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The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes
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Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Q4 Q3
The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes Yin-Yi Han a, *, Sheng-Ru Lai b, Jamie S. Partridge c, Michael Y. Wang d, Suela Sulo e, Fang-Wei Tsao d, 1, Refaat A. Hegazi c a
Trauma Department, National Taiwan University Hospital, Taiwan Department of Dietetics, National Taiwan University Hospital, Taiwan Abbott Nutrition Research & Development, Columbus, OH, USA d Abbott Nutrition Research & Development, Taiwan e Abbott Nutrition Research & Development, Chicago, IL, USA b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 January 2016 Accepted 27 September 2016
Background & aims: Patients admitted to intensive care units (ICUs) often need enteral nutrition (EN) support. For patients with type 2 diabetes (T2D), standard EN formulas may not provide ideal nutrients. The purpose was to investigate whether use of a diabetes-specific formula (DSF) could provide clinical and health economic benefits (compared to standard formulas) in critically ill patients with T2D. Methods: This study was a retrospective analysis of medical records and expenditure data covering a 5year period (2009e2013) from the hospitalization database of the National Taiwan University Hospital. Records of ICU patients who had T2D and were receiving enteral feeding with either the DSF or nondiabetes-specific formula (non-DSF) for at least 5 days were included in the analysis. Mortality, ICU length of stay (LOS), diabetes-related medications, and total costs of care (including all costs covered by the National Health Insurance and private expenses) were considered as the primary outcomes. Results: A total of 158 patient records were analyzed in the DSF group and 794 in the non-DSF group. The baseline demographics including age, gender, weight, body mass index (BMI), and comorbidity patterns were mostly comparable between the groups. Compared to those receiving non-DSF, patients with T2D receiving DSF were found to have significantly decreased mortality (5.1% vs. 12.3%, P ¼ 0.0118) and reduced need for insulin prescription (29.1% vs. 38.4%, P ¼ 0.0269). ICU LOS was shorter for DSF patients, but no statistical difference was found (13.0 days vs. 15.1 days, P ¼ 0.1843). However, significantly lower total ICU costs were reported for DSF patients (6700 USD vs. 9200 USD, P < 0.0001). Conclusions: The use of DSF in ICU patients with T2D is correlated with significant reduction in mortality and improved health economic outcomes. © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Diabetes Critical illness Enteral nutrition Diabetes-specific formulas Health economics
1. Introduction The importance of glycemic control to inpatient recovery has garnered increasing attention from healthcare professionals in the
Abbreviations: ICU, intensive care unit; EN, enteral nutrition; T2D, type 2 diabetes; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula; LOS, length of stay; BMI, body mass index; OHA, oral hypoglycemic agent. * Corresponding author. Trauma Department, National Taiwan University Hospital, No. 7, Chung Shan S Rd., Zhongzheng Dist., Taipei City 10048, Taiwan. E-mail address: [email protected] (Y.-Y. Han). 1 At the time of revision and resubmission, F.W. Tsao has left Abbott Nutrition Research & Development.
past decade [1]. Hyperglycemia is associated with complications such as cardiovascular events, recurring infections and slowed wound healing [2e5]. In critically ill inpatients with or without type 2 diabetes (T2D), elevated blood glucose can prolong recovery times and elongate hospital length of stay (LOS), increase medical expenditures, and worsen outcomes [6e9]. A number of studies in the early 2000s demonstrated that tighter control of blood glucose and prevention of hyperglycemia in hospitalized patients improved these outcomes [1,10,11]. However, attempts to prevent hyperglycemia have led to hypoglycemia in intensive care unit (ICU) patients, which can be fatal [11e13]. For those critically ill patients who are also suffering from T2D, blood glucose stability can be even more crucial and its control is more difficult to achieve [14].
http://dx.doi.org/10.1016/j.clnu.2016.09.027 0261-5614/© 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Therefore, much research in the past decade has been dedicated to determine the ideal blood glucose range for hospitalized patients with T2D and to identifying effective approaches to its achievement [10]. Glycemic control is achievable in many cases of T2D with strict control of nutrition [15,16] in addition to oral medications. However, successful integration of proper nutrition into a patient's care in the hospital setting is a challenge. Enteral nutritional (EN) formulas, orally administered nutrition supplementations that can be classified as either standard or disease-specific, have burgeoned in recent decades [17e19]. Standard formulas contain balanced amounts of macro- and micronutrients for sustaining health and are generally administered to patients who have no nutritionrelated medical conditions. Disease-specific formulas (DSF) for diabetes, which typically include a slowly-digestible carbohydrate and a higher proportion of monounsaturated fatty acids than standard formulas, appear to effectively control glucose profiles (lower postprandial glucose, hemoglobin A1c [HbA1c], and improved insulin response) in patients with diabetes; such formulas provide sufficient protein and overall calories to nourish patients in hypermetabolic states [4,19e21]. Several studies have shown that the short-term administration of DSF provides better control of postprandial glucose levels [22,23], and studies of longer DSF use suggest better long-term outcomes for patients with T2D [24,25]. Indeed, results of recent meta-analyses and systematic reviews showed that DSFs control glucose profiles more effectively than standard formulas [4,19]. Despite this evidence, it remains unclear whether the use of DSFs in critically ill, hospitalized patients with T2D would improve clinical or health economic outcomes, and more research is needed before specific clinical practice guidelines can be proposed. To address these outstanding questions, we retrospectively assessed medical records of patients admitted to the ICU at National Taiwan University Hospital between 2009 and 2013, and compared outcomes for those who did or did not use DSF enteral nutrition. The results of this retrospective analysis would support new strategies for treatment of critically ill patients with T2D and for development of new healthcare protocols and policies. 2. Materials and methods 2.1. Study design This study was designed to investigate whether patients with T2D who received DSF experienced better clinical and health economic outcomes compared to those who were administered nonDSF. This study adopted a retrospective analysis capturing clinical and expenditure data covering a 5-year period (2009e2013) from the hospitalization database of a single research center, National Taiwan University Hospital. Patient identification and confidentiality were maintained. 2.2. Ethical statement This study was approved by the local ethics committees and conducted according to Good Clinical Practice guidelines and the recommendations of the Declaration of Helsinki. 2.3. Patient population Hospitalization records were included in the analysis if the patient was 18 years old, had a diagnosis of T2D, was admitted into the ICU, and had received EN formula for at least 5 successive days during their ICU stay. Patients who had received mixed enteral formulas were excluded from the analysis. The enrolled ICU
