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Impact of cardiovascular complications among patients with Type 2 diabetes mellitus: a systematic review Expert Rev. Pharmacoecon. Outcomes Res. Early online, 1–11 (2015)

Varun Vaidya*1, Nilesh Gangan2,3 and Jack Sheehan4 1 Department of Pharmacy Practice, Pharmacy Health Care Administration, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Health Science Campus 3000 Arlington Ave., Toledo, OH 43614, USA 2 College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43606, USA 3 Pharmacy Administration, School of Pharmacy, University of Mississippi, P.O. Box 1848, University, MS 38677-1848, USA 4 AstraZeneca Pharmaceuticals, US-MA| Evidence Generation, 601 Office Center Drive, Suite 200, Fort Washington, PA 19034, USA *Author for correspondence: Tel.: +1 419 383 1516 [email protected]

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Macrovascular and microvascular complications that accompany Type 2 diabetes mellitus (T2DM) add to the burden among patients. The purpose of this systematic review is to conduct a comprehensive search of the medical literature investigating the prevalence of cardiovascular (CV) complications and assess their impact on healthcare costs, quality of life and mortality among patients with T2DM in the context of microvascular complications. A total of 76 studies and reports were used in this systematic review. Hypertension was the most prevalent complication among patients with T2DM. The additional cost burden due to CV complications was higher than any other complication except end-stage renal disease. Quality of life was much lower among patients with CV complications and T2DM, and mortality was higher than either illness alone. KEYWORDS: cardiovascular conditions . complications . healthcare costs . mortality . prevalence . quality of life .

Type 2 diabetes mellitus

Background

Type 2 diabetes mellitus (T2DM) presents a significant healthcare burden in the USA. It ranks seventh in leading causes of death [1] and contributes to morbidity as well. There has been a steady rise in total costs since 2002, with the estimated costs related to diabetes in the USA in 2012 being US$245 billion, with US$176 billion in direct costs and US$69 billion in indirect costs, making it an important chronic disease to tackle [2]. Patients with T2DM are also at increased risk of acquiring other serious macrovascular and microvascular complications. These complications add to the healthcare burden, adversely affecting quality of life and increasing healthcare utilization. Macrovascular conditions, including hypertension, myocardial infarction (MI), congestive heart failure, stroke and peripheral artery disease are the key complications associated with T2DM. The risk of macrovascular complication, such as cardiovascular (CV) conditions, in patients with T2DM is two to four-times higher compared with patients without T2DM [3]. The risk of CV 10.1586/14737167.2015.1024661

complications increases with the presence of higher levels of glycated hemoglobin (HbA1c) in blood stream. However, the causal association between glucose control and a reduction in macrovascular conditions among patients with T2DM is less well established than the association between glucose control and a reduction in microvascular complications, such as neuropathy, retinopathy and nephropathy. In addition, certain antiglycemic agents, which improve glycemic control, such as sulfonylureas, are associated with an increased risk of CV events and mortality in patients with T2DM [4–6]. Furthermore, some studies suggest that aggressive lowering of HbA1c levels with the use of antiglycemic agents increases the rate of hypoglycemia, potentially increasing the risk of CV events [7,8]. Therefore, there is a need to understand the additional burden that accompanies CV complications among T2DM patients and compare it with microvascular complications. The objective of this systematic review is to summarize the literature on the prevalence of CV complications and microvascular complications in patients with T2DM, the healthcare


2015 Informa UK Ltd

ISSN 1473-7167

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Review

Vaidya, Gangan & Sheehan

Total citations identified using approved key words (n = 6316)

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Exclusion of citations with unrelated/non English titles (n = 5901) Potentially eligible studies/reports with abstract (n = 415)

Potentially eligible studies/reports after title and abstract screening (n = 92)

Eligible studies/ report for the final report and manuscript (n = 60)

Screening of abstracts and exclusion of studies based on inclusion/exclusion criteria (n = 323)

Screening of full text and exclusion of studies based on inclusion/exclusion criteria (n = 32)

Figure 1. Article selection process.

costs associated with both the complications and its effect on quality of life and mortality and compare these parameters between both the complications of T2DM. To the authors’ knowledge, no systematic review has yet comprehensively summarized the effects of CV and microvascular complications, on healthcare costs, quality of life and mortality among patients with T2DM, highlighting the need to conduct the present study. Methods

A comprehensive database search was conducted with the use of keywords (SUPPLEMENTARY APPENDIX A [supplementary material can be found online at www.informahealthcare.com/suppl/ 10.158614737167.2015.1024661_Suppl]). Keywords and Medical Subject Headings terms were decided by reviewing the existing literature and consulting expert researchers. A search strategy containing a combination of keywords was created for each of the research questions. The database search was conducted in MEDLINE, Cochrane, CINHAL Plus and PsycINFO with the help of the approved combination of keywords or Medical Subject Headings terms. In addition, the reference lists of relevant reviews were manually searched for more articles. The literature was tracked using EndNote X5.0.1 software. Relevant studies were identified based on the inclusion criteria. Inclusion criteria

A study was considered for this review if it met the following inclusion criteria: the study was about either CV or microvascular complications in patients with T2DM; the outcome measured in the study was the prevalence, cost, quality of life or mortality related to CV or microvascular complications in doi: 10.1586/14737167.2015.1024661

patients with T2DM; the study was published before June 2013; the study was published in English; study was conducted in the USA in case of cost data to maintain the consistency of economic data. (No such restriction for studies that reported non-economic data.); and total sample included in the study was at least 50 patients. Studies were excluded if cost-related data were gathered outside of the USA and studies reported prevalence estimates prior to 2006. Search strategy & data extraction

