http://orcid.org/0000-0002-4370-8063
Figures
Abstract
Introduction
Type 2 diabetes (T2D) is a major health priority worldwide and the majority of people with diabetes live with multimorbidity (MM) (the co-occurrence of ≥2 chronic conditions). The aim of this systematic review was to explore the association between MM and all-cause mortality and glycaemic outcomes in people with T2D.
Methods
The search strategy centred on: T2D, MM, comorbidity, mortality and glycaemia. Databases searched: MEDLINE, EMBASE, CINAHL Complete, The Cochrane Library, and SCOPUS. Restrictions included: English language, quantitative empirical studies. Two reviewers independently carried out: abstract and full text screening, data extraction, and quality appraisal. Disagreements adjudicated by a third reviewer.
Results
Of the 4882 papers identified; 41 met inclusion criteria. The outcome was all-cause mortality in 16 studies, glycaemia in 24 studies and both outcomes in one study. There were 28 longitudinal cohort studies and 13 cross-sectional studies, with the number of participants ranging from 96–892,223. Included studies were conducted in high or upper-middle-income countries. Fifteen of 17 studies showed a statistically significant association between increasing MM and higher mortality. Ten of 14 studies showed no significant associations between MM and HbA1c. Four of 14 studies found higher levels of MM associated with higher HbA1c. Increasing MM was significantly associated with hypoglycaemia in 9/10 studies. There was no significant association between MM and fasting glucose (one study). No studies explored effects on glycaemic variability.
Conclusions
This review demonstrates that MM in T2D is associated with higher mortality and hypoglycaemia, whilst evidence regarding the association with other measures of glycaemic control is mixed. The current single disease focused approach to management of T2D seems inappropriate. Our findings highlight the need for clinical guidelines to support a holistic approach to the complex care needs of those with T2D and MM, accounting for the various conditions that people with T2D may be living with.
Citation: Chiang JI, Jani BD, Mair FS, Nicholl BI, Furler J, O’Neal D, et al. (2018) Associations between multimorbidity, all-cause mortality and glycaemia in people with type 2 diabetes: A systematic review. PLoS ONE 13(12): e0209585. https://doi.org/10.1371/journal.pone.0209585
Editor: Wen-Jun Tu, Chinese Academy of Medical Sciences and Peking Union Medical College, CHINA
Received: July 2, 2018; Accepted: December 8, 2018; Published: December 26, 2018
Copyright: © 2018 Chiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: T2D, Type 2 diabetes; MM, Multimorbidity; HbA1c, glycated haemoglobin; GV, Glycaemic variability; CCI, Charlson Comorbidity Index
Introduction
Type 2 diabetes (T2D) is a leading health priority. Over 424 million people live with diabetes worldwide, leading to $727 billion US dollars in healthcare expenditure [1]. It is estimated that four million people die from diabetes related causes every year, equivalent to one death every eight seconds [1].
T2D management is complex and requires continuous efforts from both clinicians and patients to implement recommendations for self-management and pharmacotherapy to achieve evidence-based targets. For patients who have other chronic conditions in addition to T2D, this complexity is amplified. This is important as T2D rarely occurs on its own–multimorbidity (MM) (presence of ≥ 2 conditions) is the norm, with approximately 85% of those living with T2D having at least one other chronic condition [2].
MM produces many challenges. It is associated with lower quality of life, increased costs, a reduced ability to make lifestyle changes and may be associated with complex therapeutic regimens [3], increasing the treatment burden experienced by the patient [4]. This in turn may challenge and overwhelm individuals, resulting in reduced adherence and poorer outcomes [4]. MM presents health professionals with increased workloads, and the clinical challenge of interactions between multiple conditions and medications (4).
While MM brings about multiple challenges in a clinical sense, it also presents multiple considerations from a conceptual perspective. The terms comorbidity and MM are often used interchangeably [5]. Only more recently has there been a clearer understanding and distinction between the two terms. Comorbidity is defined as the occurrence or existence of an additional condition that co-occurs with an index disease [6]. MM however refers to the presence of two or more chronic conditions in an individual, with no reference to an index condition [7]. The former term illustrates the traditional approach to understanding T2D along with its well-known micro- and macro-vascular complications. The latter term covers a different view where a person’s overall illness burden is the focus and provides the basis for our systematic review, which focuses on MM in people with T2D.
