance in a long list of potential confounders, we conducted cross-tabulations of baseline characteristics by exposure category. We then developed a propensity score [28]. Covariates strongly associated with exposure but unrelated to outcome were not included [29,30]. We used the greedy matching algorithm to identify two separate matched groups for each comparison group of interest, matching both on subject sex and propensity score [31]. Because of the roughly equivalent numbers of monotherapy users, we performed a 1:1 match (without replacement), with a 0.01 propensity match threshold. We matched as many as 10 biguanide monotherapy users to each combination therapy user. We used the c-statistic to assess the degree of overlap between exposure groups (c-statisticmonotherapy = 0.67; c-statisticcombination therapy = 0.70) [32] and noted that none of the potential confounders differed by greater than
Table 1 – Characteristics of nursing home residents by initiation of sulfonylureas, biguanides or both (n = 12,327). Total sample
Sociodemographics Age (Years) 50–64 65–74 75–84 85 Women Race/ethnicitya White Black Other Severe cognitive impairment Dependent in activities of daily living Body mass indexa Overweight Obese Comorbid conditionsa Osteoporosis Hypothyroidism Atherosclerotic heart disease Congestive heart failure Hypertension Hypotension Nephropathy Chronic kidney diseaseb Dementia, including Alzheimer’s diseaseb Stroke or transient ischemic attack Diabetic retinopathy Glaucoma Cataracts Macular degeneration
Propensity matched sample
Sulfonylureas (n = 5807)
Biguanide (n = 6151)
Sulfonylureas (n = 4436)
Biguanide (n = 4436)
11.7 21.4 35.5 31.4 69.1
5.9 15.1 35.5 43.5 67.0
7.3 18.0 37.1 37.6 69.5
7.0 18.3 37.4 37.4 69.5
79.9 13.4 6.5 8.7 38.9
80.7 13.2 5.9 9.4 43.1
80.6 13.6 6.0 9.5 41.6
81.0 13.0 6.3 9.2 41.7
29.5 42.4
31.1 35.1
30.4 38.5
30.2 38.5
18.9 21.1 15.5 25.3 78.0 4.1 7.5 24.1 65.6 19.2 0.8 7.9 8.3 4.3
17.5 23.2 19.1 35.3 80.6 3.9 17.5 38.5 64.8 20.3 1.0 8.8 8.5 5.8
18.5 21.8 17.4 30.9 79.3 3.9 9.7 28.7 65.2 19.9 1.0 8.3 8.6 5.0
18.5 21.4 16.7 27.3 79.4 3.6 9.4 29.3 67.4 20.0 0.9 8.4 8.6 4.9
a
Missing data for total sample: race/ethnicity (n = 30), body mass index (n = 365), osteoporosis (n = 1440), hypothyroidism (n = 1434), atherosclerotic heart disease (n = 912), heart failure (n = 887), hypertension (n = 1337), hypotension (n = 1445), nephropathy (n = 1425), stroke or transient ischemic attack (n = 268), cataracts, diabetic retinopathy, glaucoma, and macular degeneration (n = 1456). Missing data for sulfonylurea v. biguanide match: race/ethnicity (n = 26), body mass index (n = 273), osteoporosis (n = 1072), hypothyroidism (n = 1071), atherosclerotic heart disease (n = 690), heart failure (n = 674), hypertension (n = 994), hypotension (n = 1075), nephropathy (n = 1068), stroke or transient ischemic attack (n = 205), cataracts, diabetic retinopathy, glaucoma, and macular degeneration (n = 1084). b From the Chronic Condition Summary File.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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3.6% absolute difference between the comparator groups. Cox models accounting for the propensity-matched design were used to estimate adjusted hazards ratios (aHR) and 95% confidence intervals (CI). These estimates were adjusted for potential confounders. We also performed three sensitivity analyses. We first imposed additional censoring at the time of discontinuation of the index medication or at the date of initiation of insulin or any oral antidiabetic medication. Then, we censored sulfonylurea users if they discontinued sulfonylurea or if they initiated insulin. Biguanide users were censored if they switched to a treatment thought to induce hypoglycemia (e.g., sulfonylurea, meglitinide), discontinued biguanide, or initiated insulin. Lastly, we restricted the analysis to residents with no evidence of insulin use subsequent to the index date, matching on propensity score as described above, restricted to never users of insulin.