A preliminary search of all databases according to the search strategy yielded 6316 articles. During the selection process, one reviewer (N Gangan) screened the titles to match the research questions at hand and identified a subset of 415 potentially relevant articles. Subsequently, two reviewers (N Gangan and R Bechtol) independently reviewed relevant studies according to the inclusion criteria by examining the abstracts for inclusion in the evidence synthesis. If the two reviewers disagreed about whether to include an article, a third reviewer (V Vaidya) was asked to review the article, and disagreements were then resolved by consensus discussion. The reference lists of selected articles were also searched for more relevant studies. In addition, experts in the area from the University of Toledo College of Pharmacy and Pharmaceutical Sciences were contacted and asked about published or unpublished studies that were relevant to the review. FIGURE 1 illustrates selection criteria in more detail. A comparison of the prevalence, clinical burden or economic burden of CV complications to other T2DM complications was made, and that information is presented here. Results

The database search yielded a total of 60 studies that fulfilled the inclusion criteria. There were 13 studies [9–21] that estimated prevalence, whereas 18 studies [2,21–37] estimated costs, 16 studies [38–53] addressed quality of life, 13 studies [2,4–6,54–62] addressed mortality in patients with T2DM and CV and other diabetic complications. Prevalence Prevalence of CV complications among patients with T2DM

The majority of the studies of prevalence found CV complications, including hypertension (it has been shown that diabetes can have a damaging effect on arteries, increasing the risk of hypertension), to be the most prevalent complication among patients with T2DM. Prevalence of CV complications as a group of conditions among T2DM patients was reported by four studies. These studies used a wide range of patient populations in different countries. In a Dutch study, CV complications were both most prevalent and incident among all the T2DM-related complications. Overall, 64% of patients with T2DM had CV complications at the time of diagnosis, and CV complications occurred at an incidence density of 101 new cases per 1000 person-years during the 10 years after diagnosis of T2DM [9]. The prevalence was slightly lower in the UK, where a study found that the percentage of patients with CV Expert Rev. Pharmacoecon. Outcomes Res.

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Impact of CV complications among patients with T2DM

complications among those diagnosed with diabetes under the age of 40 years was 37.2% and over the age of 40 years was 50.7% after 20 years from the date of diagnosis [10]. Another study done in Spain found the prevalence of CV complications to be 22% in patients with diabetes in 2001–2002 [11]. However, the authors did not classify hypertension among CV complications and instead determined prevalence separately, which explains the low prevalence. Among the institutionalized population in USA, the estimated prevalence of CV complications in nursing home residents with diabetes in 2004 was found to be in the range of 74.1–78.9% [12]. Prevalence of CV complications generally increases among patients with T2DM as time after diabetes diagnosis progresses. Also, CV complications were more common among men than among women. Among the specific CV complications, six studies evaluated the proportion of patients with hypertension in addition to diabetes. Hypertension prevalence among the general population of patients with T2DM was relatively consistent across geographies, including the USA, Mexico, Canada and Spain (60.3–75%) [11,13,14]. In an analysis of patients in long-term care, the rate was slightly higher (81.9%), which may reflect the increased severity among hospitalized patients [15]. In an analysis of patients from Taiwan, although hypertension was the most common complication, the point estimate for the prevalence of hypertension (52%) was lower than in the other regions [16]. However, the analysis of patients in Taiwan also reported a much lower rate of hypertension in the control patients than the studies in other regions; therefore, the lower rate of hypertension in the analysis of Taiwanese patients may reflect differences in the population or differences in aspects of the data collection, and not a difference in the relationship between diabetes and hypertension risk among patients from Taiwan. In a study done in Australia, the prevalence of hypertension in elderly patients with T2DM was found to be in the same range as that in other studies, with 62% suffering from hypertension [17]. Although the studies were done in different countries, hypertension was consistently the most common complication among patients with T2DM. The next most prevalent CV condition among patients with T2DM after hypertension was ischemic heart disease or MI. Two studies analyzed the prevalence of MI in patients with T2DM. In a Swiss study of geriatric patients with diabetes, the prevalence of ischemic heart disease was 33.7%, lower than the prevalence of hypertension that was 81.9% [15]. In addition, a study done in Denmark among patients referred to a diabetes clinic for the first time with no known or suspected CV complication reported that 30% of patients with diabetes have myocardial ischemia [18]. The study also reported that some T2DM patients also had carotid artery and peripheral artery disease, showing evidence of these complications among T2DM patients [18]. Heart failure was the third most prevalent CV condition after hypertension and MI. The prevalence of heart failure measured in two studies based on comparable patient populations was consistent in both studies. The prevalence of heart failure in the elderly patients with T2DM in the informahealthcare.com

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USA was 17.9%, whereas in specific elderly veteran patients with diabetes in Australia, heart failure prevalence was 15% [17,19]. Patients with diabetes also had peripheral artery disease and deep vein thrombosis, with a prevalence of 15 and 14.9%, respectively [18,20]. Prevalence of microvascular complications in patients with T2DM

Besides CV complications, patients with T2DM also had microvascular complications, which had prevalence lower than that of CV complications. A number of studies estimated the prevalence of microvascular complications, such as retinopathy, neuropathy and nephropathy among patients with T2DM. Four studies reported the prevalence of neuropathy among patients with T2DM. In the UK, the prevalence of neuropathy was higher among older patients (‡40 years of age) than among younger patients (£40 years of age; 24.1 vs 12.3%). Interestingly, the prevalence of neuropathy is greater than the prevalence of CV complications among patients under 40 years of age, although among patients at least 40 years of age, the prevalence of CV complications is greater than neuropathy [10]. In two other studies done in the USA and Spain, the prevalence of neuropathies was consistent: 21.2% in the USA and 23.1% in Spain [11,21]. Among hospitalized patients in Taiwan, the prevalence of peripheral neuropathies was 13.4%; however, the low prevalence when compared with other studies may be due to population differences [16]. After neuropathy, retinopathy was found to be the most common microvascular comorbid condition. The prevalence of retinopathy varied in different studies according to age at diagnosis and duration of T2DM. In a study of hospitalized patients with T2DM in the UK, substantial differences in the prevalence of retinopathy were observed according to age at diagnosis. The prevalence of retinopathy increased from 4.4% among patients with T2DM under 40 years of age to 9.5% among patients with T2DM older than 40 [10]. As the time progressed after diagnosis, more patients with T2DM developed retinopathy. However, unlike CV complications, the prevalence of retinopathy remained relatively low within the first 10 years after diagnosis (9.5% for retinopathy vs 31.1% for CV complications). Similarly, in a US study, retinopathy was found in 9.8% of patients with diabetes enrolled in health plans, consistent with the rates reported in other studies [21]. Nephropathy was the least prevalent among the microvascular complications in patients with T2DM. The prevalence of nephropathy was similar in studies done in the USA and Spain. In the USA, the percentage of patients suffering from nephropathy was 6.6%, whereas in Spain, the prevalence of nephropathy was 5.7% and that of microalbuminuria was 25.4% [11,21]. Prevalence was higher among elderly patients; nephropathy affected 10.2% of the elderly population in the USA [19]. Economic burden of cardio vascular disease Total healthcare costs due to cardio vascular disease

