Introduction: Health state utility values (HSUV) for Type 2 diabetes mellitus (T2DM) complications are useful in economic evaluations to determine cost effectiveness of an intervention. However, there is a lack of reference ranges for different severity and stages of individual complications. This study aimed to provide an overview of HSUV decrement ranges for common T2DM complications focusing on different severity and stages of complications. Method: A systematic search was conducted in MEDLINE, SCOPUS, WEB OF SCIENCE. (Jan 2000 to April 2022). Included studies for HSUV estimates were from outpatient setting, regardless of treatment types, complication stages, regions and HRQoL instruments. Health Related Quality of Life (HRQoL) outcomes was to be presented as HSUV decrement values, adjusted according to social demographics and comorbidities. Adjusted HSUV decrements were extracted and compiled according to individual complications. After which, subsequently grouped into mild or severe category for comparison. Results: Searches identified 35 studies. The size of the study population ranged from 160 to 14,826. The HSUV decrement range was widest for cerebrovascular disease (stroke): -0.0060 to -0.0780 for mild stroke and -0.035 to -0.266 for severe stroke; retinopathy: mild (-0.005 to -0.0862), moderate (-0.0030 to -0.1845) and severe retinopathy (-0.023 to -0.2434); amputation: (-0.1050 to -0.2880). Different nature of complication severity defined in studies could be categorized into: those with acute nature, chronic with lasting effects, those with symptoms at early stage or those with repetitive frequency or episodes. Discussion: Overview of HSUV decrement ranges across different stages of each T2DM diabetes-related complications shows that chronic complications with lasting impact such as amputation, severe stroke with sequelae and severe retinopathy with blindness were generally associated with larger HSUV decrement range. Considerable heterogeneities exist across the studies. Promoting standardized complication definitions and identifying the most influential health state stages on HSUV decrements may assist researchers for future cost-effectiveness studies.
The global diabetes prevalence is predicted to rise 19% by 2030, and another 22% by 2045. It is alarming that three out of four adults in low-and middle-income countries are living with diabetes. Between 2000 and 2019, age-standardized mortality rates from diabetes alone increased by 3%, with 13% solely from lower-middle-income countries [[
In this context, economic evaluations have been a dominant feature in the resource allocation of diabetes prevention and management. Quality-adjusted life years (QALYs) are commonly used outcome measures required for inputs into diabetes progression simulation models. The weights (or commonly known as health state utility values, HSUV) used to calculate QALYs are based on preference-based measures of health-related quality of life (HRQOL). Published studies in patients with diabetes have assessed the impact of complications using several different approaches such as direct methods: time-trade off (TTO), standard gamble (SG) and indirect methods: 5-level EQ-5D version, (ED-5D-5L), Short-form 6-dimensional (SF-6D), Self-administered Quality of Well-Being Index (QWB-SA) and Health Utilities Index Mark 3 (HUI-3).
Previous systematic reviews to elicit HSUVs for all major diabetes complications have found considerable heterogeneity and thus were not able to conduct meta-analyses to pool utility values together [[
A motivation for this study is the lack of overview HSUV ranges for individual diabetes complications at their varying severity across all instruments, populations, regions for an overall comparison in one study. A Japanese study had previously demonstrated that utility decrement for diabetic complication varied with its severity and symptoms [[
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and The Professional Society for Health Economics and Outcomes Research (ISPOR) Good practices for outcomes research task force report 2019 [[
Studies included T2DM population in outpatient setting with diabetes-related complications regardless of treatment type, complication stage or severity and region. Studies were to be conducted in adults aged > 18 years old, published in English since January 2000 to April 2022. Both observational and experimental studies which applied direct (standard gamble, TTO) or indirect methods (EQ-5D and all its variants, SF-6D, HUI-3, QWB-SA) to elicitate HSUVs were included.
Non-original studies such as editorials, systematic reviews, meta-analysis, and guidelines were excluded. Quality of life studies associated with intervention or reported without HSUVs were excluded. Studies that reported HSUVs based on hypothetical scenarios or vignettes were excluded. Studies solely reporting HSUV estimates without adjustment for other HRQoL predictors, or direct elicitation from visual analog score (VAS) were excluded.