Despite MM presenting many challenges, there is no “gold standard” for the measurement of MM [8]. We still lack clear and comprehensive criteria for the measurement of MM and selection of chronic conditions that qualify for MM. As a result, a numerical count is an acceptable form of measurement of MM, including particular scales (e.g. Charlson Comorbidity Index) [9] that count particular conditions.
MM is common in T2D and brings many challenges, yet currently little is understood about the association between MM and outcomes in T2D. This systematic review seeks to explore literature on the association between MM condition count in people with T2D and the following two primary outcomes: 1) all-cause mortality; and 2) glycaemia (measured by HbA1c). Secondary outcomes of interest include other measures of glycaemia: 1) hypoglycaemia, 2) hyperglycaemia; and 3) glycaemic variability.
Methods
Our detailed review protocol has been published elsewhere [10] and is summarised below.
We have followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines [11] and our review is registered on the International Prospective Register of Systematic Reviews (CRD42017079500).
Search strategy
A comprehensive search strategy was used to identify empirical quantitative studies with data on associations between MM condition count and our outcomes of interest in people with T2D. Target studies were observational studies that used either a cross-sectional or longitudinal cohort design. The search was limited to papers published in English but there was no restriction on publication date. A formal database search strategy was developed in consultation with a librarian (PC) from a biomedical library and members of our author group with expertise in MM and T2D, using a combination of free text search and medical subject headings; this is shown in S1 Text. Databases searched were MEDLINE (OVID interface), EMBASE (OVID interface), CINAHL Complete (EBSCO interface), The Cochrane Library (OVID interface), and SCOPUS. The search centred around five key concepts: T2D, MM, comorbidity, glycaemia and mortality. The search was carried out to include literature published up to 28th July 2017.
Inclusion/exclusion criteria
We included empirical quantitative studies that included data on associations between MM condition count and adults with T2D and all-cause mortality or glycaemic outcomes. Full details of inclusion and exclusion criteria for studies are shown in S1 Table and discussed in detail elsewhere [10].
Data screening, extraction and analysis
The data screening process was conducted in three stages. Titles of identified studies in the searches were screened by the primary researcher (JC) with a deliberately inclusive approach to reduce the risk of missing potentially relevant studies. Abstract, full paper screening, data extraction and quality appraisal were undertaken by two individual reviewers with any inter-reviewer disagreements resolved by a third reviewer. Covidence [12], a systematic review management software, was used to store, share and assess papers, and undertake selection for inclusion (beyond the title screen). Data were extracted in a structured manner using a predefined data extraction form. Details of the data extraction instrument developed and used are published elsewhere [10]. Data were analysed using a prespecified Population, Exposure, Comparator, Outcomes (PECO) framework which was an adapted framework based on the Cochrane PICO statement where “I” for intervention is replaced with an “E” for exposure. “Study Characteristics” were also included in the framework to take characteristics including study design, setting, period of study, and aims and objectives into account. This PECO approach is acceptable as informed by the Cochrane Handbook [13] and has been utilised previously in a range of published systematic reviews [14, 15]. During data analysis and synthesis, we grouped the included studies according to the two outcomes of interest (all-cause mortality and glycaemia), further subgrouping the latter into different measures of glycaemia. We then considered the implications of the overall findings for each of the outcomes, in order to identify knowledge gaps and clarify the key messages from the evidence, including implications for future research and clinical guidelines for the management of people with T2D.
Quality appraisal
Quality appraisal was conducted by two reviewers independently. All studies were assessed using the Newcastle-Ottawa quality assessment scale [16] which was informed by recommendations from the Cochrane Handbook on assessing the quality of non-randomised studies [13]. The Newcastle-Ottawa quality assessment scale utilises a star system to judge three broad domains of the included studies: the selection of the study groups; the comparability of the groups; and the ascertainment of the outcome of interest. We adapted the quality assessment scale to suit our systematic review; shown in S2 Text. The Newcastle-Ottawa quality assessment scale was designed so that it could be modified for specific systematic reviews for non-randomised studies. For example, in the comparability domain, the scale asks the review authors to select the two most important factors that the included studies should control for. The scale’s face/content validity and inter-rater reliability have been established [16] and our approach with the modified scale has been previously used in a published systematic review [14]. Studies were not excluded based on the quality appraisal because our aim was to develop a comprehensive understanding of the existing literature that explored associations between MM and T2D.