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with the indirect costs associated with these services. Studies included in this review evaluated the mean annual cost per patient and some also compared it between patients with T2DM with and without CV complications. A study based on 2002 Medicaid claims data found the total per patient healthcare cost to be 38.9% higher in patients with CV complications than in patients without CV complications [22]. Among patients with CV complications, hypertension significantly impacted the total healthcare costs, with 55.6% higher total healthcare costs compared with patients with T2DM without hypertension. Another study that analyzed administrative claims data for patients with T2DM enrolled in a commercial HMO health plan in 2004 found a threefold increase in mean total cost per year for patients with macrovascular disease compared with patients with T2DM without macrovascular disease [21,23]. The diagnosis of any CV complication increased the total healthcare costs 1.7-fold for patients with diabetes. Similarly, a study based on the elderly population with T2DM found a 58% increase in the total cost for patients with diabetes with at least one CV complication compared with patients without CV complication [24]. Direct medical costs

The direct medical costs comprise emergency room/ hospitalization costs, outpatient costs and prescription drug costs. Direct medical costs for diabetes alone and for diabetes with CV complication were calculated in three studies. Each of these studies showed an increase in direct medical costs for patients with T2DM and CV complications compared with patients with T2DM without CV complications. For patients enrolled in a Michigan HMO in 2000, the direct medical costs increased by 10–30% annually in patients with cerebrovascular disease or peripheral vascular disease and by 60–90% annually for patients diagnosed with MI or angina [25]. Direct medical costs for patients enrolled in managed care health plans were reported to be 70–150% higher for patients with T2DM and CV complication than the costs for patients with T2DM without CV complication when costs were adjusted to 2010 values [26]. An analysis of administrative claims data from 90 healthcare plans across the USA showed that the average direct medical costs per patient with T2DM for first CV-related hospitalization were US$17,435 and subsequently for first recurrent CV hospitalization were US$18,488 [27]. The medical costs increased with recurrent CV events and follow-up. At the national level, US$17.6 billion in direct medical expenditures were attributable to CV complications for patients with diabetes in 2002, the highest contributor among chronic conditions [28]. Cost due to hospitalizations was the major contributor to the increase in healthcare expenditures due to CV complications in patients with T2DM. CV complications were responsible for US$19.4 billion in hospital inpatient costs in 2012 in patients with T2DM, which was significantly higher than costs for other chronic complications [2]. Similarly, doi: 10.1586/14737167.2015.1024661

physician office visits contributed US$2.1 billion, emergency department visits contributed US$0.8 billion and outpatient visits contributed 0.6 billion to CV complication-related costs attributable to diabetes, with all being highest in comparison with those for other chronic conditions [2]. Two studies done using patient-level data found a relative increase in emergency room/hospitalization costs, outpatient costs and prescription drug costs due to CV complications. The total emergency room/hospitalization costs increased 3.5-times, while total outpatient costs increased by 35.3% and total prescription drug costs increased by 15.1% for patients with T2DM with CV complication in West Virginia [22]. In a retrospective analysis of administrative claims, the inpatient costs for patients with T2DM and macrovascular disease increased more than threefold, the prescription costs increased 1.6-times and the outpatient costs increased 3.24-times [23]. Hospitalization costs were the major contributor to the direct medical costs associated with CV complications in patients with T2DM at patient level as well. Costs of hospitalizations associated with coronary artery bypass grafting procedures, MI, angina and other ischemic heart disease were significant for patients with T2DM. The direct costs increased considerably at the patient level for patients with end-stage renal disease (ESRD) on dialysis. However, population cost burden for CV complications in patients with T2DM was more than that for ESRD. The reason for this difference is that the frequency of a CV complication is higher than that of ESRD. Disease-specific direct medical costs were evaluated in four studies. FIGURE 2 illustrates a comparison of annual direct medical costs for various complications in patients with T2DM. The per-person annual direct medical costs were highest for congestive heart failure (US$15,137), with other CV complication falling in the range of US$7684–US$10,778. In another study, the direct medical costs for MI and stroke comorbid to T2DM were found to be US$27,630 and US$40,616, respectively, for patients enrolled in a state HMO, whereas in 2000, the direct medical costs for MI and stroke comorbid to T2DM were found to be US$25,000 and 27,000, respectively [25,29]. Another study evaluated the mean direct costs that were charged by the medical treatment provider, which amounted to US$9850 for angina, 14,104 for stroke, 30,066 for heart failure and 41,695 for MI in patients with T2DM [30]. Analysis of national administrative claims according to 2006 costs showed the direct medical costs to be US$26,035 for MI, 11,178 for heart failure, 7038 for angina and 11,802 for stroke in patients with T2DM [27]. Indirect medical costs

Two studies conducted by the American Diabetes Association estimated the indirect medical costs for the US population. The indirect cost comprised expenditures related to lost workdays, restricted activity days, mortality and permanent disability. In the 2002 study, information was obtained from National Health Interview Survey, Bureau of Labor Statistics Expert Rev. Pharmacoecon. Outcomes Res.