hospitalizations with T2D diagnoses were stratified into two groups depending on the EN formula administrated d either the DSF group (Glucerna Select®) or the non-DSF group. Comparisons were performed between these two groups. 2.4. Outcomes Participating patients' medical records were examined for determination of EN use parameters including number of days, volume of supplement used, and calories administered. Primary endpoints measured the clinical outcomes including ICU mortality, insulin prescription and hospital length of stay (LOS). Besides, the health economic outcomes such as total health care costs and relevant items (e.g., fees for examinations and nutritional supplements) were also examined. These costs included fees covered by both health insurance and patients' self-payment. Mortality was defined as death occurring in the ICU or during hospitalization. LOS was defined as the number of days the patient remained in the corresponding facility. Health expenditure was determined by summing all costs, including supplies, covered by the National Health Insurance and the patient personally. Glycemic status was determined indirectly by the percentage of patients who had been prescribed insulin. Use of oral hypoglycemic agents (OHA) was also considered. 2.5. Statistical considerations Study data were presented in a descriptive manner. Categorical variables were reported as frequency and proportion. The distribution of the continuous variables was tested via the KolmogoroveSmirnov test; mean ± standard deviation was reported for normally distributed data, while median and range were reported for the non-normally distributed data additionally. Group comparison analyses were performed using the Chi-square test for all categorical variables, while Student t-test or Wilcoxon Rank Sum test was used for all continuous variables as applicable. Effect sizes of variables of interest were also calculated via the Cohen d or the odds ratio as applicable. A two-tailed P-value < 0.05 was considered statistically significant. A sensitivity test was performed to determine whether the initial findings were consistent in a more homogenous subset of enrolled patients. All analyses were performed via SAS 9.4 software. 3. Results 3.1. Patient baseline characteristics Between 2009 and 2013, a total of 406,471 hospitalization records were entered into the database of National Taiwan University Hospital. Of these, there were 61,811 ICU hospitalizations, and 2087 of these patients had a T2D diagnosis. After excluding those patients who received mixed EN formulas, records of 158 patients who received DSF and 794 who received non-DSF were included in the analysis (Fig. 1). Patients were older adults and mostly male. There were no significant gender, age, weight, or body mass index (BMI) differences between the groups (P values > 0.05). With the exception of cardiovascular disease and renal failure, comorbidity patterns were also comparable between groups (Table 1). Primary results including mortality rates, LOS, insulin prescription, and expenditures are shown in Fig. 2. 3.2. ICU mortality A significantly lower mortality rate was reported for the DSF group (5.1% vs. 12.3%, P ¼ 0.0118).
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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glycemic status often requires insulin in addition to dietary control and oral medication. Therefore, a comparison was made for the percentages of patients in the DSF and non-DSF groups that were prescribed insulin therapy. The insulin prescription rate did not differ between the two groups at ICU admission, but there was a significant difference between groups at ICU discharge. Patients in the DSF group had a significantly lower insulin prescription rate (at ICU admission, 27.8% vs. 32.1%, P ¼ 0.2912; at discharge, 29.1% vs. 38.4%, P ¼ 0.0269) (Fig. 2). OHA prescription rates were not statistically conclusive due to the wide variety of prescribed medications. 3.5. Health economic outcomes
Fig. 1. Hospitalization selection flow. Notes: Abbreviations as follows, ICU, intensive care units; T2D, type 2 diabetes; EN, enteral nutritional; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula.
3.3. Hospital length of stay Although the mean LOS in the ICU was almost 2 days shorter for the DSF group compared to the non-DSF group, the difference was found to be statistically non-significant (13.0 days [median: 11 days] vs. 15.1 days [median: 12 days], P ¼ 0.1843). A higher percentage of patients in the DSF group was transferred from the ICU into the follow-on general ward for recovery compared to those in the non-DSF group (71.5% vs. 61.6%, P ¼ 0.018). There was no significant difference in the LOS in the general ward or both wards combined (Table 2).
3.4. Insulin prescription The degree to which patients with T2D were prescribed insulin to help stabilize their blood glucose is suggestive of the state of their diabetic condition and overall health, since poorly-controlled
The ICU expenditures were significantly lower for patients in the DSF group than for those in the non-DSF group by 27.2% (6700 USD [median: 5600 USD] vs. 9200 USD [median: 7230 USD], P < 0.0001). Also, the DSF group had significantly lower expenditure in followon general ward per day (236 USD [median: 190 USD] vs. 265 USD [median: 220 USD], P ¼ 0.0165) as for both ICU and follow-on wards combined (10,600 USD [median: 8780 USD] vs. 12,980 USD [median: 10,190 USD], P ¼ 0.0074). Specifically, the cost of examinations was significantly lower for the DSF group than for the nonDSF group (1190 USD [median: 930 USD] vs. 1530 USD [median: 1200 USD], P ¼ 0.0002). Furthermore, the daily examination cost was also significantly lower in the DSF group (Table 3). The costs of EN administrated with different formulas were also considered in our assessment. The DSF group required significantly fewer days of EN supplementation than the non-DSF group in the ICU (12.6 days [median: 10.5 days] vs. 13.9 days [median: 11 days], P ¼ 0.0471). DSF appeared to have been better tolerated than nonDSF, as the prescription coverage of DSF in the ICU stay was slightly higher than non-DSF (12.6 of 13 days vs. 13.9 of 15.1 days). The total nutritional costs (both ICU stays and follow-on general ward stays combined) were comparable between the groups; however, the nutritional costs incurred in the ICU specifically (160 USD for DSF [median: 100 USD] vs. 200 USD for non-DSF [median: 200 USD]), and even the daily cost incurred in the ICU (13 USD for DSF [median: 10 USD] vs. 15 USD for non-DSF [median: 10 USD]) and both wards combined, were lower for the DSF group.