3.
Results
Among those initiating biguanides, 43.5% were 85 years of age whereas 31.4% of sulfonylurea initiators were 85 years, respectively (Table 1). Dependency in ADLs was common (38.9% sulfonylurea initiators, 43.1% biguanides). Obesity and co-morbid conditions were prevalent. Oral glucocorticoid use was similar across sulfonylurea initiators (19.3%) and biguanide initiators (20.9%). Bisphosphonates were used in 9.4% of sulfonylurea initiators and 7.7% of biguanide initiators. Parathyroid hormone use was rare (<0.2%). Calcitonin use and estrogen replacement therapy was uncommon (calcitonin: 1.9% sulfonylurea and 2.6% biguanide; estrogen: 2.8% sulfonylurea and 1.8% biguanide). Before the propensity matching, chronic kidney disease and chronic heart failure appeared to be more common in biguanide initiators relative to SU initiators. After propensity matching, the prevalence estimates are very similar for those initiating sulfonylureas and biguanides. Few residents initiated sulfonylureas and biguanides. For those identified, distributions of potential confounders were similar (within 2%) in the propensity matched samples (data not shown). Five percent experienced a hospitalization for hypoglycemia during the follow-up period (Table 2). Falls documented on the MDS were more common than hospitalizations for falls (41.0% versus 5.0%, respectively). During the follow-up period, 4.2% experienced a fall-associated fracture, with hip being the most common fracture site. Overall, the rate of hospitalization for hypoglycemia was highest among the residents initiating combination therapy (sulfonylurea and biguanides) at 6.9 per 100 person-years, and lowest among biguanide initiators at 2.0 per 100 person-years (Fig. 1, Table 3). The rate of hospitalizations for hypoglycemia was higher in sulfonylurea initiators relative to residents initiating biguanides (aHR: 2.37; 95% CI: 1.86–3.01) (Panel A, Fig. 1). Analyses by gender revealed comparable effects in men and women (Table 3). The propensity-matched analysis comparing the rate of hospitalization with hypoglycemia among nursing home residents initiating combined sulfonylurea and biguanides to those initiating sulfonylureas alone suggested an excess rate with combination therapy (aHR: 1.41;
Table 2 – Proportion of hypoglycemia, fall, and fracture related events among the total eligible population using an intention-to-treat analysis (n = 12,327)a.
Hospitalized for hypoglycemia Any fall Fall documented on Minimum Data Set Hospitalization for fall Any fall-associated fractureb Hip fracture Humerus fracture Radius/ulna fracture Tibia/fibula fracture Ankle fracture Hand fracture Skull/face fracture
Percent
Number of events
5.1 41.0 40.1
626 5060 4939
5.0 4.2 2.7 0.4 0.2 0.4 0.4 0.1 0.3
621 497 333 55 24 49 50 14 39
a As propensity score development and matching was conducted per specific outcome of interest, we show data from the total sample for the hip fracture outcome intention-to-treat analysis. b Including hip, humerus, radius/ulna, tibia/fibula, ankle, radius/ ulna, hand, and/or skull/face.