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Impact of CV complications among patients with T2DM

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and Social Security Administration on Annual cost (2010 US$) each of the aforementioned categories of Congestive heart failure indirect costs. The 2001 annual earnings $15,137 Coronary heart disease $10,778 for civilian noninstitutional population from 2001 Bureau of Labor Statistics Angina $7684 were used to estimate average indirect costs per day. Indirect costs attributable Transient ischemic attack $10,223 to diabetes, and its complications were Treated hypertension $8107 found to be US$39.8 billion for the entire US population, which included Painful neuropathy $8218 costs due to disability and lost work Clinical nephropathy $9720 days [28]. However, the study did not break out indirect costs according to the Proliferative retinopathy $12,820 complication type. The second study was more recent and used data derived from Figure 2. Unadjusted annual direct medical costs by complications in patients the 2009–2011 National Health Interwith T2DM. view Survey and the average annual earnData taken from [26]. ings from 2011 Current Population Survey. The study found that the USA incurred US$7.8 billion in 2012 for lost productivity due to T2DM [33]. ESRD caused a very large increase in healthcare deaths from CV complications among patients with T2DM [2]. costs for patients with T2DM. Progression to ESRD resulted in incremental medical costs of US$56,745 compared to patients with macroalbuminuria [33]. Much of these ESRD Costs due to microvascular complications of T2DM Microvascular complications, such as nephropathy, neuropathy costs were due to higher outpatient costs resulting from dialyand retinopathy, also significantly contribute toward the cost sis. In comparison with the costs of CV complication, ESRD associated with T2DM. FIGURE 3 illustrates the total national costs were significantly higher because of additional care expenditure due to all complications among patients with through dialysis. However, the frequency of ESRD is lower T2DM. Microvascular complications in combination contrib- than that of CV complications in patients with T2DM, resultute US$12 billion in healthcare costs to the nation. Microvas- ing in higher cost burden of CV complications at the populacular complications as a group were evaluated in a study of tion level. Another study found the average event cost elderly employees with diabetes in a large organization that (diagnostic test and visits cost) of microalbuminuria to be reported total costs of US$33,696 per person annually for US$62 per person and that of proteinuria to be US$69 per microvascular complications. These costs exceeded the costs for person; if these abnormalities progressed to ESRD, the average CV complications (US$23,240) [24]. However, the lower preva- Medicare payments were US$53,659 annually [29]. Patients lence of microvascular complications compared with CV com- with renal insufficiency before having diabetes had 41.8% plications suggests that cost for CV complications will remain higher total diabetes-related costs after diagnosis of diabetes [34]. high at the population level. Among specific microvascular complications, a total of four studies evaluated the effect of diabetic neuropathy on diabetic 1.8 4.9 costs. O’Brien et al. [29] found event costs per person for neuropathy, which include costs associated with resource use (tests 5.3 and consulting) specific to the clinical event, to be lower than 3.9 the same event costs among patients with CV complication [29]. Neurological Another study found the direct medical costs for diabetic neuPeripheral vascular Cardiovascular ropathy to be US$3657 per patient, which includes costs for Renal tests, physician visits or inpatient visits and medications [30]. If Ophthalmic diabetic neuropathy is associated with pain, the excess healthcare costs for treating neuropathy may be as much as 23 US$8500 per patient [31]. The national cost estimate for neuropathy along with diabetes for the year 2001 was US$10.1 billion [32]. For nephropathy, the annual medical costs for microalbuminuria alone, the first stage of nephropathy, was Figure 3. Health care expenditures attributed to diabetes US$2764 in one of the studies [33]. If microalbuminuria in by complications (in billion dollars) patients progressed to macroalbuminuria, it resulted in Data taken from [2]. US$3618 in additional medical costs for patients with informahealthcare.com

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Another study of ESRD evaluated the direct medical costs (outpatient and medication costs) along with hospitalization, which came out to be US$63,173 [24]. In 2001, the annual resource use for management of diabetes and ESRD at an advanced state beyond the first year was US$37,022, which was more costly than resource use for acute MI (US$1678) [35]. A study in patients with T2DM who were members of Kaiser Permanente found that CV complications increased costs by 50% and abnormal renal function increased diabetes costs by 65%, whereas ESRD increased costs by 771% [36]. At a population level, CV complications contribute most to costs among patients with diabetes, whereas at an individual level, progression to ESRD results in the greatest increase in costs [36]. Cost for retinopathy was evaluated in two studies. The event cost for proliferative retinopathy was US$1044, whereas direct annual medical costs were US$5034 [29,30]. Of the total healthcare costs due to complications, nephropathy contributed 21%, neuropathy 17% and retinopathy 10% of the costs of complications, which were lower than macrovascular complications, which accounted for 52% of the costs [37]. Quality of life & productivity Effect of CV & microvascular complications of diabetes on quality of life & productivity of patients with T2DM

A number of studies reported the association of quality of life with complications in patients with T2DM. However, only a few studies compared the reduction in health-related quality of life between CV and other complications. The common consensus was that the presence of any comorbidity reduced the quality of life, with the diagnosis of additional complication further reducing the quality of life. Two studies found that the number of complications of diabetes and the number of comorbid illnesses were factors related to lower quality of life among patients with diabetes [38,39]. The effect on health-related quality of life varied across different complications in different studies. In Germany, newly diagnosed patients with T2DM, aged 30–55 years, indicated CV complications to be the major reason for work absence [40]. A study in the Netherlands found that patients with diabetes and CV complication have lower quality of life on all dimensions than patients without CV complication [41]. A study of patients with diabetes in four European countries found that the high prevalence of hypertension and heart failure was related to lower quality of life [42], whereas a study in Singapore found coronary heart disease, nephropathy and peripheral neuropathy were associated with lower scores on a quality of life assessment compared with retinopathy [43,44]. Stroke had the greatest negative impact among the CV complications on the quality of life index among patients with diabetes in Norway [45]. In the UK, coronary artery disease, peripheral vascular disease and autonomic neuropathy were significantly associated with low quality of life [46]. Among complications of T2DM, CV complications were not reported to be the highest contributor in reducing quality doi: 10.1586/14737167.2015.1024661