HRQoL outcomes were to be presented as HSUV decrement (disutility values), preferably adjusted according to social demographics and other predictors of HRQoL. Focusing on HSUV decrements allow broad overview comparison to be made as baseline HSUV will differ for each study depending on valuation methods, tariffs and populations.
Computer simulations of economic models allow projection of long-term clinical outcomes, aiding policy makers in deciding on cost-effective interventions for certain populations. Diabetes economic models were identified from Mount Hood Diabetes Challenge Registry to identify complication types with impact on HSUVs [[
The electronic databases Medline, Scopus, Web of Science Core collection (including conference proceedings) were searched. Initial database searches were conducted from December 2021 to February 2022 and subsequently updated to include sources through April 2022.
Our search strategy included keywords such as diabetes, complications (coronary heart disease, heart failure, stroke, nephropathy, retinopathy, neuropathy, amputation, foot ulcer), quality of life, health utility values. 'Utility value' was a very generic term which broaden sensitivity of the search. In order to test for completeness, relevant search terms were identified and added to the search strategy by scanning the top retrieved articles for relevant synonyms such as 'utility scores' and other similar synonyms. The full search strategy can be found in S1 Table. Included studies were entered into the reference manager Mendeley to remove duplicates. Initial title and abstract screening were conducted by one researcher. Citations were imported into Covidence, a web-based collaboration software platform [[
The data extraction items were created based on Checklist for Reporting Valuation Studies (CREATE), National Institute of Health and Care Excellence (NICE) Technical Support Document, and ISPOR Good Practices for Outcomes Research Task Force Report [[
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Table 1 Summary of included studies: Characteristics of population and recruitment setting.
Author/Year Country /Tariff Mean age/T2DM duration (years) Comorbidities N, number of participants HSUV DM population HSUV in DM without complica-tion Self-report (S) or medical record (M) Respondent recruitment and setting T2DM Medication (%) Statistical Methods Clarke(1), 2002 UK/UK 62.3 / 10.6 NR 3192 0.70 0.79 M UKPDS study patients. Questionnaires mailed NR Tobit model Coffey (2), 2002 US/NR 57.6 / 10.4 Hypertension, ↑lipid 2041 0.69 NR S Outpatient specialty clinics OHA 39%, insulin 54% Multiple linear regression Tabaei (3), 2004 US/NR 56 / 9 Hypertension, ↑lipid 888 NR NR S Outpatient specialty clinics diet, insulin, OHA Multiple linear regression Bagust (4), 2005 UK/UK 67 / 9.9 NR 4641 0.69 0.79 M Code-2 Study pts: epidemiological registry, Questionnaire-survey Oral 57.4%; insulin 17.1% OLS/TTO model Tung (5), 2005 Taiwan/NR 60–70 / >10 NR 406 0.92 0.94 M Household registry community survey. Face to face interviews. OHA and insulin Multiple linear regression P. Clarke (6), 2006 UK/UK 61.6 / 6 Hypertension, ↑lipid 4051 0.76 0.85 M Lipids in Diabetes Study pts. Outpt clinic and GP registers of diabetics NR Step wise regression Maddigan (7), 2006 Canada/Canada 61.7 / 9.4 Cataract, depression 5134 0.90 0.88 M Canadian Community Health Survey Cycle CCHS (include non-DM). General population survey insulin users 15.6% Bootstrap variance Wexler (8), 2006 U.S/NR 66 / 9.6 Copd, ↑lipid, hypertension 909 0.70 0.84 M Hospital based clinic, community health