95% CI: 0.98–2.05). The rate of falls by monotherapy treatment type was high among all groups (Panel B, Fig. 1), approximately 40 per 100 residents per year. Fractures at fall-associated sites were similar among sulfonylurea and biguanide initiators (3.1 and 2.9 per 100 person-years, respectively) (Panel C, Fig. 1). For combination therapy, a similar estimate of effect as observed for falls was observed for hospitalizations associated with falls (aHR: 0.65; 95% CI: 0.34–1.22). To provide comparisons to previous research, we also separated out hip fractures and evaluated them as a separate outcome. The rate of hip fractures was 2.0 per 100 resident years in both the sulfonylurea and biguanide groups (aHR: 1.20; 95% CI: 0.90–1.60). Regardless of age of residents or level of dependency in ADLs, sulfonylurea initiation was associated with excess rate of severe hypoglycemia (Table 4). Falls tended to be more common in those initiating sulfonylureas relative to biguanide initiators among aged 75 to 84 years (aHR: 1.11; 95% CI: 0.98– 1.26), but not in the younger or older age groups. The association between sulfonylurea initiation and falls was apparent only in those with moderate limitations in ADLs (aHR: 1.13; 95% CI: 1.01–1.26). The results of the analyses of fallassociated fractures mirrored what was observed for falls. The association between initiation of sulfonylureas and severe hypoglycemia in the as-treated analyses censoring on date of initiation of insulin or oral antidiabetic agent or discontinuation of initial medication was greater than in the intention-to-treat analyses (aHR 4.94; 95% CI: 2.98–8.20). No effect was observed for falls (aHR 1.01; 95% CI: 0.90–1.13) or fallassociated fractures (aHR 1.02; 95% CI: 0.70–1.49). In the second sensitivity analysis, the association between sulfonylureas initiation and severe hypoglycemia was also more pronounced than in the intention-to-treat analysis (aHR 4.17; 95% CI: 2.65–6.58). No effect was observed for falls (aHR 1.02; 95% CI: 0.91–1.14) or fall-associated fractures (aHR 1.03; 95% CI: 0.72–1.48). Among residents for whom we did not find any evidence of insulin use, sulfonylurea initiation was associated with an increased rate of severe hypoglycemic events (aHR:
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Fig. 1 – Kaplan–Meier estimates of the cumulative incidence of hospitalization for hypoglycemia (A), falls (B), and hospitalization for fractures (C) by sulfonylurea and biguanide initiation. Fractures included those where the clinical site may be suggestive of fall-associated fracture.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Table 3 – Sulfonylurea initiation and hypoglycemia, fall, and fall-associated fracture among propensity-matched samples using an intention-to-treat analysis. Hospitalization for hypoglycemia Events Person- Rateb years Overall Initiation of monotherapy Sulfonylureas
289
6307
4.6
Biguanides Women Sulfonylureas
132
6518
2.0
179
4471
4.0
Biguanides Men Sulfonylureas
86
4605
1.9
110
1835
6.0
Biguanides
46
1913
2.4
34
522
6.5
99
4800
2.1
Overall Combined versus monotherapy Sulfonylureas/ biguanides Biguanide
Events
2.37 (1.86–3.01) Referent 2.28 (1.69–3.08) Referent 2.53 (1.73–3.81) Referent
2.96 (1.94–4.51) Referent
Falls Person- Rateb Events years
1864
4560
40.9
1844
4546
1282
Hospitalization for fractures at sites associated with fallsa Personyears
Rateb Events Personyears
194
6174
3.1
40.6
0.98 (0.90–1.06) Referent
180
6305
2.9
3216
39.9
1.01 (0.92–1.11)
157
4319
3.6
1244
3251
38.3
Referent
134
4418
3.0
582
1345
43.3
0.91 (0.79–1.04)
37
1855
2.0
600
1295
46.3
Referent
46
1886
2.4
143
406
35.2
0.91 (0.76–1.10)
11
516
2.1
1312
3325
39.5
Referent
121
4533
2.7
Rateb
1.13 (0.89–1.44) Referent 1.25 (0.96–1.63) Referent 0.77 (0.45–1.32) Referent
0.82 (0.43–1.54) Referent
CI: confidence interval. a Including hip fracture (ICD-9-CM 820), radius/ulna fracture (ICD-9-CM 813), humerus fracture (ICD-9-CM 812), 4) hand (ICD-9-CM 814-817), tibia/fibula (ICD-9-CM 823), ankle (ICD-9-CM 824), or skull/face: (ICD-9-CM 800, 804). b Per 100 person-years.
3.20; 95% CI: 2.12–4.82), but not falls (aHR: 1.04; 95% CI: 0.94– 1.15) or fall-associated fractures (aHR: 1.14; 95% CI: 0.83–1.56).
4.