Results
Retrieved studies
In total, 4,882 papers were identified with our search strategy, and 41 subsequently met our inclusion criteria. Fig 1 demonstrates the inclusion and exclusion of papers at each stage of the screening stages utilising the PRISMA flow diagram [11].
Included studies and their characteristics
We included 41 studies in our review. Twenty-four studies [17–40] had glycaemia as an outcome, 16 studies [41–56] had all-cause mortality as an outcome and one study [57] included both outcomes.
Key descriptive information of the included studies is summarised in Table 1 below. Participant numbers ranged from 96 to 892,223. There were 28 longitudinal cohort studies [18, 21, 28, 29, 32–37, 40–57] and 13 cross-sectional studies [17, 19, 20, 22–27, 30, 31, 38, 39]. All included studies were conducted in high or upper-middle-income countries.
Measure of MM
The measure of MM condition count used in the included studies varied considerably. The majority of studies (24/41 (59%)) [19, 21, 27, 28, 30–37, 39–41, 43, 46, 49–53, 55, 57] measured MM in terms of the Charlson Comorbidity Index (CCI) [9]. MM was represented as a simple count of conditions that were available in the study datasets in 15 studies (32%) [17, 18, 22–25, 29, 38, 44, 47, 48, 50, 52, 54, 56]. The remaining studies measured MM with other indices including the chronic diseases score [20], cumulative illness rating scales [26], total illness burden index [42], severity of illness index [45] and the Elixhauser index [52], or a combination of multiple MM measures [50, 52]. The measure of MM for each of the studies is summarised in S2 Table. This further highlights the heterogeneity of included studies. Meta-analysis was not possible due to variation in measurement of MM.
Only 11/41 (27%) [20, 26, 29, 38, 42, 43, 47, 50, 52, 54, 57] studies had the primary objectives of exploring the relationship between MM and our outcomes of interest, however, all included studies provided data about the association between MM and mortality or glycaemia. 9/41 (22%) studies [24, 27, 28, 33, 37, 39, 46, 49, 56] had broad scoping aims of determining factors that were associated with mortality or glycaemia outcomes. More than half, 21/41 (51%) studies [17–19, 21–23, 25, 30–32, 34–36, 40, 41, 44, 45, 48, 51, 53, 55] did not state the investigation of MM as a research objective, but contained MM count as a covariate when exploring the impact of other factors on mortality or glycaemia, including data allowing us to identify the association between MM count and our outcomes of interest. The research aims included describing the effects of a range of factors (e.g. medication adherence, treatment complexity, anti-diabetic oral treatment, treatment interactions, social support, economic burden, obesity) on glycaemic control and mortality. This wide range of research objectives demonstrates the heterogeneity of the included studies.
Description of the demographics of patients included in the studies is summarised in Table 2 below. The mean age of participants ranged from 38 to 83 years; this was unclear or could not be calculated from the data provided in seven studies [23, 25, 27, 35, 38, 45, 48, 49]. Gender of participants were not described in two studies [23, 49] and in those that did (n = 39) [17–22, 24–48, 50–57], the percentage of female ranged from 2% to 70%. Ethnicity was reported in 11 studies [19, 20, 24, 29, 31, 32, 39, 44, 45, 49, 53] and socioeconomic status was seldom reported (n = 7) [29, 32, 38–40, 52, 54]. Full details of participants are shown in S2 Table.
Quality appraisal
The quality appraisal of the included studies is summarised in S2 Text. Generally, the papers were of moderate to high quality based on the Newcastle-Ottawa quality assessment scale. There were 12 (29%) papers assessed as representative of the general T2D population as they were based on large national datasets. Furthermore, under the comparability domain, only 10 (24%) of the 41 included studies considered both age and known duration of diabetes in their data analyses.