Table 1 Demographics. Characteristics
Age (years) Gender Male Female Weight BMI Comorbiditiesy Cardiovascular diseases Infection Sepsis Gastrointestinal or liver Tumor Respiratory Neurological Hematological Renal failure Metabolic Trauma Others
DSF
Non-DSF
N ¼ 158
N ¼ 794
mean ± SD median (range)
73.7 ± 9.1 74.0 (49.0e101.0)
74.0 ± 11.3 76.0 (23.0e98.0)
0.2991 (np)
n (%) n (%) mean ± SD median (range) mean ± SD
91 (57.6) 67 (42.4) 59.0 ± 12.6 57.7 (38.5e97.8) 23.0 ± 5.0
451 (56.8) 343 (43.2) 60.9 ± 13.5 59.7 (54.0e105.3) 23.8 ± 4.7
0.8540 (c)
n n n n n n n n n n n n
43 (27.2) 15 (9.5) 0 (0.0) 19 (12) 4 (2.5) 2 (1.3) 13 (8.2) 2 (1.3) 0 (0.0) 12 (7.6) 5 (3.2) 33 (20.9)
151 (19.0) 71 (8.9) 7 (0.9) 60 (7.6) 29 (3.7) 11 (1.4) 48 (6) 33 (4.2) 49 (6.2) 50 (6.3) 15 (1.9) 146 (18.4)
0.0259* 0.9450 0.4998 0.0888 0.6418 >0.9999 0.3980 0.1256 0.0026* 0.6692 0.4733 0.5336
(%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
p-value
0.2021 (np) 0.2449 (p)
Notes: *P-value < 0.05 was considered statistically significant. Method: (p) ¼ T test, (np) ¼ Wilcoxon Rank Sum test, (c) ¼ Chi-square test. Normal Assumption test: KolmogoroveSmirnov test. y: Diagnoses were made between ICU admission and start of EN.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Fig. 2. Summary of primary endpoints including ICU mortality rates (%), LOS (days), insulin prescription (%), and expenditures (USD). Notes: *P-value < 0.05 was considered statistically significant. Method: (c)¼Chi-square test, (np) ¼ Wilcoxon Rank Sum test. Normal Assumption test: KolmogoroveSmirnov test. Abbreviations as follow, ICU, intensive care units; LOS, length of stay; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula. Table 2 Summary of Length of Stay (LOS) for relevant wards during the hospitalization. Variables ICU stay (days) mean ± SD median (range) Follow-on general ward stay (days) mean ± SD median (range) Total hospital stay (days) mean ± SD median (range)
DSF
Non-DSF
N ¼ 158 13.0 ± 6.8 11.0 (5.0e41.0) N ¼ 113 (71.5%)
N ¼ 794 15.1 ± 11.2 12.0 (5.0e182.0) N ¼ 489 (61.6%)
24.8 ± 20.2 19.0 (1.0e106.0) N ¼ 158 30.7 ± 20.8 26.0 (5.0e116.0)
24.2 ± 25.0 15.0 (1.0e231.0) N ¼ 794 29.9 ± 24.6 23.0 (5.0e252.0)
p-value 0.1843 (np) Cohen's d: 0.20 0.0180* (c) Odds Ratio: 1.57 0.1696 (np) Cohen's d: 0.02 0.2517 (np) Cohen's d: 0.03
Notes: *P-value < 0.05 was considered statistically significant. Method: (np) ¼ Wilcoxon Rank Sum test, (c) ¼ Chi-square test. Normal Assumption test: KolmogoroveSmirnov test.
3.6. Sensitivity test In addition to all preliminary findings described above (Fig. 2, Tables 2 and 3), a sensitivity test was performed to confirm the results in a more homogenous subset of the two groups by excluding those patients with cardiovascular disease and renal failure diagnoses. DSF was provided to 115 patients, and non-DSF was given to 641 patients with T2D. The demographics (age, weight, and BMI) remained comparable between the groups. The results of the sensitivity analysis coincided with the preliminary findings: All hospitalization costs were also significantly reduced in the DSF group within this selective patient cohort (29% relative reduction in the ICU, 22% relative reduction in the follow-on general ward, and 24% relative reduction in both wards combined,
compared to the non-DSF group). Finally, significantly improved mortality rates were also observed in the DSF group (5.2% vs. 12.8%, P ¼ 0.0297). 4. Discussion In the 21st century, health economic burdens are rapidly rising in Taiwan and elsewhere in the world [26,27]. Precipitating a variety of complications throughout the body, T2D is associated with a heightened risk of morbidity and mortality. The blood glucose variations caused by T2D are especially threatening to a critically ill patient in the ICU. Insulin administration is powerful to control hyperglycemia, but may render the patients at risk of hypoglycemia. Besides, the relevant monitoring can be labor-intensive.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Table 3 Summary of hospitalization expenditures. Variables (USD)
Expenditure in ICU Daily expenditure in ICU Expenditure in follow-on general ward Daily expenditure in follow-on general ward Expenditure in both wards combined Daily expenditure in both wards combined Specific cost Examination Daily examination
DSF
Non-DSF
N ¼ 158
N ¼ 794
p-value
mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range)
6700 ± 4220 5600 (1930e2953) 522 ± 210 480 (270e1700) 5450 ± 5260 3720 (350e26,770) 236 ± 170 190 (90e1470) 10,600 ± 6590 8780 (1980e42,590) 395 ± 180 350 (150e1310)
9200 ± 7560 7230 (1810e9850) 637 ± 350 550 (260e4880) 6130 ± 6940 3650 (20e56,200) 265 ± 170 220 (20e2420) 12,980 ± 9450 10,190 (2070e98,500) 510 ± 300 440 (150e3140)
<0.0001* (np) Cohen's d: 0.35 <0.0001* (np) Cohen's d: 0.34 0.9216 (np) Cohen's d: 0.10 0.0165* (np) Cohen's d: 0.16 0.0074* (np) Cohen's d: 0.26 <0.0001* (np) Cohen's d: 0.41
mean ± SD median (range) mean ± SD median (range)
1190 ± 900 930 (130e7410) 44 ± 30 39 (9e148)
1530 ± 1170 1200 (80e9090) 64 ± 50 51 (7e410)
0.0002* (np) Cohen's d: 0.31 <0.0001* (np) Cohen's d: 0.44
Notes: *P-value < 0.05 was considered statistically significant. Method: (np) ¼ Wilcoxon Rank Sum test. Normal Assumption test: KolmogoroveSmirnov test.