Discussion
Despite the biologically plausible chain of events that may link sulfonylurea use to increased risk of fractures (e.g., sulfonylurea use leads to hypoglycemia which leads to falls and fractures) and the concern of aging-related changes in pharmacokinetics and pharmacodynamics, the few studies attempting to quantify the association between sulfonylureas and fall-associated fractures have yielded contradictory results [9] and rarely included elderly nursing home residents. Sulfonylurea initiation was associated with severe hypoglycemia, with the association with falls apparent only in NH residents with moderate limitations in activities of daily living. No association between initiation of sulfonylureas and fractures was observed in this study. Our study extends previous research by documenting the rate of severe hypoglycemia in the nursing home. In a clinical trial population, 1.2% of patients randomized to receive sulfonylureas experienced serious hypoglycemic events in a year. In our population, the rate of hospitalization for hypoglycemia is markedly higher (4.6 per 100 person-years). Our study demonstrated that sulfonylurea initiation was associated with an excess risk of severe hypoglycemia among a medically complex nursing home population. Among geriatric patients, the excess risk of severe hypoglycemia
associated with sulfonylurea use has been attributed to prescribing of sulfonylureas despite the presence of critical contraindications (e.g., renal insufficiency) [33]. Compromised renal function is typical of many nursing home residents and may interfere with the clearance of sulfonylureas, placing residents at risk for life-threatening hypoglycemia. We were unable to determine the appropriateness of sulfonylurea initiation. Estimating the impact of sulfonylurea use on hypoglycemic events not requiring hospitalizations was beyond the capabilities of the administrative data used. Hypoglycemia as a result of sulfonylurea use is often subclinical [8]. As such, it is likely that the extent of hypoglycemia in the nursing home population is greater than we were able to document using administrative data sources. Age, multiple co-morbidity, renal insufficiency, and sulfonylurea use are known risk factors of hypoglycemia. In the nursing home setting, educating staff to recognize and treat hypoglycemia would be prudent. Despite the confirmation of the association between sulfonylurea and hypoglycemic events, we did not show an association between initiation of sulfonylureas and fractures. Our study confirms previous work showing that over three years of follow-up, 80% of residents experienced at least one fall. We found that the association between sulfonylurea initiation and rate of falls was confined to those with moderate limitations in activities of daily living. Causes of falls are multifactorial in the nursing home setting. The fraction of falls actually attributable to sulfonylurea use may be relatively small compared to other more commonly used medications,
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Table 4 – Sulfonylurea initiation and hypoglycemia, fall, and fall-associated fractures among propensity-matched samples stratified by age and ADLs. Severe hypoglycemia
Falls
Hospitalization for fractures at sites associated with fallsa
Events
Personyears
Rateb
Events
Personyears
Rateb
Events
Personyears
Rateb
Events
Personyears
Rateb
Age 50–74 years Sulfonylureas
91
1658
5.5
406
1299
31.3
1662
2.5
40
1710
2.3
421
1243
33.9
0.93 (0.79–1.09) Referent
41
Biguanides
2.67 (1.71–4.15) Referent
35
1665
2.1
1.00 (0.59–1.69) Referent
104
2455
4.2
756
1693
44.7
86
2375
3.6
55
2524
2.2
703
1785
39.4
1.11 (0.98–1.26) Referent
70
2478
2.8
100
2167
4.6
691
1547
44.7
65
2114
3.1
39
2248
1.7
697
1519
45.9
1.02 (0.89–1.16) Referent
74
2142
3.5
Minimal limitations in ADLs (0–2) 100 2180 Sulfonylureas
4.6
681
1537
44.3
75
2143
3.5
746
1490
50.1
0.91 (0.80–1.04) Referent
81
2222
3.6
942
1951
48.3
99
2771
3.6
879
2012
43.7
1.13 (1.01–1.26) Referent
73
2844
2.6
220
1038
21.2
23
1215
1.9
203
1026
19.8
1.03 (0.82–1.30) Referent
23
1207
1.9
Age 75–84 years Sulfonylureas Biguanides Age 85+ years Sulfonylureas Biguanides
2318
2.1
Moderate limitations in ADLs (3–4) Sulfonylureas 124 2873
4.3
Biguanides
Biguanides
48
48
Dependent in ADLs (5–6) 63 Sulfonylureas Biguanides
34
2948
1.6
1215
5.2
1229
2.8
2.00 (1.37–2.91) Referent
2.64 (1.71–4.08) Referent
2.21 (1.47–3.34) Referent
2.73 (1.83–4.06) Referent
2.50 (1.49–4.20) Referent
1.37 (0.95–1.99) Referent
0.95 (0.63–1.46) Referent
0.98 (0.69–1.41) Referent
1.29 (0.92–1.81) Referent
1.00 (0.49–2.05) Referent
ADL: activity of daily living; CI: confidence interval. a Including hip fracture (ICD-9-CM 820), radius/ulna fracture (ICD-9-CM 813), humerus fracture (ICD-9-CM 812), 4) hand (ICD-9-CM 814-817), tibia/fibula (ICD-9-CM 823), ankle (ICD-9-CM 824), or skull/face: (ICD-9-CM 800, 804). b Per 100 person-years.