All-cause mortality
We identified 17/41 studies [41–57] that included sufficient data to explore the association between MM condition count and all-cause mortality. All but two studies [41, 52] demonstrated that increasing MM count is associated with statistically significant increased odds ratios (ORs) or hazard ratios (HRs) of death. Studies differed in the analytic methods used to determine the relationship between MM and mortality. These included: two-sample t-test to compare MM between surviving and non-surviving participants; multivariable logistic regression models; and multivariable Cox proportional hazard models. Furthermore, MM was treated in analysis either as a continuous or categorical variable in different studies. For studies that showed a significant increase in mortality whilst treating increasing MM as a continuous variable, the HRs from Cox proportional hazard models that explored MM represented by CCI ranged from 1.22 to 1.95 [50, 51, 53, 55]. Whilst the study that represented MM as total illness burden index, the HR was 1.02 [42]. Studies that reported MM in categories presented more difficulties in comparing the results because they differed in the MM categories that were treated as reference groups [43–49, 54, 56]. This varied from treating 0 conditions, 1 condition, 0–2 CCI and 1–2 CCI as reference in the analyses. The OR results therefore also varied greatly. The OR for mortality was 1.26 for having 1+ conditions in addition to T2D when 0 conditions was the reference group [54], whilst the OR for mortality was 5.46 for CCI of 5+ when CCI of 1–2 was the reference group [43]. The HR results also varied extensively. When CCI of 0–2 was the reference group, the HR for CCI of 3–4 was 1.4 [46]. When having 1 condition in addition to T2D was the reference group, the HR for having 3+ conditions was 21.12 [56]. Despite the heterogeneity of the studies, it is evident that increasing MM count, irrespective of the measure used, is associated with increased all-cause mortality. A summary of the results can be found in S3 Table.
Glycaemia
We identified 25 studies [17–40, 57] that explored associations between MM condition count and glycaemic outcomes. Fourteen studies [17, 19, 20, 22–24, 26, 29, 31, 32, 35, 37–39] reported HbA1c, 10 studies [18, 21, 27, 28, 30, 33, 34, 36, 40, 57] hypoglycaemia, and one study [25] measured glycaemia in terms of fasting plasma glucose. All results of the included studies are summarised in S3 Table.
HbA1c.
The majority of studies (10/14)[17, 20, 22–24, 26, 29, 31, 35, 38] showed no association with MM count while four studies [19, 32, 37, 39] found that increased MM count was associated with higher HbA1c. These four studies used different methods of data analysis (S3 Table). Heterogeneity was also seen in the analysis of the effect on HbA1c (continuous for the linear regression model but categorical for the remaining statistical methods).
Hypoglycaemia.
An increase in MM count was significantly associated with hypoglycaemia in nine of the 10 included studies that presented hypoglycaemia as a glycaemic outcome [18, 21, 27, 28, 33, 34, 36, 40, 57]. Nine of these studies presented MM in terms of the CCI. However, the analysis of data differed greatly (S3 Table). For those that treated MM as a continuous variable using the CCI, the ORs for hypoglycaemia ranged from 1.06 to 1.37 per 1 unit increase in CCI [28, 33]. Similar to the mortality studies, the hypoglycaemia studies that reported MM in categories also presented difficulties in comparing the results due the various reference categories used. One study that used logistic regression models categorised CCI into 1 (reference group), 2, 3, 4 and 5+ with ORs for hypoglycaemia of 1.00, 1.31, 1.81, 2.49 and 4.80, respectively [27]. Another study that used Cox proportional hazard models categorised CCI into 0 (reference group), 1, 2, 3, 4 and 5+; the results showed HRs of 1.00, 1.04, 1.22, 1.16, 1.34 and 1.38, respectively [40]. Despite this heterogeneity, it is evident in the included studies that an increase in MM count is associated with a significantly increased risk of hypoglycaemia.
Fasting plasma glucose.
One study explored the relationship between MM count and glycaemia as a continuous measure of fasting plasma glucose [25]. The study used a multivariable linear regression model to investigate the association between increasing number of conditions and fasting plasma glucose, and found no statistically significant association.
Study heterogeneity
Heterogeneity of the included studies can be seen in multiple aspects. It arises from the multiple MM measures used in the included studies, the treatment of MM in data analysis either as continuous or categorical variables and the different statistical analyses used. This is summarised in Figs 2 and 3. As a result, meta-analysis and sub-group analysis are not possible.
Discussion
Summary of results
To the best of our knowledge, this is the first systematic review to synthesise the existing evidence on associations between MM, all-cause mortality and glycaemia in people with T2D.
The key findings from our review were that increased MM condition count in those with T2D is significantly associated with all-cause mortality and hypoglycaemia. However, the evidence of effects on other measures of glycaemia including HbA1c and fasting plasma glucose is mixed. No studies explored the associations of MM with glycaemic variability.
How this fits in with current knowledge
Our findings are consistent with previous literature where increasing MM has been shown to be associated with increased mortality in people with T2D [58–60]. Our findings demonstrated this in a range of settings, countries and study sample sizes. Furthermore, despite variations in the methodologies, measures of MM and statistical analyses, the evidence still suggests an increase in risk of death with increasing MM.