Treatment approaches utilizing appropriate nutritional strategy provide a fundamental and safer way to prevent hyperglycemia without causing hypoglycemia; therefore, it may benefit patient's outcomes and overall healthcare economics. Our evaluation of reallife data revealed a compelling correlation between the use of DSF EN supplementation and the improvement on clinical and economic outcomes for ICU patients with T2D. The most striking finding was the highly significant decrease in mortality for ICU patients who had been administered with DSF instead of non-DSF. As previous studies have demonstrated the strong association between lower mortality rates and controlled glycemic level [6,11], the improvement of mortality rate shown in our study may be attributed to the clinical benefits of DSF in glycemic control. Given the negative impact that prolonged hospitalizations could have on patients' safety and quality of life [28], a reduction of almost 2 days noted in the DSF group merits attention, despite the statistically non-significant difference found in ICU LOS. Even though our study did not assess blood glucose levels or glycemic variability, insulin prescription records might be able to reflect blood glucose status and glycemic variation in patients with T2D. Such association has been shown in other studies [12]. The findings demonstrated significantly lower insulin prescription rate at ICU discharge for the DSF group compared to the non-DSF group, while the insulin prescription rates at ICU admission were comparable between groups. Thus DSF offered superior glycemic control in comparison to other nutritional formulations not designed specifically for T2D patients. As a result, the favorable glycemic control offered by DSF led to lower increments in insulin prescription rate at ICU discharge, as compared with non-DSF. Higher coverage rate of EN days during the entire ICU stay in DSF group was shown in our study. The results suggested that patients receiving DSF showed higher EN tolerance. In addition to basic nutrition provision, EN specifically helps maintain gut integrity, modulate stress and the systemic immune response, and attenuate disease severity [29]. All these result in improved clinical outcomes in the setting of critical illness. Another crucial benefit that DSF brings to the critically ill patients is its high protein content. The stress in critical illness triggers hypercatabolism, which leads to profound loss of lean body mass. The importance of protein supplement under such condition should be emphasized. DSF fulfills the need for critical care nutrition high protein supplement of at least 1.2 g/kg/day, which is consistently recommended by guidelines. Therefore, DSF is probably a preferred choice for critically ill
patients with T2D due to its benefits in glycemic control and high protein content [29,30]. Aside from improving outcomes, DSF also demonstrated overall improvement of healthcare economic outcomes. Patients in the DSF group had significantly lower expenditures (i.e., 27.2% less) than those in the non-DSF group. Related costs including those incurred in ICU, examinations, and nutrition support were also lower in patients receiving DSF. These findings are of particular interest as treatment strategies that reduce the overall cost of care are important to the sustainability of health care systems worldwide. This study has several limitations. First, our study utilized retrospective data, and thus inherited the limitations associated with retrospective study designs. Specifically, given the nature of the information captured in medical claims, it was not possible to determine with certainty whether use of non-DSF or DSF was directed by the preferences of physician, nursing or pharmacy staff, patients' tolerance to EN, etc. Although prescription tendency may lead to study bias, the large number of medical records over a long observation period included in the study could minimize the potential prescription bias among non-DSF and DSF. Second, variables of interest including serum glucose level over time or OHA prescription patterns were not captured due to limited data availability. Therefore, we used insulin prescription to infer the efficacy on glycemic control at the time of ICU discharge. Future research efforts in this area may focus on employing prospective study designs. Given the need of controlling T2D progression and healthcare expenditure, our results suggested that proper nutritional support, tailored to nutrition-sensitive conditions such as ICU patients with T2D, can have a positive impact on both clinical and economic outcomes. The ICU mortality, patients' need for insulin prescriptions, and healthcare costs during ICU stay, follow-on general ward stay, or both stays combined were all significantly reduced in the DSF group. Therefore, these findings highlight the importance of adapting DSF as the EN formula for ICU patients with T2D. They also underscore the need for further research to generate supporting evidence regarding glycemic control with growing populations in need of diabetic management globally.
Disclosure statement This study is sponsored by Abbott Laboratories, USA.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Funding sources Financial support for the publication was provided by Abbott Nutrition. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[10]
[11] [12]
Statement of authorship Authorship contributions are listed below: Conception and design of study: Y.Y. Han, F.W. Tsao. Acquisition of data: Y.Y. Han, F.W. Tsao. Analysis and/or interpretation of data: Y.Y. Han, S.R. Lai, Michael Y.H. Wang, J.S. Partridge, S. Sulo, F.W. Tsao, R.A. Hegazi. Drafting, revising and approval of the manuscript including the important intellectual content: Y.Y. Han, J.S. Partridge, S. Sulo, F.W. Tsao, R.A. Hegazi. Conflict of interest statement YY, Han and SR, Lai were involved in the conduct of the study as investigators. Other authors are employees of Abbott Nutrition, and as such copyright is owned by Abbott Nutrition. The information presented in this article is based on clinical evidence and is not affected by any financial relationship. No additional known conflicts of interests exist and no honoraria were offered or received for co-author participation in the writing of the present report.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
Acknowledgements The authors acknowledge statistical assistance provided by the Taiwan Clinical Trial Statistical Center, Training Center, and Pharmacogenomics Laboratory, which is founded by National Research Program for Biopharmaceuticals (NRPB) at the Ministry of Science and Technology of Taiwan; MOST 104-2325-B-002-032), and the Department of Medical Research in National Taiwan University Hospital. The authors also acknowledge the writing suggestions provided by Cecilia Hofmann and her associates. References [1] Davidson P, Kwiatkowski CA, Wien M. Management of hyperglycemia and enteral nutrition in the hospitalized patient. Nutr Clin Pract Off Publ Am Soc Parenter Enteral Nutr 2015 Oct;30(5):652e9. PubMed PMID: 26084507. [2] Berlanga-Acosta J, Schultz GS, Lopez-Mola E, Guillen-Nieto G, GarciaSiverio M, Herrera-Martinez L. Glucose toxic effects on granulation tissue productive cells: the diabetics' impaired healing. BioMed Res Int 2013;2013: 256043. PubMed PMID: 23484099. PMCID: 3591209. [3] Ceriello A, Davidson J, Hanefeld M, Leiter L, Monnier L, Owens D, et al., International Prandial Glucose Regulation Study Group. Postprandial hyperglycaemia and cardiovascular complications of diabetes: an update. Nutr Metab Cardiovasc Dis 2006 Oct;16(7):453e6. PubMed PMID: 16934443. [4] Ojo O, Brooke J. Evaluation of the role of enteral nutrition in managing patients with diabetes: a systematic review. Nutrients 2014 Nov;6(11):5142e52. PubMed PMID: 25412151. PMCID: PMC4245584. [5] Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003 Feb;31(2):359e66. PubMed PMID: 12576937. [6] Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med 2008 Nov;36(11):3008e13. PubMed PMID: 18824908. [7] Newton CA, Young S. Financial implications of glycemic control: results of an inpatient diabetes management program. Endocr Pract 2006 JuleAug;12(3): 43e8. PubMed PMID: 16905516. [8] Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2004 Oct 11;164(18):2005e11. PubMed PMID: 15477435. [9] Qaseem A, Chou R, Humphrey LL, Shekelle P, Clinical Guidelines Committee of the American College of P. Inpatient glycemic control: best practice advice