of life; however, this was not surprising because CV complications mainly include asymptomatic conditions, such as hypertension. Diabetic neuropathy, in particular, differed in its effect on quality of life according to studies of all complications of diabetes. Among patients in Singapore, diabetic neuropathy had the greatest reduction in scores on quality of life [43]. Whereas results from studies in China, Norway and Belgium found diabetic neuropathy reduced quality of life similar to the effect seen with CV complications [43,45,47,48]. Quality of life was significantly altered by painful diabetic neuropathy [47]. In a study in the state of Virginia among patients from three institutions, both peripheral and autonomic neuropathies were found to be associated with poor quality of life [49]. Lloyd et al. found that peripheral sensory neuropathy was associated with lower scores on SF-36 quality of life scale compared with other complications of diabetes [46]. A few studies also stated that diabetic retinopathy affects quality of life. A study done among the Latino population in the USA found severe diabetic retinopathy to be associated with worse health-related quality of life against no diabetic retinopathy [50]. Outside the USA, diabetic retinopathy was found to affect the quality of life of patients with diabetes in Germany and Australia [38,51]. However, the effect of retinopathy was less than that of neuropathy. Major amputations and foot ulcers further reduced the quality of life [52]. A study stated that overall, going from least to most severe, quality of life was reduced in following order by complications of diabetes: peripheral vascular disease, other heart diseases, transient ischemic attack, cerebrovascular accident, non-painful diabetic neuropathy, congestive heart failure, dialysis, stroke, painful neuropathy and amputation (FIGURE 4) [53]. However, the order was not found to be consistent in all studies. Mortality Mortality due to CV complications among patients with T2DM in the USA

Five studies looked at different patient populations with T2DM to evaluate the mortality rates among these patients with a CV condition. FIGURE 5 (McEwen et al.) shows a comparison of additional mortality incurred due to complications in patients with T2DM. In general, macrovascular complications had a larger impact on mortality than microvascular complications [54]. The 30-day mortality rate after hospitalization with MI among elderly patients with diabetes was 19%, which was greater than that for patients without diabetes hospitalized with MI (16%) [55]. After 1 year, the mortality rate increased to 24% among the diabetic cohort, which was comparatively higher than among non-diabetic patients with MI (19%) [56]. In a sample of adults with diabetes enrolled in 10 health plans, the 8-year mortality rate was 19%; 40% of deaths were due to CV complications [54]. In the most parsimonious model, neuropathy, angina, MI, coronary angioplasty and congestive heart failure were the best predictors of all-cause mortality. The odds of death were higher in patients with diabetes and comorbid hypertension, congestive heart failure, stroke, angina and MI Expert Rev. Pharmacoecon. Outcomes Res.

Impact of CV complications among patients with T2DM

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an analysis of the Munich Stroke Registry showed that 16.9% of patients with diabetes died after hospitalization for stroke [61]. In Lithuania, the 28-day and 1-year mortality rates were higher in patients with diabetes and comorbid MI than in patients without diabetes, and the risk increased with heart failure [62]. In summary, MI, stroke and heart failure were the main CV conditions that increased the risk of mortality among patients with T2DM outside the USA. Discussion

It is clear from this systematic review that the prevalence of CV complications is very high among patients with T2DM. Cerebral vascular accident Peripheral vascular Approximately 15–81% of patients with (stroke) disease T2DM had at least one of the CV conditions. Findings from the review showed Hemiplegia that hypertension was the most prevalent Figure 4. Relative percentage decrease in Health Utility Scores according to CV complication, followed by MI and complications in patients with T2DM. heart failure. The prevalence of CV comT2DM: Type 2 diabetes mellitus. plications was found to be higher among Data taken from [53]. institutionalized than noninstitutionalized patients with T2DM. However, based on than in patients with diabetes without these conditions [57]. In the studies reviewed, the prevalence of CV complications difa study of patients with diabetes in Washington State, 42.7% fered according to the region where the study was conducted. of deaths were attributed to atherosclerotic CV complica- Because of the differing populations in various studies included tion [58]. In 2012 in the USA, 110,000 deaths were due to CV in this review, it was not possible to observe the yearly trend in complications among patients with diabetes, whereas the prevalence of CV complications. Patients diagnosed with 73,000 deaths were due to diabetes alone [2]. Findings from diabetes early in life were more likely to experience CV comorthese studies suggest that CV condition is a serious risk for bidity later in life than late-onset patients. death among patients with T2DM in the USA. Microvascular complications were the second most prevalent In addition, pharmacological treatment of T2DM with cer- after CV complications among patients with T2DM. The prevtain medications, such as sulfonylureas, was also reported to be alence of microvascular complications ranged from 4.4 to correlated with CV events leading to death in three studies [4–6]. 25.4%. Neuropathy was the most common microvascular comA meta-analysis concluded that there is a potential association plication, but patients also had nephropathy and retinopathy. of sulfonylureas with CV deaths based on observational studies The prevalence of neuropathy almost doubled in the institureporting significant association between sulfonylurea use and tionalized patients with T2DM. The high rates of comorbidity CV-related deaths. The University Group Diabetes Program reported can still be an underestimation because rates are calcu(UGDP), a long-term prospective clinical trial, also reported lated through disease episodes reported by the patients. The that patients treated for 5–8 years with tolbutamide (hypoglyce- actual statistic may show still higher rates. mic drug belonging to sulfonylurea class) had a rate of CV In terms of economic burden, the total healthcare costs for mortality approximately 2.5-fold greater than that of patients patients with T2DM and CV complications in the USA were treated with diet alone [59]. 58% greater than the healthcare cost for treating diabetes alone. This increase included direct medical costs in the range of Mortality due to CV complications among patients with T2DM US$8805–US$9648. CV complications, as a group, were the outside the USA second highest contributor after ESRD in terms of additional Four studies evaluated the mortality rate due to CV conditions healthcare costs. The added cost due to CV complications was in patients with T2DM in countries outside the USA. In the driven by MI, stroke, heart failure and hypertension in decreasNetherlands, 18% of patients with diabetes died due to MI after ing order. The total costs for CV complications were the highhospital admission, and the 5-year mortality rate was also found est for the age group of 55–64 years. Compared with to be high. In China, the in-hospital mortality rate for patients ESRD and CV complications, other complications of diabetes with diabetes after ischemic stroke was 18.2% [60]. In Germany, had a lower impact. Direct medical costs ranged from informahealthcare.com