We found no convincing evidence of an association between MM count and HbA1c. This was unexpected as it has been well-established that HbA1c is an important clinical outcome to consider in people with T2D and glycaemic management is a key component of clinical guidelines for T2D. This suggests that the association of MM with mortality that we identified is not necessarily strongly mediated by glycaemia. Studies that have explored the relationship between HbA1c and mortality showed conflicting results where some studies suggested that increased HbA1c was significantly associated with increased mortality [61, 62] however, another demonstrated that the use of intensive therapy to target HbA1c levels below 6.0% increased the rate of death [63]. This mixed picture regarding the relationship between MM count and HbA1c highlights the need for future research to examine how people with T2D and their health professionals approach glycaemic management and targets in the context of MM. It is recognised in many clinical guidelines that HbA1c targets should be individualised based on factors such as age, diabetes duration and MM conditions [64, 65].
We found a significant association between MM and hypoglycaemia with 9/10 studies demonstrating this. Previous studies have suggested that the presence of coexisting conditions may increase a person’s vulnerability to both adverse clinical outcomes, including death, and severe hypoglycaemia [66, 67]. This hypoglycaemia could be as a result of over-treatment or intensive treatment for those that are less healthy (i.e. with greater MM), but a key paper from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed that mortality among those that reported hypoglycaemia was higher for those receiving standard treatment than those receiving intensive treatment [68]. Hypoglycaemia could be a mediating factor for those with increased MM who ultimately have an increased risk of death. It is interesting to note that the one study [30] in our review that reported no association between MM and hypoglycaemia, used self-report hypoglycaemia as an outcome, which was highlighted as a study limitation, as hypoglycaemia awareness may be impaired and / or patient recall may be inaccurate [69, 70].
Another key finding is that despite our comprehensive search of the literature, there was no study that explored the effects of MM count on glycaemic variability. Glycaemic variability, which refers to fluctuations in blood (or interstitial fluid) glucose levels, is a relatively new measure of glycaemia in people with T2D. There is growing interest in targeting reduced glycaemic variability as an independent clinical goal because higher glucose variability is thought to be associated with the development of chronic diabetes complications [71]. It is clear that there is a need for new knowledge to be generated to further understand the association between glycaemic variability and MM, and whether it will be clinically important or just another surrogate marker with little clinical importance to people with T2D.
Methodological findings and implications
The studies included in our review were highly heterogenous, particularly in the way that MM was measured. There is no consensus as to what is the best method to measure MM, and which is most appropriate to use to predict mortality and other clinical outcomes. Monami et al, however, demonstrated that using a condition count was not inferior to the more complex CCI (which applies weightings to the count) when predicting mortality in people with T2D [50]. The attribution of different weights to comorbidities, based on the severity, in the CCI does not seem to add prognostic value in predicting mortality relative to a simple condition count. Moreover, as evident in our findings, increasing counts of conditions and other indices other than the CCI can also be significant predictors of all-cause mortality in people with T2D. Although our findings suggest that various measures of MM showed significant associations with increased mortality, we cannot identify the best measure of MM in predicting mortality. Nor can we identify the type of multimorbid conditions that could have stronger associations with mortality and glycaemia. Piette and Kerr have recommended that multimorbid conditions should be qualitatively assessed as concordant (related to T2D) or discordant (unrelated to T2D) [72] and argue that condition counts are insufficient in describing MM. Therefore, the implications for future research are that well-designed comparative studies of separate measures including concordant and discordant conditions are warranted using large international datasets. Finally, while it will be essential to understand what patterns of MM are associated with the worst outcomes it will also be important to investigate the mechanisms underpinning the increased mortality experienced by those with T2D and MM. Importantly, it will be essential to explore to what extent poor outcomes are explained by biology and how much is a result of health-care systems that may be fragmented and failing to provide coordinated, supportive and holistic care, tailored to the needs of people with complex health care problems [73].
Strengths and limitations
Key strengths of our review are our adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines, our comprehensive search strategy, and that all screening and data extraction were performed by two reviewers independently.
We restricted our search to studies in the English language, which might be viewed as a limitation, although there is increasing evidence that this is unlikely to be a particular problem [74]. We did not apply any geographical limitations, and our review included studies from a variety of countries, all of which were high-income countries or upper-middle-income countries according to the United Nations country classifications. However, there were no studies conducted in low-income countries. We also recognise the limitation of cross-sectional studies in terms of assessment of temporality however, cross-sectional studies provide a snapshot of the relationship between MM count and glycaemia related outcomes of interest.