independent effects of multiple co-morbidities, and environmental factors. Approximately 5% of falls result in fractures, 5% in serious soft-tissue injuries, and 2% in hospitalization or immobilization for an extended period, which may lead to further functional decline [34]. Nursing home residents have a disproportionate rate of hip fracture resulting from falls and higher mortality rates after hip fracture than communitydwelling older people [35]. Nevertheless, we did not find an association between sulfonylurea initiation and fractures. The clinical relevance of strategies to avoid falls and fractures in residents must not be minimized. Our study must be considered with a few caveats in mind. The data shown represent real world prescribing practice in a population often excluded from clinical trials by virtue of their age, institutionalization, or medical complexity. Confounding is reduced because we applied propensity score methods, although residual confounding by indication is possible. No measures of bone mineral density were available. If we had bone mineral density information, we would have been able to explore why we observed an association between sulfonylurea initiation and falls, but not fractures. We assumed that residents actually initiated the oral antidiabetic therapy which appeared in the Medicare Part D claims files. Although
differential effects of sulfonylureas have been documented [36], we could not estimate the effect of different sulfonylurea agents. Nondifferential misclassification is possible because we included fractures at sites typically associated with falls, whether or not the fracture co-occurred with a fall-associated ICD-9 injury code, and we did not limit codes to the primary code. The median length of follow-up time available in the current study limited our ability to evaluate the long-term effects of sulfonylurea on risk of falls and fractures. If sulfonylureas were thought to influence bone metabolism, a longer period of study would be necessary. Relative to biguanides, sulfonylureas confer an increased rate of serious hypoglycemia, which is markedly higher than in community-dwelling older adults. The rate of falls and fractures associated with sulfonylurea initiation were not consistently statistically higher than biguanides. An excess rate of falls associated with sulfonylurea initiation was observed in residents with moderate limitations in activities of daily living. Falls and fractures may be occurring at such a high rate in this setting that the additional risk from sulfonylurea-induced hypoglycemia was not apparent. Initiating diabetes medication in elderly nursing home residents must be done with care.
Please cite this article in press as: Lapane KL, et al. Sulfonylureas and risk of falls and fractures among nursing home residents with type 2 diabetes mellitus. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.05.009
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Author contributions Dr. Lapane had full access to the data used in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Lapane, Jesdale, Rajpathak, and Ms. Pimentel. Acquisition of data: Dr. Dube´, Lapane. Analysis and interpretation of data: Drs. Lapane, Jesdale. Drafting of manuscript: Dr. Lapane, Jesdale. Critical revision of manuscript for important intellectual content: Ms. Pimentel, Drs. Lapane, Jesdale, Dube´, and Rajpathak. Obtained funding: Dr. Lapane. Study supervision: Dr. Lapane. Final approval of the manuscript to be submitted: Ms. Pimentel, Drs. Lapane, Jesdale, Dube´, and Rajpathak.
Sponsor’s role The funding source had no role in the collection, management, and analysis of the data. The study protocol underwent review at Merck prior to the initiation of the study.
Acknowledgments This study was funded by a contract to Dr. Lapane from US Outcomes Research, Merck & Co., Inc. Dr. Rajpathak is employed by Merck and Co., Inc. Conflict of interest statement We have no additional financial support or relationships that may pose a conflict of interest.
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