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Ong KY, Kwan YH, Tay HC, Tan DS, Chang JY. Prevalence of dysglycaemic events among inpatients with diabetes mellitus: a Singaporean perspective. Singap Med J 2015 Jul;56(7):393e400. PubMed PMID: 26243976. PMCID: PMC4520918. Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care 2014 Jan;37(1):S120e43. PubMed PMID: 24357208. Dyson PA, Kelly T, Deakin T, Duncan A, Frost G, Harrison Z, et al., Diabetes UK Nutrition Working Group. Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes. Diabet Med 2011 Nov;28(11):1282e8. PubMed PMID: 21699560. Cangelosi MJ, Auerbach HR, Cohen JT. A clinical and economic evaluation of enteral nutrition. Curr Med Res Opin 2011 Feb;27(2):413e22. PubMed PMID: 21192760. Brown B, Roehl K, Betz M. Enteral nutrition formula selection: current evidence and implications for practice. Nutr Clin Pract Off Publ Am Soc Parenter Enteral Nutr 2015 Feb;30(1):72e85. PubMed PMID: 25516537. Elia M, Ceriello A, Laube H, Sinclair AJ, Engfer M, Stratton RJ. Enteral nutritional support and use of diabetes-specific formulas for patients with diabetes: a systematic review and meta-analysis. Diabetes Care 2005 Sep;28(9): 2267e79. PubMed PMID: 16123506. Glucerna Select, Abbott Laboratories, http://glucerna.com/. Breuillard C, Darquy S, Curis E, Neveux N, Garnier JP, Cynober L, et al. Effects of a diabetes-specific enteral nutrition on nutritional and immune status of diabetic, obese, and endotoxemic rats: interest of a graded arginine supply. Crit Care Med 2012 Aug;40(8):2423e30. PubMed PMID: 22622404. Ceriello A, Lansink M, Rouws CH, van Laere KM, Frost GS. Administration of a new diabetes-specific enteral formula results in an improved 24h glucose profile in type 2 diabetic patients. Diabetes Res Clin Pract 2009 Jun;84(3): 259e66. PubMed PMID: 19307037. Hofman Z, Lansink M, Rouws C, van Drunen J, Kuipers H. Diabetes specific tube feed results in improved glycaemic and triglyceridaemic control during 6 h continuous feeding in diabetes patients. e-SPEN Eur e-Journal Clin Nutr Metab 2007;2(2):44e50. Leon-Sanz M, Garcia-Luna PP, Sanz-Paris A, Gomez-Candela C, Casimiro C, Chamorro J, et al., Abbott SPAI-97-004 Study Cooperative Group. Glycemic and lipid control in hospitalized type 2 diabetic patients: evaluation of 2 enteral nutrition formulas (low carbohydrate-high monounsaturated fat vs high carbohydrate). J Parenter Enteral Nutr 2005 JaneFeb;29(1):21e9. PubMed PMID: 15715270. Pohl M, Mayr P, Mertl-Roetzer M, Lauster F, Lerch M, Eriksen J, et al. Glycaemic control in type II diabetic tube-fed patients with a new enteral formula low in carbohydrates and high in monounsaturated fatty acids: a randomised controlled trial. Eur J Clin Nutr 2005 Nov;59(11):1221e32. PubMed PMID: 16077745. International Diabetes Federation Atlas. 6th ed. 2013. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, et al., Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011 Jul 2;378(9785):31e40. PubMed PMID: 21705069. Teno JM, Fisher E, Hamel MB, Wu AW, Murphy DJ, Wenger NS, et al. Decisionmaking and outcomes of prolonged ICU stays in seriously ill patients. J Am Geriatr Soc 2000 May;48(5 Suppl.):S70e4. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al., Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of critical care medicine (SCCM) and American Society for parenteral and enteral nutrition (A.S.P.E.N.). J Parenter Enteral Nutr 2016 Feb;40(2):159e211. doi: 10.1177. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr 2009;28: 387e400.
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Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Original article
Q4 Q3
The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes Yin-Yi Han a, *, Sheng-Ru Lai b, Jamie S. Partridge c, Michael Y. Wang d, Suela Sulo e, Fang-Wei Tsao d, 1, Refaat A. Hegazi c a
Trauma Department, National Taiwan University Hospital, Taiwan Department of Dietetics, National Taiwan University Hospital, Taiwan Abbott Nutrition Research & Development, Columbus, OH, USA d Abbott Nutrition Research & Development, Taiwan e Abbott Nutrition Research & Development, Chicago, IL, USA b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 January 2016 Accepted 27 September 2016
Background & aims: Patients admitted to intensive care units (ICUs) often need enteral nutrition (EN) support. For patients with type 2 diabetes (T2D), standard EN formulas may not provide ideal nutrients. The purpose was to investigate whether use of a diabetes-specific formula (DSF) could provide clinical and health economic benefits (compared to standard formulas) in critically ill patients with T2D. Methods: This study was a retrospective analysis of medical records and expenditure data covering a 5year period (2009e2013) from the hospitalization database of the National Taiwan University Hospital. Records of ICU patients who had T2D and were receiving enteral feeding with either the DSF or nondiabetes-specific formula (non-DSF) for at least 5 days were included in the analysis. Mortality, ICU length of stay (LOS), diabetes-related medications, and total costs of care (including all costs covered by the National Health Insurance and private expenses) were considered as the primary outcomes. Results: A total of 158 patient records were analyzed in the DSF group and 794 in the non-DSF group. The baseline demographics including age, gender, weight, body mass index (BMI), and comorbidity patterns were mostly comparable between the groups. Compared to those receiving non-DSF, patients with T2D receiving DSF were found to have significantly decreased mortality (5.1% vs. 12.3%, P ¼ 0.0118) and reduced need for insulin prescription (29.1% vs. 38.4%, P ¼ 0.0269). ICU LOS was shorter for DSF patients, but no statistical difference was found (13.0 days vs. 15.1 days, P ¼ 0.1843). However, significantly lower total ICU costs were reported for DSF patients (6700 USD vs. 9200 USD, P < 0.0001). Conclusions: The use of DSF in ICU patients with T2D is correlated with significant reduction in mortality and improved health economic outcomes. © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Diabetes Critical illness Enteral nutrition Diabetes-specific formulas Health economics
1. Introduction The importance of glycemic control to inpatient recovery has garnered increasing attention from healthcare professionals in the
Abbreviations: ICU, intensive care unit; EN, enteral nutrition; T2D, type 2 diabetes; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula; LOS, length of stay; BMI, body mass index; OHA, oral hypoglycemic agent. * Corresponding author. Trauma Department, National Taiwan University Hospital, No. 7, Chung Shan S Rd., Zhongzheng Dist., Taipei City 10048, Taiwan. E-mail address: [email protected] (Y.-Y. Han). 1 At the time of revision and resubmission, F.W. Tsao has left Abbott Nutrition Research & Development.
past decade [1]. Hyperglycemia is associated with complications such as cardiovascular events, recurring infections and slowed wound healing [2e5]. In critically ill inpatients with or without type 2 diabetes (T2D), elevated blood glucose can prolong recovery times and elongate hospital length of stay (LOS), increase medical expenditures, and worsen outcomes [6e9]. A number of studies in the early 2000s demonstrated that tighter control of blood glucose and prevention of hyperglycemia in hospitalized patients improved these outcomes [1,10,11]. However, attempts to prevent hyperglycemia have led to hypoglycemia in intensive care unit (ICU) patients, which can be fatal [11e13]. For those critically ill patients who are also suffering from T2D, blood glucose stability can be even more crucial and its control is more difficult to achieve [14].