Important strengths of our review are that we conducted an exhaustive search of five electronic databases and our tight inclusion and exclusion criteria allowed us to gather any data that explored associations between MM and our outcomes of interest, even if the study did not specifically aim to explore this relationship.
A major advantage of our review is that it brings together information about the effects of MM in people with T2D from various sources to create a comprehensive picture of its effects on a number of outcomes. However, one limitation is that the included studies and therefore study participants were highly heterogenous, making comparisons between studies difficult, which prevented meta-analyses and limited us to a narrative synthesis. The large variation arose from the many ways MM is defined, the way outcomes are reported and the varying methods of statistical analyses. Another limitation of our review is that we did not explore the effects of specific multimorbid conditions on our outcomes of interest. While specific comorbidities such as diabetic nephropathy may potentially have contributed to hypoglycaemia as an endpoint in the included studies we were not able to explore this. Our focus is on the overall burden of illness experienced by people with T2D in the form of a MM count. The impact of specific conditions on outcomes in people with MM could be explored in future studies.
Conclusions
We have reviewed the existing literature to provide a comprehensive summary of the effects of MM count in people with T2D on all-cause mortality and glycaemic outcomes. Our findings show that MM is significantly associated with increased mortality and hypoglycaemia. However, the effects of MM on other measures of glycaemic control, particularly HbA1c, is mixed.
Our review findings emphasise the need for clinical guidelines and clinicians to support a holistic approach to the complex care needs of those with T2D living MM, where care of the whole person should be the primary concern, an approach that accounts for the full range of conditions that people with T2D may be living with.
Supporting information
S1 Table. Inclusion and exclusion criteria for papers.
https://doi.org/10.1371/journal.pone.0209585.s001
(DOCX)
S2 Text. Adapted Newcastle-Ottawa quality assessment scale.
https://doi.org/10.1371/journal.pone.0209585.s005
(DOCX)
References
- 1.
International Diabetes Federation. IDF Diabetes Atlas 8th Edition. 2017.
- 2.
Australian Bureau of Statistics. National Health Survey: First Result, 2014–15. 2015.
- 3. Harris MF, Dennis S, Pillay M. Multimorbidity: Negotiating priorities and making progress. AFP. 2013;42(12):850–4. pmid:24324984
- 4. Mair FS, May CR. Thinking about the burden of treatment. Bmj. 2014;349:g6680. pmid:25385748.
- 5. Fortin M, Lapointe L, Hudon C, Vanasse A. Multimorbidity is common to family practice: is it commonly researched? Canadian family physician Medecin de famille canadien. 2005;51:244–5. pmid:16926936; PubMed Central PMCID: PMC1472978.
- 6. Feinstein AR. The Pre-Therapeutic Classification of Co-Morbidity in Chronic Disease. Journal of chronic diseases. 1970;23(7):455–68. pmid:26309916.
- 7. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. The Lancet. 2012;380:37–43.
- 8. Diederichs C, Berger K, Bartels DB. The measurement of multiple chronic diseases—a systematic review on existing multimorbidity indices. The journals of gerontology Series A, Biological sciences and medical sciences. 2011;66(3):301–11. pmid:21112963.
- 9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of chronic diseases. 1987;40(5):373–83. pmid:3558716.
- 10. Chiang JI, Furler J, Mair FS, Jani B, Nicholl BI, Jenkins A, et al. Impact of multimorbidity count on all-cause mortality and glycaemic outcomes in people with type 2 diabetes: a systematic review protocol. BMJ open. 2018;8(4). pmid:29626050
- 11. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 2015;4:1. pmid:25554246; PubMed Central PMCID: PMC4320440.
- 12.
Covidence systematic review software: Veritas Health Innovation, Melbourne, Australia. Available from: www.covidence.org.
- 13.
Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] 2011. Available from: http://handbook.cochrane.org.
- 14. Morgan AD, Sharma C, Rothnie KJ, Quint JK. Chronic obstructive pulmonary disease and the risk of stroke: a systematic review protocol. BMJ open. 2016;6(11).
- 15. Whaley P, Halsall C, Ågerstrand M, Aiassa E, Benford D, Bilotta G, et al. Implementing systematic review techniques in chemical risk assessment: Challenges, opportunities and recommendations. Environment International. 2016;92–93:556–64. https://doi.org/10.1016/j.envint.2015.11.002 pmid:26687863
- 16.
Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [cited 2017 28 July]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
- 17. Abbatecola AM, Bo M, Armellini F, D'Amico F, Desideri G, Falaschi P, et al. Tighter glycemic control is associated with ADL physical dependency losses in older patients using sulfonylureas or mitiglinides: Results from the DIMORA study. Metabolism: Clinical & Experimental. 2015;64(11):1500–6. https://doi.org/10.1016/j.metabol.2015.07.018 pmid:26318195.
- 18. Abbatecola AM, Bo M, Barbagallo M, Incalzi RA, Pilotto A, Bellelli G, et al. Severe hypoglycemia is associated with antidiabetic oral treatment compared with insulin analogs in nursing home patients with type 2 diabetes and dementia: results from the DIMORA study. Journal of the American Medical Directors Association. 2015;16(4):349.e7-12. https://doi.org/10.1016/j.jamda.2014.12.014 pmid:25669671.
- 19. Bae JP, Lage MJ, Mo D, Nelson DR, Hoogwerf BJ. Obesity and glycemic control in patients with diabetes mellitus: Analysis of physician electronic health records in the US from 2009–2011. J Diabetes Complications. 2016;30(2):212–20. https://doi.org/10.1016/j.jdiacomp.2015.11.016 pmid:26689451.
- 20. El-Kebbi IM, Ziemer DC, Cook CB, Miller CD, Gallina DL, Phillips LS. Comorbidity and glycemic control in patients with type 2 diabetes. Archives of Internal Medicine. 2001;161(10):1295–300. pmid:11371257.
- 21. Fonseca V, Chou E, Chung HW, Gerrits C. Economic burden of hypoglycemia with basal insulin in type 2 diabetes. American Journal of Managed Care. 2017;23(2):114–22. pmid:28245655.
- 22. Foran E, Hannigan A, Glynn L. Prevalence of depression in patients with type 2 diabetes mellitus in Irish primary care and the impact of depression on the control of diabetes. Irish Journal of Medical Science. 2015;184(2):319–22. https://doi.org/10.1007/s11845-014-1110-7 pmid:24723006.
- 23. Fox KM, Gerber Pharmd RA, Bolinder B, Chen J, Kumar S. Prevalence of inadequate glycemic control among patients with type 2 diabetes in the United Kingdom general practice research database: A series of retrospective analyses of data from 1998 through 2002. Clinical Therapeutics. 2006;28(3):388–95. https://doi.org/10.1016/j.clinthera.2006.03.005 pmid:16750453.
- 24. Frei A, Herzog S, Woitzek K, Held U, Senn O, Rosemann T, et al. Characteristics of poorly controlled Type 2 diabetes patients in Swiss primary care. Cardiovascular Diabetology. 2012;11:70. https://doi.org/10.1186/1475-2840-11-70 pmid:22704274.
- 25. Gallegos-Carrillo K, Garcia-Pena C, Duran-Munoz CA, Flores YN, Salmeron J. Relationship between social support and the physical and mental wellbeing of older Mexican adults with diabetes. Revista de Investigacion Clinica. 2009;61(5):383–91. pmid:20184098.
- 26. Hudon C, Fortin M, Dubois MF, Almirall J. Comorbidity and glycemia control among patients with type 2 diabetes in primary care. Diabetes, Metabolic Syndrome and Obesity Targets and Therapy. 2008;1:33–7. pmid:21437154.
- 27. Kim HM, Seong JM, Kim J. Risk of hospitalization for hypoglycemia among older Korean people with diabetes mellitus: Interactions between treatment modalities and comorbidities. Medicine. 2016;95(42):e5016. https://doi.org/10.1097/MD.0000000000005016 pmid:27759630.
- 28. Kostev K, Dippel FW, Rathmann W. Predictors of hypoglycaemia in insulin-treated type 2 diabetes patients in primary care: a retrospective database analysis. Primary Care Diabetes. 2014;8(2):127–31. https://doi.org/10.1016/j.pcd.2013.10.001 pmid:24183472.
- 29. Luijks H, Biermans M, Bor H, van Weel C, Lagro-Janssen T, de Grauw W, et al. The Effect of Comorbidity on Glycemic Control and Systolic Blood Pressure in Type 2 Diabetes: A Cohort Study with 5 Year Follow-Up in Primary Care. PLoS ONE [Electronic Resource]. 2015;10(10):e0138662. https://doi.org/10.1371/journal.pone.0138662 pmid:26426904.