centre. General population survey: mail/phone OHA and/or insulin General linear modelling- Smith (9), 2008 US/US 65.6 / 7.1 ESRF, macular edema 2074 0.82 0.94 M community based population. Random mail survey OHA and/or insulin Linear regression Lloyd (10), 2008 UK/UK 62.2 / NR Neuropathy, nephropathy 319 0.83 0.77 M T2DM with DR: general population (advertisement/database). In clinic /survey- face to face interviews/phone NR Mixed model and regression analysis Solli (11), 2010 Norway/UK 64 / 10 Hypertension, ↑lipid 521 0.81 0.85 S Members of diabetic association. Questionnaires mailed OHA and Insulin Multivariate logistic regression Quah (12), 2011 Singapore/S'pore 63 / < 5 Hypertension, ↑lipid 699 0.91 0.91 S T2DM fr public primary care polyclinics. Questionnaire at routine visit. systematic sampling OHA/insulin/diet Multiple regression analysis Marrett (13), 2011 US/US 58 / 7.3 Angina, heart attack, stroke, peripheral vascular, heart failure 1984 0.81 0.85 S Internet based survey with self-reported T2DM with OHA. Survey time point, randomly contacted 50% on OHA Multiple linear regression O'reilly (14), 2011 Canada/US 63.7 / 8.2 NR 1143 0.75 NR S Community dwelling T2DM, volunteered to be screened for RCT. Questionnaires mailed 323 (28%) on insulin OLS Bootstrap standard errors Lee (15), 2012 Korean/Korean 57.5 / NR Hypertension, ↑lipid 1072; 858 NR 0.84 M 3 outpt clinic from three institute in diverse regions. Consecutive sampling: 1st, time of clinic visit; 2nd, follow up OHA ± insulin Backward elimination Zhang (16), 2012 US/US 62 / 11.3 Hypertension, ↑lipid 7327 0.80 0.92 M random sample fr health care plans. pts contacted and completed survey Diet, OHA ± insulin Multivariate linear regression Luk (17), 2014 Hongkong/UK 59.2 / 8.9 Hypertension, ↑lipid 14,826 0.90 0.98 S T2DM disease registry, referrals fr hospital and community clinics. 5 yrs data collection. OHA ± insulin Multivariate regression Harris (18), 2014 Canada/Canada 55 / NR NR 1696 0.71 0.82 S French/ Eng; include T1 and 2, without diabetes. web based & gen pop survey NR Non-parametric bootstrapping Kiadaliri (19), 2014 Sweden/UK 66.1 / 9 NR 1757 NR 0.88 M National diabetes registry–from hospital, primary care, clinics. Survey during outpatient visits diet as OHA ± insulin OLS regression Pan (20),2016 China/China 64.9 / < 10 55% with comorbidities 289 0.88 0.96 S Tertiary hospital. Questionnaire after routine clinical examination NR BCA bootstrap and OLS Hayes (21), 2016 Australia,Asia,EU,US/US, Poland,China 65.8 / 7.9 Macro and microvascular complication 11,140 0.82 0.83 M ADVANCE trial patients. Longitudinal, at study entry, 2, 4 years, trial close out. NR Fixed-effect longitudinal regression Jiao (22), 2017 Hongkong/Hongkong 64.84 /10-17 Hypertension, ↑lipid. 1275 0.86 0.88 M T1&2 diabetics in outpatient clinic- hospital-based specialist clinic. Contacted within one month to fill questionnaire NR OLS with robust std errors. Riandini (23), 2019 Singapore/Japan 60–64 /10-16 Hypertension, ↑lipid. Heart disease, PAD, arthritis 160 NR 0.77 M T2DM NR Multivariable Regression Pan (24), 2018 China/China 67.9/10.3–12.2 Hypertension 913 0.98 0.99 M Community-based survey on T2DM-CDC health records. Detailed interview with questionnaire NR Generalised linear regression Shao (25), 2019 US, Canada/Canada 62.6/10.55 Macro/ microvascular complication 8713 NR 0.72 S ACCORD Trial pts: high risk CVD. Trial scheduled visits NR OLS/Fixed effects Takahara (26), 2019 Japan/Japan 64 / 15 Musculo, dental, respi, gastro, urinary, cutaneous hearing impairmt 4963 0.90 0.94 M 13 centres, outpatient. All