http://dx.doi.org/10.1016/j.clnu.2016.09.027 0261-5614/© 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Therefore, much research in the past decade has been dedicated to determine the ideal blood glucose range for hospitalized patients with T2D and to identifying effective approaches to its achievement [10]. Glycemic control is achievable in many cases of T2D with strict control of nutrition [15,16] in addition to oral medications. However, successful integration of proper nutrition into a patient's care in the hospital setting is a challenge. Enteral nutritional (EN) formulas, orally administered nutrition supplementations that can be classified as either standard or disease-specific, have burgeoned in recent decades [17e19]. Standard formulas contain balanced amounts of macro- and micronutrients for sustaining health and are generally administered to patients who have no nutritionrelated medical conditions. Disease-specific formulas (DSF) for diabetes, which typically include a slowly-digestible carbohydrate and a higher proportion of monounsaturated fatty acids than standard formulas, appear to effectively control glucose profiles (lower postprandial glucose, hemoglobin A1c [HbA1c], and improved insulin response) in patients with diabetes; such formulas provide sufficient protein and overall calories to nourish patients in hypermetabolic states [4,19e21]. Several studies have shown that the short-term administration of DSF provides better control of postprandial glucose levels [22,23], and studies of longer DSF use suggest better long-term outcomes for patients with T2D [24,25]. Indeed, results of recent meta-analyses and systematic reviews showed that DSFs control glucose profiles more effectively than standard formulas [4,19]. Despite this evidence, it remains unclear whether the use of DSFs in critically ill, hospitalized patients with T2D would improve clinical or health economic outcomes, and more research is needed before specific clinical practice guidelines can be proposed. To address these outstanding questions, we retrospectively assessed medical records of patients admitted to the ICU at National Taiwan University Hospital between 2009 and 2013, and compared outcomes for those who did or did not use DSF enteral nutrition. The results of this retrospective analysis would support new strategies for treatment of critically ill patients with T2D and for development of new healthcare protocols and policies. 2. Materials and methods 2.1. Study design This study was designed to investigate whether patients with T2D who received DSF experienced better clinical and health economic outcomes compared to those who were administered nonDSF. This study adopted a retrospective analysis capturing clinical and expenditure data covering a 5-year period (2009e2013) from the hospitalization database of a single research center, National Taiwan University Hospital. Patient identification and confidentiality were maintained. 2.2. Ethical statement This study was approved by the local ethics committees and conducted according to Good Clinical Practice guidelines and the recommendations of the Declaration of Helsinki. 2.3. Patient population Hospitalization records were included in the analysis if the patient was 18 years old, had a diagnosis of T2D, was admitted into the ICU, and had received EN formula for at least 5 successive days during their ICU stay. Patients who had received mixed enteral formulas were excluded from the analysis. The enrolled ICU
hospitalizations with T2D diagnoses were stratified into two groups depending on the EN formula administrated d either the DSF group (Glucerna Select®) or the non-DSF group. Comparisons were performed between these two groups. 2.4. Outcomes Participating patients' medical records were examined for determination of EN use parameters including number of days, volume of supplement used, and calories administered. Primary endpoints measured the clinical outcomes including ICU mortality, insulin prescription and hospital length of stay (LOS). Besides, the health economic outcomes such as total health care costs and relevant items (e.g., fees for examinations and nutritional supplements) were also examined. These costs included fees covered by both health insurance and patients' self-payment. Mortality was defined as death occurring in the ICU or during hospitalization. LOS was defined as the number of days the patient remained in the corresponding facility. Health expenditure was determined by summing all costs, including supplies, covered by the National Health Insurance and the patient personally. Glycemic status was determined indirectly by the percentage of patients who had been prescribed insulin. Use of oral hypoglycemic agents (OHA) was also considered. 2.5. Statistical considerations Study data were presented in a descriptive manner. Categorical variables were reported as frequency and proportion. The distribution of the continuous variables was tested via the KolmogoroveSmirnov test; mean ± standard deviation was reported for normally distributed data, while median and range were reported for the non-normally distributed data additionally. Group comparison analyses were performed using the Chi-square test for all categorical variables, while Student t-test or Wilcoxon Rank Sum test was used for all continuous variables as applicable. Effect sizes of variables of interest were also calculated via the Cohen d or the odds ratio as applicable. A two-tailed P-value < 0.05 was considered statistically significant. A sensitivity test was performed to determine whether the initial findings were consistent in a more homogenous subset of enrolled patients. All analyses were performed via SAS 9.4 software. 3. Results 3.1. Patient baseline characteristics Between 2009 and 2013, a total of 406,471 hospitalization records were entered into the database of National Taiwan University Hospital. Of these, there were 61,811 ICU hospitalizations, and 2087 of these patients had a T2D diagnosis. After excluding those patients who received mixed EN formulas, records of 158 patients who received DSF and 794 who received non-DSF were included in the analysis (Fig. 1). Patients were older adults and mostly male. There were no significant gender, age, weight, or body mass index (BMI) differences between the groups (P values > 0.05). With the exception of cardiovascular disease and renal failure, comorbidity patterns were also comparable between groups (Table 1). Primary results including mortality rates, LOS, insulin prescription, and expenditures are shown in Fig. 2. 3.2. ICU mortality A significantly lower mortality rate was reported for the DSF group (5.1% vs. 12.3%, P ¼ 0.0118).
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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glycemic status often requires insulin in addition to dietary control and oral medication. Therefore, a comparison was made for the percentages of patients in the DSF and non-DSF groups that were prescribed insulin therapy. The insulin prescription rate did not differ between the two groups at ICU admission, but there was a significant difference between groups at ICU discharge. Patients in the DSF group had a significantly lower insulin prescription rate (at ICU admission, 27.8% vs. 32.1%, P ¼ 0.2912; at discharge, 29.1% vs. 38.4%, P ¼ 0.0269) (Fig. 2). OHA prescription rates were not statistically conclusive due to the wide variety of prescribed medications. 3.5. Health economic outcomes
Fig. 1. Hospitalization selection flow. Notes: Abbreviations as follows, ICU, intensive care units; T2D, type 2 diabetes; EN, enteral nutritional; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula.
3.3. Hospital length of stay Although the mean LOS in the ICU was almost 2 days shorter for the DSF group compared to the non-DSF group, the difference was found to be statistically non-significant (13.0 days [median: 11 days] vs. 15.1 days [median: 12 days], P ¼ 0.1843). A higher percentage of patients in the DSF group was transferred from the ICU into the follow-on general ward for recovery compared to those in the non-DSF group (71.5% vs. 61.6%, P ¼ 0.018). There was no significant difference in the LOS in the general ward or both wards combined (Table 2).