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conditions known to increase mortality rates among patients with diabetes. Among the microvascular complications, only nephropathy had a significant effect on mortality in patients with T2DM.

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Cardiovascular conditions Complications

Figure 5. Mortality due to complications among patients with T2DM. T2DM: Type 2 diabetes mellitus. Data taken from [54].

US$2764–US$8500 for patients with other complications of diabetes, such as retinopathy, neuropathy and nephropathy. It was also observed that certain antidiabetic drugs belonging to the class sulfonylureas increase the risk of CV events, which, in turn, could increase the cost burden [4]. Because of this potential adverse effect, developers of new diabetic medications are now required by the US FDA to assess safety related to CV events. As a result, newer drugs, such as saxagliptin and alogliptin belonging to the class of dipeptidyl peptidase-4 inhibitors, were recently shown to be CV neutral in separate clinical trials: SAVOR [63] and EXAMINE [64] potentially improving condition and reducing costs in contrast with some antihyperglycemic medications [4,6,8,65]. Besides the economic burden, quality of life of patients with T2DM was also reported to be worsened due to the number of comorbid illnesses that include CV complications. The CV complications that affected quality of life significantly were stroke, heart failure, coronary heart disease, congestive heart failure and hypertension. However, compared with CV complications, painful neuropathy and amputations had a larger effect on quality of life. Although a direct relation was shown between disease condition and reduced quality of life, age and duration of diabetes may also play an important role in reducing quality of life, which could not be controlled for in the analyses. The mortality rates among patients with diabetes along with CV complications were observed to be much higher than the mortality rates of diabetes or CV disease alone. Hypertension, congestive heart failure, stroke, angina and MI were the CV doi: 10.1586/14737167.2015.1024661

In all of the studies that were included, the method of data collection differed, which might have affected the results giving us a broad range of prevalence and costs values. Especially for the calculation of indirect costs, there is no gold standard to determine the values. Owing to the variation in data collection, patient population and settings, it was not possible to conduct a meta-analysis. Therefore, a descriptive overview was given on the prevalence, healthcare costs, quality of life and mortality. Any constraints applied by establishing the exclusion criteria for the systematic review would have limited the applicability of the review findings. However, these exclusion criteria were applied to restrict the complexity of data. Conclusion

Macrovascular complications are the most common complications found in patients with T2DM. They represent the second most expensive group of complications after ESRD and have a significant impact on the quality of life of patients suffering from it. In case of mortality, CV complications have the greatest impact. There are areas to be improved in future research on economic burden of CV complications. For example, the existing body of literature lacks studies estimating indirect costs associated with the CV complications. Although it is very challenging to estimate indirect costs, it is an important component in economic evaluations to ascertain the magnitude of the total costs. Expert commentary

T2DM is a major contributor to the healthcare costs in the USA. The cost burden of T2DM intensifies with the diagnosis of other complications. As research continues to develop medications for T2DM, it is imperative to focus on accompanying complications. It is evident from the findings of this systematic review that the prevalence of complications in patients with T2DM considerably increased total healthcare expenditures and affected the quality of life. CV diseases, such as hypertension, MI and heart failure, add to the healthcare costs of patients with T2DM and contribute to mortality. Five-year view

In the near future, prevention and adequate control of complications of T2DM will play a major role in containing overall health care expenditures. The aggressive lowering of HbA1c levels has shown to be very effective in controlling T2DM and consequent complications. However, it has also been observed that such aggressive approach may actually increase the risk of CV complications, possibly by increasing the risk of hypoglycemia. The future focus will be on achieving the optimum HbA1c control with treatments that do not negatively impact Expert Rev. Pharmacoecon. Outcomes Res.

Impact of CV complications among patients with T2DM

CV complications. The FDA has already issued regulations to developers of new diabetic medications to assess CV safety during clinical trials.

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Acknowledgements

We would like to acknowledge Mr. Robert Bechtol and Mr. Wade Lee for their assistance in the literature search.

Review

Financial & competing interests disclosure

This systematic review was funded by Bristol-Myers Squibb and AstraZeneca. J Sheehan is an employee of AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues .

Cardiovascular (CV) conditions were the most prevalent followed by microvascular conditions.

.

At a patient level, end-stage renal disease was the highest contributor to total costs (US$56,700–US$63,000 per patient) as well as direct costs followed by CV (US$7500– US$25,000 per patient) and microvascular conditions (US$9000– US$14,000). However, at a population level, CV conditions were the highest contributor to healthcare expenditures (US$23 billion).

.

The presence of any chronic comorbidity reduced the quality of life significantly in Type 2 diabetes mellitus patients.

.

CV conditions were the major contributor to mortality among Type 2 diabetes mellitus patients.

1.

2.

3.

4.

5.

6.

7.

8.

Center for Disease Control and Prevention. Available from: www.cdc.gov/nchs/data/dvs/ deaths_2010_release.pdf [Accessed 17 April 2013] American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36(4):1033-46 Center for Disease Control and Prevention (CDC). National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA; 2008. Available from: www. cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf [Accessed 16 October 2013]

9.

10.

11.

Phung OJ, Schwartzman E, Allen RW, et al. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 2013;30(10): 1160-71

12.