meds Multivariate regression model Yfantoupoulos (27), 2019 Greece/UK 67.02 / 15.1 Hypertension, ↑lipid 938 0.71 0.82 M One hospital centre+57 private centres. Interview insulin users only OLS regression Zhang Yi, (28)2020 China/China 59.6 / 7.91 Hypertension, ↑lipid 7081 0.87 0.92 S 75 hospitals in 9 cities. Survey at clinics OHA only OLS regression Pham (29), 2020 Vietnam/Vietnam 61.5/ 7 Hypertension 214 0.94 1.00 M Police and general public. Hospital outpatient visits NR Tobit regression Chao (30), 2020 China/China 59.5 /1 0.5 Hypertension, ↑lipid, complications 12,583 0.94 0.99 M BEYOND II trial pts. hospital-based, multi-center cohort study. Physician administered questionnaires All on insulin. +/- OHA; OLS regression Chen (31), 2021 China/China 60.1 / 10.1 Macro/microvascular complications 507 0.88 0.95 S Outpatient in endocrine, nephron clinic, dialysis centre. OHA ± insulin, diet OLS regression Kuo (32), 2021 Taiwan/Taiwan 57.48 / 4.54 Hypertension, ↑lipid, liver disease, depression, cancer, copd, connective tissue disease 2104 0.84 0.98 M National Health Interview Survey (NHIS) 2009–2013 + national Health Insurance Research Database (NHIRD) 2002–2013. Survey data from outpatient, inpatient, emergency medical records. OHA ± insulin, diet Multivariable ordinary least sq regression models (OLS) Laxy (33), 2021 Germany/Germany 72.5 / 11.5 Hypertension, cancer, asthma, chronic bronchitis 8755 0.78 NR S Population based cross sectional (2016). Postal survey/telephone interviews NR Linear regression Neuwahl (34), 2021 US/US 59 / 6.8 14.0% had a history of cardiovascular disease 5103 0.79 NR M LOOK-AHEAD trial: overweight and obese HUI-3 at baseline, 3, 6, 9, and 12 months; every 6 months through 10 years; and once during years 10–13. 15.4% on insulin Fixed effect model Keng (35), 2022 UK/UK 62.8 / 9.7 Hypertension 11,683 NR 0.906 M ASCEND trial patients- with DM, without CV disease. Questionnaires sent at end of 7-year study. Ace-inhibitors, statin OLS regression
Published HSUV for all stages and severity of T2DM complications were extracted. When presented with multiple HSUVs, marginal utility reported in comparison with the absence of complication were preferred over disutilities alone. HSUV were elicited using standard conversion algorithms. Regression analysis were used to estimate decrements while adjusting for confounding variables such as, clinical characteristics (duration of diabetes, age onset of diabetes, body mass index, treatment, urine protein, HbA1C), diabetes related complications (stroke, heart disease, foot ulcers, amputation, neuropathy, nephropathy, retinopathy) and presence of comorbidities (hypertension, hyperlipidaemia, depression, cancer, chronic bronchitis, asthma). Only adjusted HSUV decrement estimates from statistical models were extracted, along with the uncertainty represented by 95% confidence intervals or standard errors. Whenever HSUVs were reported from multiple statistical models, the best fitting model preferred by the authors were extracted.
Since experience using formal synthesis methods is limited for HSUVs with high degree of heterogeneity in valuation methods and patient population, this review was conducted without meta-analysis. Synthesis methods were by vote-counting based on direction of effect. Informal methods to investigate heterogeneity included ordering tables by methodology characteristics such as study characteristics (country, tariff, ethnic, study design), population characteristics (inclusion/exclusion criteria, age, HbA1c, comorbidities), complications and timing of HSUV collection etc.