3.4. Insulin prescription The degree to which patients with T2D were prescribed insulin to help stabilize their blood glucose is suggestive of the state of their diabetic condition and overall health, since poorly-controlled
The ICU expenditures were significantly lower for patients in the DSF group than for those in the non-DSF group by 27.2% (6700 USD [median: 5600 USD] vs. 9200 USD [median: 7230 USD], P < 0.0001). Also, the DSF group had significantly lower expenditure in followon general ward per day (236 USD [median: 190 USD] vs. 265 USD [median: 220 USD], P ¼ 0.0165) as for both ICU and follow-on wards combined (10,600 USD [median: 8780 USD] vs. 12,980 USD [median: 10,190 USD], P ¼ 0.0074). Specifically, the cost of examinations was significantly lower for the DSF group than for the nonDSF group (1190 USD [median: 930 USD] vs. 1530 USD [median: 1200 USD], P ¼ 0.0002). Furthermore, the daily examination cost was also significantly lower in the DSF group (Table 3). The costs of EN administrated with different formulas were also considered in our assessment. The DSF group required significantly fewer days of EN supplementation than the non-DSF group in the ICU (12.6 days [median: 10.5 days] vs. 13.9 days [median: 11 days], P ¼ 0.0471). DSF appeared to have been better tolerated than nonDSF, as the prescription coverage of DSF in the ICU stay was slightly higher than non-DSF (12.6 of 13 days vs. 13.9 of 15.1 days). The total nutritional costs (both ICU stays and follow-on general ward stays combined) were comparable between the groups; however, the nutritional costs incurred in the ICU specifically (160 USD for DSF [median: 100 USD] vs. 200 USD for non-DSF [median: 200 USD]), and even the daily cost incurred in the ICU (13 USD for DSF [median: 10 USD] vs. 15 USD for non-DSF [median: 10 USD]) and both wards combined, were lower for the DSF group.
Table 1 Demographics. Characteristics
Age (years) Gender Male Female Weight BMI Comorbiditiesy Cardiovascular diseases Infection Sepsis Gastrointestinal or liver Tumor Respiratory Neurological Hematological Renal failure Metabolic Trauma Others
DSF
Non-DSF
N ¼ 158
N ¼ 794
mean ± SD median (range)
73.7 ± 9.1 74.0 (49.0e101.0)
74.0 ± 11.3 76.0 (23.0e98.0)
0.2991 (np)
n (%) n (%) mean ± SD median (range) mean ± SD
91 (57.6) 67 (42.4) 59.0 ± 12.6 57.7 (38.5e97.8) 23.0 ± 5.0
451 (56.8) 343 (43.2) 60.9 ± 13.5 59.7 (54.0e105.3) 23.8 ± 4.7
0.8540 (c)
n n n n n n n n n n n n
43 (27.2) 15 (9.5) 0 (0.0) 19 (12) 4 (2.5) 2 (1.3) 13 (8.2) 2 (1.3) 0 (0.0) 12 (7.6) 5 (3.2) 33 (20.9)
151 (19.0) 71 (8.9) 7 (0.9) 60 (7.6) 29 (3.7) 11 (1.4) 48 (6) 33 (4.2) 49 (6.2) 50 (6.3) 15 (1.9) 146 (18.4)
0.0259* 0.9450 0.4998 0.0888 0.6418 >0.9999 0.3980 0.1256 0.0026* 0.6692 0.4733 0.5336
(%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
p-value
0.2021 (np) 0.2449 (p)
Notes: *P-value < 0.05 was considered statistically significant. Method: (p) ¼ T test, (np) ¼ Wilcoxon Rank Sum test, (c) ¼ Chi-square test. Normal Assumption test: KolmogoroveSmirnov test. y: Diagnoses were made between ICU admission and start of EN.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Fig. 2. Summary of primary endpoints including ICU mortality rates (%), LOS (days), insulin prescription (%), and expenditures (USD). Notes: *P-value < 0.05 was considered statistically significant. Method: (c)¼Chi-square test, (np) ¼ Wilcoxon Rank Sum test. Normal Assumption test: KolmogoroveSmirnov test. Abbreviations as follow, ICU, intensive care units; LOS, length of stay; DSF, diabetes-specific formula; Non-DSF, non-diabetes-specific formula. Table 2 Summary of Length of Stay (LOS) for relevant wards during the hospitalization. Variables ICU stay (days) mean ± SD median (range) Follow-on general ward stay (days) mean ± SD median (range) Total hospital stay (days) mean ± SD median (range)
DSF
Non-DSF
N ¼ 158 13.0 ± 6.8 11.0 (5.0e41.0) N ¼ 113 (71.5%)
N ¼ 794 15.1 ± 11.2 12.0 (5.0e182.0) N ¼ 489 (61.6%)
24.8 ± 20.2 19.0 (1.0e106.0) N ¼ 158 30.7 ± 20.8 26.0 (5.0e116.0)
24.2 ± 25.0 15.0 (1.0e231.0) N ¼ 794 29.9 ± 24.6 23.0 (5.0e252.0)
p-value 0.1843 (np) Cohen's d: 0.20 0.0180* (c) Odds Ratio: 1.57 0.1696 (np) Cohen's d: 0.02 0.2517 (np) Cohen's d: 0.03
Notes: *P-value < 0.05 was considered statistically significant. Method: (np) ¼ Wilcoxon Rank Sum test, (c) ¼ Chi-square test. Normal Assumption test: KolmogoroveSmirnov test.