Wheeler S, Moore K, Forsberg CW, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia 2013. [Epub ahead of print]

13.

Forst T, Hanefeld M, Jacob S, et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res 2013;10(4):302-14

14.

Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358(24):2545-59 Kheirbek RE, Alemi F, Zargoush M. Comparative effectiveness of hypoglycemic

informahealthcare.com

16.

Luijks H, Schermer T, Bor H, et al. Prevalence and incidence density rates of chronic comorbidity in type 2 diabetes patients: an exploratory cohort study. BMC Med 2012;10:128

Chang K. Comorbidities, quality of life and patients’ willingness to pay for a cure for type 2 diabetes in Taiwan. Public Health 2010;124(5):284-94

17.

Song SH, Hardisty CA. Early onset type 2 diabetes mellitus: a harbinger for complications in later years – clinical observation from a secondary care cohort. QJM 2009;102(11):799-806

Caughey GE, Roughead EE, Vitry AI, et al. Comorbidity in the elderly with diabetes: identification of areas of potential treatment conflicts. Diabetes Res Clin Pract 2010; 87(3):385-93

18.

Jurado J, Ybarra J, Solanas P, et al. Prevalence of cardiovascular disease and risk factors in a type 2 diabetic population of the North Catalonia diabetes study. J Am Acad Nurse Pract 2009;21(3):140-8

Poulsen MK, Henriksen JE, Dahl J, et al. Myocardial ischemia, carotid, and peripheral arterial disease and their interrelationship in type 2 diabetes patients. J Nucl Cardiol 2009;16(6):878-87

19.

Suh DC, Kim CM, Choi IS, Plauschinat CA. Comorbid conditions and glycemic control in elderly patients with type 2 diabetes mellitus, 1988 to 1994 to 1999 to 2004. J Am Geriatr Soc 2008; 56(3):484-92

20.

Piazza G, Goldhaber SZ, Kroll A, et al. Venous thromboembolism in patients with diabetes mellitus. Am J Med 2012;125(7): 709-16

21.

Pelletier EM, Shim B, Ben-Joseph R, Caro JJ. Economic outcomes associated with microvascular complications of type 2 diabetes mellitus: results from a US claims data analysis. Pharmacoeconomics 2009;27(6):479-90

22.

Mody R, Kalsekar I, Kavookjian J, et al. Economic impact of cardiovascular co-morbidity in patients with type 2 diabetes. J Diabetes Complications 2007;21(2):75-83

23.

Gandra SR, Lawrence LW, Parasuraman BM, et al. Total and component health care costs in a non-Medicare HMO population of patients

medications among veterans. J Manag Care Pharm 2013;19(9):740-4

References

15.

Zhang X, Decker FH, Luo H, et al. Trends in the prevalence and comorbidities of diabetes mellitus in nursing home residents in the United States: 1995-2004. J Am Geriatr Soc 2010;58(4):724-30 Gee ME, Janssen I, Pickett W, et al. Prevalence, awareness, treatment, and control of hypertension among Canadian adults with diabetes, 2007 to 2009. Can J Cardiol 2012;28(3):367-74 Vijayaraghavan M, He G, Stoddard P, Schillinger D. Blood pressure control, hypertension, awareness, and treatment in adults with diabetes in the United States-Mexico border region. Rev Panam Salud Publica 2010;28(3):164-73 Zekry D, Frangos E, Graf C, et al. Diabetes, comorbidities and increased long-term mortality in older patients admitted for geriatric inpatient care. Diabetes Metab 2012;38(2):149-55

doi: 10.1586/14737167.2015.1024661

Review

Vaidya, Gangan & Sheehan

with and without type 2 diabetes and with and without macrovascular disease. J Manag Care Pharm 2006;12(7):546-54

Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.

24.

Erwin G, Iyer S, Rajagopalan R, et al. Type 2 diabetes mellitus treatment patterns and healthcare costs in the elderly population. Dis Manag Health Outcomes 2006;14(2):75-83

25.

Brandle M, Zhou H, Smith BR, et al. The direct medical cost of type 2 diabetes. Diabetes Care 2003;26(8):2300-4

26.

Li R, Bilik D, Brown MB, et al. Medical costs associated with type 2 diabetes complications and comorbidities. Am J Manag Care 2013;19(5):421-30

27.

Straka RJ, Liu LZ, Girase PS, et al. Incremental cardiovascular costs and resource use associated with diabetes: an assessment of 29,863 patients in the US managed-care setting. Cardiovasc Diabetol 2009;8:53

36.

Brown JB, Pedula KL, Bakst AW. The progressive cost of complications in type 2 diabetes mellitus. Arch Intern Med 1999;159(16):1873-80

37.

Caro JJ, Ward AJ, O’Brien JA. Lifetime costs of complications resulting from type 2 diabetes in the U.S. Diabetes Care 2002;25(3):476-81

38.

Davidov E, Breitscheidel L, Clouth J, et al. Diabetic retinopathy and health-related quality of life. Graefes Arch Clin Exp Ophthalmol 2009;247(2):267-72

48.

Cong JY, Zhao Y, Xu QY, et al. Health-related quality of life among Tianjin Chinese patients with type 2 diabetes: a cross-sectional survey. Nurs Health Sci 2012;14(4):528-34

49.

Chyun DA, Melkus GD, Katten DM, et al. The association of psychological factors, physical activity, neuropathy, and quality of life in type 2 diabetes. Biol Res Nurs 2006; 7(4):279-88

50.

Mazhar K, Varma R, Choudhury F, et al. Severity of diabetic retinopathy and health-related quality of life: the Los Angeles Latino Eye Study. Ophthalmology 2011; 118(4):649-55

39.

Glasgow RE, Ruggiero L, Eakin EG, et al. Quality of life and associated characteristics in a large national sample of adults with diabetes. Diabetes Care 1997;20(4):562-7

51.

40.