Complications were grouped into 2 subsets: macrovascular and microvascular, as well as individual complication types and severity for overview comparison. HSUV decrements were extracted for individual complication and stratified according to severity whenever possible (S2 Table). Cardiovascular complications in diabetes involves premature atherosclerosis [[
All stages of diabetic kidney disease (persistent albuminuria, persistently reduced estimated glomerular filtration rate [eGFR <60 ml/min per 1.73 m
Mild diabetic neuropathy commonly presents with numbness while severe forms are when patients are unable to heel-walk. After reviewing the included studies, we categorized severe neuropathy where pain symptoms were present [[
Although severe hypoglycemia is often defined when patients are unable to self-treat and needing the assistance of others, its definition varies greatly from the included studies [[
Where complications were broadly defined by an umbrella term, HSUVs were extracted as it is and categorized as 'undefined', without being able to stratify into different levels of severity. Ranges of HSUV decrements across macrovascular and microvascular complications, as well as across each individual type of complications were compared. HSUV decrements from self-report complications and those obtained from medical records were compared. When longitudinal studies reported HSUV for event year when complication was experienced or as history before event year, results from fixed effect model were used to address the bias caused by time-invariant covariates [[
Quality of studies (risk of bias) were assessed using the modified elements of critical appraisal outlined by McMaster University and from National Institute for Health and Care Excellence (NICE) Technical Support Document [[
Initial searching yielded many results with generic terms for HRQoL such as 'quality of life' and 'health state.' Keywords were refined to be more specific to increase the relevance and efficiency of more focused search. For example, 'quality of life' terms had to be incorporated with 'utility values or similar terms to exclude irrelevant studies which reported quality of life without reporting utility values. After removing duplicates, a total of 428 primary utility-elicitation studies were identified from multiple, iterative searching [[
Graph: Note: PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Table 1 summarizes background information about the included studies for the past two decades, including the study country, country tariff adopted for the study, adjusted comorbidities and statistical methods applied. For the duration of 2000–2010, studies were mainly from Western countries such as United Kingdom (n = 4) [[
Mean age ranged from 60–70 years old; mean duration of diabetes from 19 studies consisted of patients with < 10 years diabetes, 14 studies consisted of patients with 10 or more years of diabetes and two did not report. The size of the study population ranged from 160 to 14,826. A total of six studies recruited patients from randomized controlled trial (RCT) while the remaining 29 studies were population-based study [[
One RCT oversampled overweight and obese patients while another RCT excluded patients with cardiovascular disease and impaired renal function [[
Although overall quality of the included studies fulfilled the NICE guidelines criteria, 7 did not detail if sample size was achieved, 8 studies did not state clear inclusion or exclusion criteria and response rates. 26 studies utilized appropriate tariff matching to the local setting, 5 were mismatched, 3 were unreported. 2 did not report uncertainty measurement (S3 Table).
All studies included macrovascular and microvascular complications except for eight single studies which reported HSUV for only one complication: retinopathy [[
In the recent years, studies reporting HSUV for complications included different severity of complication (e.g., TIA, stroke with sequelae instead of just stroke; MI, angina instead of just coronary heart disease; proteinurea, dialysis instead of just nephropathy) [[
All studies utilized indirect or direct measures for HSUV valuation: 15 studies utilized EQ-5D-3L, nine EQ-5D-5L, four utilized HUI-3, two used QWB-SA, SF-6D and TTO each, and one used Standard Gamble. TTO range of HSUV decrements were larger compared to EQ-5D-3L, SF-6D and HUI-3 while EQ-5D-5L HSUV decrement range was larger compared to the EQ-5D-3L (Fig 2).
Graph: Note. standard gamble (SG); time-trade off (TTO); 5-level EQ-5D version, (ED-5D-5L); Short-form 6-dimensional (SF-6D); Self-administered Quality of Well-Being Index (QWB-SA); Health Utilities Index Mark 3 (HUI-3).
Considerable heterogeneity exists within studies due to difference in methods used (e.g., EQ-5D, SF-6D etc.), valuation methods (e.g., TTO, SG), tariffs used, inclusion and exclusion criteria of study population, and adjustments for different co-variates. These may result in a highly variable HSUV. In consideration of all these reasons, a formal synthesis may not be meaningful. Therefore, meta-analysis was not performed but range of HSUV decrements were reported instead.
Range of HSUV decrement were largest with cerebrovascular disease (stroke), retinopathy and amputation. Severe stages of stroke with sequelae, retinopathy with blindness and amputation were generally associated with largest HSUV decrements. Overall, there were no standardization of complication stage selected for HSUV elicitation. For example, 'nephropathy' could be defined in one study as eGFR < 30mL/min with proteinuria whereas in another study, stratified by many stages of severity: microalbuminaemia, eGFR 15-60mL/min, and end-stage renal failure (ESRF) or dialysis while some used an overall umbrella term [[
HSUV decrement range (Fig 3) will be presented and discussed with details of each individual complication types (Figs 4–10).