3.6. Sensitivity test In addition to all preliminary findings described above (Fig. 2, Tables 2 and 3), a sensitivity test was performed to confirm the results in a more homogenous subset of the two groups by excluding those patients with cardiovascular disease and renal failure diagnoses. DSF was provided to 115 patients, and non-DSF was given to 641 patients with T2D. The demographics (age, weight, and BMI) remained comparable between the groups. The results of the sensitivity analysis coincided with the preliminary findings: All hospitalization costs were also significantly reduced in the DSF group within this selective patient cohort (29% relative reduction in the ICU, 22% relative reduction in the follow-on general ward, and 24% relative reduction in both wards combined,
compared to the non-DSF group). Finally, significantly improved mortality rates were also observed in the DSF group (5.2% vs. 12.8%, P ¼ 0.0297). 4. Discussion In the 21st century, health economic burdens are rapidly rising in Taiwan and elsewhere in the world [26,27]. Precipitating a variety of complications throughout the body, T2D is associated with a heightened risk of morbidity and mortality. The blood glucose variations caused by T2D are especially threatening to a critically ill patient in the ICU. Insulin administration is powerful to control hyperglycemia, but may render the patients at risk of hypoglycemia. Besides, the relevant monitoring can be labor-intensive.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Table 3 Summary of hospitalization expenditures. Variables (USD)
Expenditure in ICU Daily expenditure in ICU Expenditure in follow-on general ward Daily expenditure in follow-on general ward Expenditure in both wards combined Daily expenditure in both wards combined Specific cost Examination Daily examination
DSF
Non-DSF
N ¼ 158
N ¼ 794
p-value
mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range) mean ± SD median (range)
6700 ± 4220 5600 (1930e2953) 522 ± 210 480 (270e1700) 5450 ± 5260 3720 (350e26,770) 236 ± 170 190 (90e1470) 10,600 ± 6590 8780 (1980e42,590) 395 ± 180 350 (150e1310)
9200 ± 7560 7230 (1810e9850) 637 ± 350 550 (260e4880) 6130 ± 6940 3650 (20e56,200) 265 ± 170 220 (20e2420) 12,980 ± 9450 10,190 (2070e98,500) 510 ± 300 440 (150e3140)
<0.0001* (np) Cohen's d: 0.35 <0.0001* (np) Cohen's d: 0.34 0.9216 (np) Cohen's d: 0.10 0.0165* (np) Cohen's d: 0.16 0.0074* (np) Cohen's d: 0.26 <0.0001* (np) Cohen's d: 0.41
mean ± SD median (range) mean ± SD median (range)
1190 ± 900 930 (130e7410) 44 ± 30 39 (9e148)
1530 ± 1170 1200 (80e9090) 64 ± 50 51 (7e410)
0.0002* (np) Cohen's d: 0.31 <0.0001* (np) Cohen's d: 0.44
Notes: *P-value < 0.05 was considered statistically significant. Method: (np) ¼ Wilcoxon Rank Sum test. Normal Assumption test: KolmogoroveSmirnov test.
Treatment approaches utilizing appropriate nutritional strategy provide a fundamental and safer way to prevent hyperglycemia without causing hypoglycemia; therefore, it may benefit patient's outcomes and overall healthcare economics. Our evaluation of reallife data revealed a compelling correlation between the use of DSF EN supplementation and the improvement on clinical and economic outcomes for ICU patients with T2D. The most striking finding was the highly significant decrease in mortality for ICU patients who had been administered with DSF instead of non-DSF. As previous studies have demonstrated the strong association between lower mortality rates and controlled glycemic level [6,11], the improvement of mortality rate shown in our study may be attributed to the clinical benefits of DSF in glycemic control. Given the negative impact that prolonged hospitalizations could have on patients' safety and quality of life [28], a reduction of almost 2 days noted in the DSF group merits attention, despite the statistically non-significant difference found in ICU LOS. Even though our study did not assess blood glucose levels or glycemic variability, insulin prescription records might be able to reflect blood glucose status and glycemic variation in patients with T2D. Such association has been shown in other studies [12]. The findings demonstrated significantly lower insulin prescription rate at ICU discharge for the DSF group compared to the non-DSF group, while the insulin prescription rates at ICU admission were comparable between groups. Thus DSF offered superior glycemic control in comparison to other nutritional formulations not designed specifically for T2D patients. As a result, the favorable glycemic control offered by DSF led to lower increments in insulin prescription rate at ICU discharge, as compared with non-DSF. Higher coverage rate of EN days during the entire ICU stay in DSF group was shown in our study. The results suggested that patients receiving DSF showed higher EN tolerance. In addition to basic nutrition provision, EN specifically helps maintain gut integrity, modulate stress and the systemic immune response, and attenuate disease severity [29]. All these result in improved clinical outcomes in the setting of critical illness. Another crucial benefit that DSF brings to the critically ill patients is its high protein content. The stress in critical illness triggers hypercatabolism, which leads to profound loss of lean body mass. The importance of protein supplement under such condition should be emphasized. DSF fulfills the need for critical care nutrition high protein supplement of at least 1.2 g/kg/day, which is consistently recommended by guidelines. Therefore, DSF is probably a preferred choice for critically ill
patients with T2D due to its benefits in glycemic control and high protein content [29,30]. Aside from improving outcomes, DSF also demonstrated overall improvement of healthcare economic outcomes. Patients in the DSF group had significantly lower expenditures (i.e., 27.2% less) than those in the non-DSF group. Related costs including those incurred in ICU, examinations, and nutrition support were also lower in patients receiving DSF. These findings are of particular interest as treatment strategies that reduce the overall cost of care are important to the sustainability of health care systems worldwide. This study has several limitations. First, our study utilized retrospective data, and thus inherited the limitations associated with retrospective study designs. Specifically, given the nature of the information captured in medical claims, it was not possible to determine with certainty whether use of non-DSF or DSF was directed by the preferences of physician, nursing or pharmacy staff, patients' tolerance to EN, etc. Although prescription tendency may lead to study bias, the large number of medical records over a long observation period included in the study could minimize the potential prescription bias among non-DSF and DSF. Second, variables of interest including serum glucose level over time or OHA prescription patterns were not captured due to limited data availability. Therefore, we used insulin prescription to infer the efficacy on glycemic control at the time of ICU discharge. Future research efforts in this area may focus on employing prospective study designs. Given the need of controlling T2D progression and healthcare expenditure, our results suggested that proper nutritional support, tailored to nutrition-sensitive conditions such as ICU patients with T2D, can have a positive impact on both clinical and economic outcomes. The ICU mortality, patients' need for insulin prescriptions, and healthcare costs during ICU stay, follow-on general ward stay, or both stays combined were all significantly reduced in the DSF group. Therefore, these findings highlight the importance of adapting DSF as the EN formula for ICU patients with T2D. They also underscore the need for further research to generate supporting evidence regarding glycemic control with growing populations in need of diabetic management globally.
Disclosure statement This study is sponsored by Abbott Laboratories, USA.
Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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Funding sources Financial support for the publication was provided by Abbott Nutrition. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Statement of authorship Authorship contributions are listed below: Conception and design of study: Y.Y. Han, F.W. Tsao. Acquisition of data: Y.Y. Han, F.W. Tsao. Analysis and/or interpretation of data: Y.Y. Han, S.R. Lai, Michael Y.H. Wang, J.S. Partridge, S. Sulo, F.W. Tsao, R.A. Hegazi. Drafting, revising and approval of the manuscript including the important intellectual content: Y.Y. Han, J.S. Partridge, S. Sulo, F.W. Tsao, R.A. Hegazi. Conflict of interest statement YY, Han and SR, Lai were involved in the conduct of the study as investigators. Other authors are employees of Abbott Nutrition, and as such copyright is owned by Abbott Nutrition. The information presented in this article is based on clinical evidence and is not affected by any financial relationship. No additional known conflicts of interests exist and no honoraria were offered or received for co-author participation in the writing of the present report.
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Please cite this article in press as: Han Y-Y, et al., The clinical and economic impact of the use of diabetes-specific enteral formula on ICU patients with type 2 diabetes, Clinical Nutrition (2016), http://dx.doi.org/10.1016/j.clnu.2016.09.027
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