Julius U, Gross P, Hanefeld M. Work absenteeism in type 2 diabetes mellitus: results of the prospective Diabetes Intervention Study. Diabete Metab 1993; 19(1 Pt 2):202-6

Fenwick EK, Xie J, Ratcliffe J, et al. The impact of diabetic retinopathy and diabetic macular edema on health-related quality of life in type 1 and type 2 diabetes. Invest Ophthalmol Vis Sci 2012;53(2):677-84

52.

Ragnarson Tennvall G, Apelqvist J. Health-related quality of life in patients with diabetes mellitus and foot ulcers. J Diabetes Complications 2000;14(5):235-41

28.

Hogan P, Dall T, Nikolov P, American Diabetes A. Economic costs of diabetes in the US in 2002. Diabetes Care 2003;26(3):917-32

41.

de Visser CL, Bilo HJ, Groenier KH, et al. The influence of cardiovascular disease on quality of life in type 2 diabetics. Qual Life Res 2002;11(3):249-61

53.

29.

O’Brien JA, Shomphe LA, Kavanagh PL, et al. Direct medical costs of complications resulting from type 2 diabetes in the U.S. Diabetes Care 1998;21(7):1122-8

42.

30.

Pelletier EM, Smith PJ, Boye KS, et al. Direct medical costs for type 2 diabetes mellitus complications in the US commercial payer setting: a resource for economic research. Appl Health Econ Health Policy 2008;6(2-3):103-12

Venskutonyte L, Brismar K, Ohrvik J, et al. Self-rated health predicts outcome in patients with type 2 diabetes and myocardial infarction: a DIGAMI 2 quality of life sub-study. Diab Vasc Dis Res 2013;10(4): 361-7

Zhang P, Brown MB, Bilik D, et al. Health utility scores for people with type 2 diabetes in U.S. managed care health plans: results from Translating Research Into Action for Diabetes (TRIAD). Diabetes Care 2012; 35(11):2250-6

54.

43.

Venkataraman K, Wee HL, Leow MK, et al. Associations between complications and health-related quality of life in individuals with diabetes. Clin Endocrinol (Oxf) 2013;78(6):865-73

McEwen LN, Karter AJ, Waitzfelder BE, et al. Predictors of mortality over 8 years in type 2 diabetic patients: translating Research Into Action for Diabetes (TRIAD). Diabetes Care 2012;35(6):1301-9

55.

44.

Green AJ, Bazata DD, Fox KM, Grandy S. Quality of life, depression, and healthcare resource utilization among adults with type 2 diabetes mellitus and concomitant hypertension and obesity: a prospective survey. Cardiol Res Pract 2012;2012:404107

Chyun D, Vaccarino V, Murillo J, et al. Acute myocardial infarction in the elderly with diabetes. Heart Lung 2002;31(5): 327-39

56.

Chyun D, Vaccarino V, Murillo J, et al. Cardiac outcomes after myocardial infarction in elderly patients with diabetes mellitus. Am J Crit Care 2002;11(6):504-19

57.

Koek HL, Soedamah-Muthu SS, Kardaun JW, et al. Short- and long-term mortality after acute myocardial infarction: comparison of patients with and without diabetes mellitus. Eur J Epidemiol 2007; 22(12):883-8

58.

Lin EH, Heckbert SR, Rutter CM, et al. Depression and increased mortality in diabetes: unexpected causes of death. Ann Fam Med 2009;7(5):414-21

59.

The University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of pheniformin therapy. Diabetes 1975; 24(Suppl 1):65-184

31.

Dworkin RH, Malone DC, Panarites CJ, et al. Impact of postherpetic neuralgia and painful diabetic peripheral neuropathy on health care costs. J Pain 2010;11(4):360-8

32.

Gordois A, Scuffham P, Shearer A, et al. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26(6):1790-5

33.

Nichols GA, Vupputuri S, Lau H. Medical care costs associated with progression of diabetic nephropathy. Diabetes Care 2011; 34(11):2374-8

34.

Burke J, Kovacs B, Borton L, Sander S. Health care utilization and costs in type 2 diabetes mellitus and their association with renal impairment. Postgrad Med 2012;124(2):77-91

35.

O’Brien JA, Patrick AR, Caro J. Estimates of direct medical costs for microvascular and macrovascular complications resulting from type 2 diabetes mellitus in the United States in 2000. Clin Ther 2003;25(3):1017-38

doi: 10.1586/14737167.2015.1024661

45.

Solli O, Stavem K, Kristiansen IS. Health-related quality of life in diabetes: the associations of complications with EQ-5D scores. Health Qual Life Outcomes 2010;8:18

46.

Lloyd A, Sawyer W, Hopkinson P. Impact of long-term complications on quality of life in patients with type 2 diabetes not using insulin. Value Health 2001;4(5):392-400

47.

Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab 2009; 35(3):206-13

Expert Rev. Pharmacoecon. Outcomes Res.

Impact of CV complications among patients with T2DM

60.

Expert Review of Pharmacoeconomics & Outcomes Research Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.

61.

62.

Zhang XD, Chen YR, Ge L, et al. Features of stroke in Chinese diabetes patients: a hospital-based study. J Int Med Res 2007; 35(4):540-6 Braun KF, Otter W, Sandor SM, et al. All-cause in-hospital mortality and comorbidity in diabetic and non-diabetic patients with stroke. Diabetes Res Clin Pract 2012;98(1):164-8 Jancaityte L, Rastenyte D. Short-term and one-year prognosis of diabetic patients with

informahealthcare.com

a first-ever myocardial infarction. Medicina (Kaunas) 2007;43(7):555-61 63.

Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369(14):1317-26

64.

White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369(14):1327-35

65.

Review

Morgan CL, Mukherjee J, Jenkins-Jones S, et al. Association between first-line monotherapy with sulphonylurea versus metformin and risk of all-cause mortality and cardiovascular events: a retrospective, observational study. Diabetes Obes Metab 2014;16(10):957-62

doi: 10.1586/14737167.2015.1024661