Graph: (A) macrovascular complications (B) microvascular complications (C) hypoglycemia.
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Cardiovascular complication (Fig 4, S4 Table). When cardiovascular complications were all grouped together under one umbrella term (undefined), overall HSUV decrement range were wider (-0.008 to -0.185) compared to angina and MI reported separately. When angina and MI were both reported together in a single study, angina HSUV decrement were almost always larger than MI. Heart failure HSUV's were mostly reported under one umbrella term without stratifying into disease severity (S2 Fig).
Cerebrovascular (stroke) complication (Fig 5, S5 Table). Range of HSUV decrement for mild stroke was -0.006 to -0.078 while severe stroke recorded a wider range of HSUV decrement from -0.035 to -0.266. When stroke was used as an umbrella term without further stratifying severity, HSUV decrement range was in between the mild and severe HSUV ranges (-0.020 to -0.202). HSUV decrement for intracranial hemorrhage stroke was only reported in one study [[
Nephropathy (Fig 6, S6 Table). Only 4 studies included proteinuria HSUV decrement values, ranging from -0.017 to -0.048 [[
Retinopathy (Fig 7, S7 Table). Generally, when retinopathy was stratified into stages of severity, there was a stark difference between ranges of mild (-0.005 to -0.086), moderate (-0.003 to -0.185) and severe retinopathy (-0.023 to -0.243) HSUV decrements. Unilateral blindness had similar HSUV decrement ranges to moderate retinopathy while bilateral blindness had larger HSUV decrement. However, no clear difference was seen if compared between unilateral or bilateral diabetic retinopathy [[
Neuropathy (Fig 8, S8 Table). Range of HSUV decrement for undefined neuropathy is narrow (-0.014 to -0.084) whereas severe stages had broader HSUV decrement range from -0.060 to -0.187. Where painful neuropathy was present, there was almost a doubling of the HSUV decrement. The largest reported HSUV decrement for neuropathy was -0.187 [[
Foot ulcer/amputation (Fig 9, S9 Table). Foot ulcer HSUV decrement ranges (-0.080 to -0.170) share almost similar ranges with amputation HSUVs (-0.060 to -0.280) [[
Hypoglycemia (Fig 10, S10 Table). The HUSV decrement range for hypoglycemia almost doubled for each stage as it progressed from mild, moderate, severe to very severe hypoglycemia [[
Overall, the findings from this review showed that milder stages of complications often showed smaller HSUV decrements compared to severe stages. Definition across complication types and stages vary widely in HSUV studies. Different nature of complication severity: those with acute onset, those with chronic or lasting effects, those with symptoms at early stage, or those with repetitive frequency or episodes may have impacted the range of HSUV for each complication. Chronic complications with lasting impact such as amputation, severe stroke with sequelae, severe retinopathy with blindness were generally associated with largest HSUV decrements (Fig 11).
Graph: Fig 11 info:doi/10.1371/journal.pone.0297589.g011
Acute clinical events may be associated with large HSUV decrement due to high levels of pain and discomfort during the event.
Cardiovascular. Generally, HSUV decrement range for both angina and myocardial infarction (MI) were small with most ranging between -0.06 to -0.018. One recent large UK study (n = 11,683) did not find any acute impact of MI on HSUV decrement observed in other studies [[
Larger HSUV decrement ranges are reported when cardiovascular complications are defined under broad umbrella term such as 'heart disease', 'ischemic heart disease', 'coronary heart disease' encompassing acute clinical events of angina, myocardial infarction and heart failure. Currently, no consensus exists on how to define HSUV changes within these acute events therefore discrete event simulation models have been recommended by using discrete health status to capture these changes [[
Heart failure. Staging of heart failure severity by New York Heart Association (NYHA) classification system was absent in most HSUV elicitation studies, where they were classified under one umbrella term. Those with largest HSUV decrement values for heart failure were from a mixture of population-based studies and RCTs, two from UK and three from Taiwan and China [[
Cerebrovascular (stroke). In a meta-analysis by Mok et al, the range of HSUV decrement for stroke were -0.101 to -0.006 [[
Longitudinal studies included in our review found a difference of HSUV decrement in 'event year' effect compared to 'history of' effect [[
Some complications do not seem to significantly affect HRQoL at earlier stages but gradually worsen as disease progresses to severe stages, such as nephropathy and retinopathy [[
Nephropathy. Nephropathy definition between studies were found to vary widely, with different severity stages chosen to elicitate HSUV. Almost all diabetic patients typically progress from initial diagnosis to microalbuminuria, macroalbuminuria and elevated plasma creatinine (+ 175 mmol/L) or ESRF [[
The larger upper range of HSUV decrements for ESRF (-0.050 to -0.175) compared to Mok's narrower range (-0.055 to -0.050) could be due to sample size. (Mok et al, n = 2, versus n = 8 in the current review). As nephropathy progresses to advanced stages, patients were more likely to have poor HRQoL particularly in mobility and usual activity dimensions [[
Diabetic Retinopathy (DR). The current review findings showed that there were marked inconsistencies with methods of reporting HSUV for diabetic retinopathy. Considerable heterogeneity exists in definition and measurement of retinopathy stages. Previous economic evaluation models have defined DR in 4 stages, absent (NoDR), non-sight-threatening (Non-STDR), sight-threatening (STDR), and bilateral blindness (BB) [[
Generic EQ-5D or SF-6D estimates were found to be largely unresponsive to visual conditions possibly due to the lack of vision specific dimension [[
Another challenge for DR HSUV elicitation lies on unstandardized anchors in retinopathy studies. Although the current review did not find much difference, one systematic review on DR reported small decrements when HSUV decrement was anchored to Worse Seeing Eye (WSE), as compared when anchored to Best Seeing Eye (BSE). The updated NICE guideline addressed similar issues and recommended other condition-specific preference-based measure or direct valuation of own health for retinopathy HSUVs [[
The following microvascular complications related to the lower limbs are peripheral neuropathy, foot ulcer and amputation.
Neuropathy. Mild neuropathy showed lower range of HSUV decrements while severe neuropathy with pain showed larger HSUV decrements. Majority of studies did not stratify neuropathy into severity levels and grouped it under one umbrella term [[
Foot ulcer/ amputation. The current review findings were consistent with many other previous reviews[[
We observed that HSUV decrements for foot ulcer and amputation were almost similar in some studies, implying that both foot-related complications though at different stages, may exert similar HSUV impact. Interestingly, a Thai study has shown that foot ulcer HSUV decrements were larger than amputation, especially among those who had weight-bearing problems and those with ischemic diabetic foot [[
A large prospective, observational study, Eurodiale (European Study Group on Diabetes and the Lower Extremity) conducted in 14 European centers, reported that minor amputation was not associated with a negative impact on HRQoL in patients with diabetic foot ulcers [[
Although these are treatment-related adverse events for diabetes, hypoglycemia is often classified as a diabetes-related complication.
Hypoglycemia. One Malaysian study stratified hypoglycemia severity both by time (nocturnal or daytime) and frequency of attacks. The authors found that severe hypoglycemia (defined by increased frequency or nocturnal hypoglycemia) has greater HSUV decrement compared with non-severe hypoglycemia, consistent with the current review findings [[
Studies over the recent years have seen lower HSUV decrements for hypoglycemia complication. Comparing two studies which included only oral agents, Marrett (2011) reported HSUV decrement of -0.21 whereas Zhang (2020) reported HSUV decrement of -0.008. Hypoglycemia episodes increase with insulin secretagogues, which may explain the larger HSUV decrement in Marrett's study where 50% of study subjects were on sulphonylureas [[
It was interesting to note that majority of elicitation studies for the earlier 10 years (2002–2010) were published from European countries and the latter 10 years (2011–2021) seen an increase publication from Asian countries. We did not find a similar consistency with a previous review where East and Southeast Asian population yielded more conservative values of utility decrement [[
In a 5-year longitudinal study conducted by Hayes et al with over 11,000 participants across 4 regions, Australasia, Asia, Europe and North America, there were no significant differences in the HSUV changes associated with incident complications in the fixed-effects longitudinal model, even though mean EQ-5D-3L utility scores differed depending on the value set used [[
A variety of elicitation methods were used, indirect methods such as EQ-5D, HUI-3, QWB-SA, SF-6D questionnaires as well as direct methods namely SG and TTO. Two authors utilized different generic measures to compare HSUV decrements. A U.K. study revealed an equivalent decline of HSUV on both the EQ-5D and HUI-3 while a Korean study reported larger Spearman's coefficient between the EQ-5D and the SF-6D scales occurring only in some HRQoL dimensions [[
HSUV decrement ranges from self-reported complications were narrower compared to those from medical records. Self-reported complications may be incomplete as patients could only be aware of certain symptomatic complications, not accounting for other non-symptomatic complications. However, advantages include possibly more accurate reflection on quality-of-life measures especially for symptomatic complications. A U.S study pointed out that HSUV for different stages of diabetes-related complications should focus on those that affect symptoms and functioning as self-reported data helps to assess patients' awareness of complications which may affect quality of life [[
Several limitations were encountered during the review. First, many studies did not define severity of complications and used only an umbrella term, rendering difficulty in categorizing some complication types to synthesize data for the purpose of the review. Second, although included studies reported measures of uncertainty by adjusting for sociodemographic and presence of multiple complications, the variable types were inconsistently reported across studies. This may not reflect the full range of uncertainty in the studies. Third, considerable heterogeneity was found across study population, country, study instruments, statistical methods for modelling and definition of individual complications. Therefore, pooling of estimates were not attempted but instead, range of HSUVs were reported to provide an overview for comparison. Despite those limitations, the strengths of the current study were that most included studies were from observational population-based studies, reducing the chance of bias or selective reporting. Another notable strength was, we attempted to classify individual complications by severity to provide uniformity for comparison of HSUV decrement ranges across the expected heterogenicity, allowing a broad overview for comparison.
In conclusion, this systematic review compared the HSUV decrement ranges for different diabetes-related complications of different severity, elicited with direct and indirect methods. Severe stages of complications often present with larger HSUV decrement ranges compared to the milder stages. Understanding each individual complication and its nature of severity helps future researchers identify appropriate HSUV to populate economic models. The findings of this study provide informed outcomes to researchers in the presence of multiple heterogeneities (variation of study populations, countries, study instruments, statistical methods for modelling and definition of complication stages) when identifying HSUV for economic evaluation and policy analysis. Future studies could explore which health state would produce the most influential HSUV of each complication for cost effectiveness studies.
S1 Checklist
Prisma checklist.
(PDF)
S1 Table
Search strategies.
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S2 Table
Summary of included studies sample size and severity groups.
(PDF)
S3 Table
Risk of bias assessment criteria.
(PDF)
S4 Table
HSUV decrement and definition for cardiovascular complication.
(PDF)
S5 Table
HSUV decrement and definition for stroke complication.
(PDF)
S6 Table
HSUV decrement and definition for nephropathy complication.
(PDF)
S7 Table
HSUV decrement and definition for retinopathy complication.
(PDF)
S8 Table
HSUV decrement and definition for neuropathy complication.
(PDF)
S9 Table
HSUV decrement and definition for foot ulcer and amputation complication.
(PDF)
S10 Table
HSUV decrement and definition for hypoglycemia complication.
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S1 File
Abbreviation.
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S2 File
Data extraction form items.
(PDF)
S3 File
Risk of bias assessment criteria.
(PDF)
S4 File
Risk of bias table.
(PDF)
S1 Fig
Overview of HSUV decrement ranges by reporting methods.
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S2 Fig
HSUV decrement for heart failure complication.
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The authors gratefully acknowledge Saravana Kumar for guidance on conducting the systematic review and Annushiah Vasan Thakumar for proofreading the final manuscript.
By Michelle Hwee Pheng Tan; Siew Chin Ong; Nurul Ain Mohd Tahir; Adliah Mhd Ali and Norlaila Mustafa
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