- 30. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Self-report of hypoglycemia and health-related quality of life in patients with type 1 and type 2 diabetes. Endocrine Practice. 2013;19(5):792–9. https://doi.org/10.4158/EP12382.OR pmid:23757608.
- 31. Mosen DM, Glauber H, Stoneburner AB, Feldstein AC. Assessing the association between medication adherence and glycemic control. American Journal of Pharmacy Benefits. 2017;9(3):82–8.
- 32. Pollack M, Chastek B, Williams SA, Moran J. Impact of treatment complexity on adherence and glycemic control: an analysis of oral antidiabetic agents. Journal of Clinical Outcomes Management. 2010;17(6):257–65. pmid:105037353. Language: English. Entry Date: 20100903. Revision Date: 20150711. Publication Type: Journal Article.
- 33. Quilliam BJ, Simeone JC, Ozbay AB. Risk factors for hypoglycemia-related hospitalization in patients with type 2 diabetes: a nested case-control study. Clinical Therapeutics. 2011;33(11):1781–91. https://doi.org/10.1016/j.clinthera.2011.09.020 pmid:22018449.
- 34. Rathmann W, Kostev K, Gruenberger JB, Dworak M, Bader G, Giani G. Treatment persistence, hypoglycaemia and clinical outcomes in type 2 diabetes patients with dipeptidyl peptidase-4 inhibitors and sulphonylureas: a primary care database analysis. Diabetes, Obesity & Metabolism. 2013;15(1):55–61. https://doi.org/10.1111/j.1463-1326.2012.01674.x pmid:22862879.
- 35. Romero SP, Garcia-Egido A, Escobar MA, Andrey JL, Corzo R, Perez V, et al. Impact of new-onset diabetes mellitus and glycemic control on the prognosis of heart failure patients: a propensity-matched study in the community. International Journal of Cardiology. 2013;167(4):1206–16. https://doi.org/10.1016/j.ijcard.2012.03.134 pmid:22560913.
- 36. Signorovitch JE, Macaulay D, Diener M, Yan Y, Wu EQ, Gruenberger JB, et al. Hypoglycaemia and accident risk in people with type 2 diabetes mellitus treated with non-insulin antidiabetes drugs. Diabetes, Obesity & Metabolism. 2013;15(4):335–41. https://doi.org/10.1111/dom.12031 pmid:23121373.
- 37. Svensson E, Baggesen LM, Thomsen RW, Lyngaa T, Pedersen L, Norrelund H, et al. Patient-level predictors of achieving early glycaemic control in Type 2 diabetes mellitus: a population-based study. Diabetic Medicine. 2016;33(11):1516–23. https://doi.org/10.1111/dme.13184 pmid:27412570.
- 38. Teljeur C, Smith SM, Paul G, Kelly A, O'Dowd T. Multimorbidity in a cohort of patients with type 2 diabetes. Eur J Gen Pract. 2013;19(1):17–22. https://doi.org/10.3109/13814788.2012.714768 pmid:23432037.
- 39. Walker RJ, Smalls BL, Egede LE. Social determinants of health in adults with type 2 diabetes—Contribution of mutable and immutable factors. Diabetes Research & Clinical Practice. 2015;110(2):193–201. https://doi.org/10.1016/j.diabres.2015.09.007 pmid:26411692.
- 40. Yu HC, Tsai WC, Kung PT. Does the pay-for-performance programme reduce the emergency department visits for hypoglycaemia in type 2 diabetic patients? Health Policy & Planning. 2014;29(6):732–41. https://doi.org/10.1093/heapol/czt056 pmid:23894069.
- 41. Castro-Rodriguez M, Carnicero JA, Garcia-Garcia FJ, Walter S, Morley JE, Rodriguez-Artalejo F, et al. Frailty as a Major Factor in the Increased Risk of Death and Disability in Older People With Diabetes. Journal of the American Medical Directors Association. 2016;17(10):949–55. https://doi.org/10.1016/j.jamda.2016.07.013 pmid:27600194.
- 42. Greenfield S, Billimek J, Pellegrini F, Franciosi M, De Berardis G, Nicolucci A, et al. Comorbidity affects the relationship between glycemic control and cardiovascular outcomes in diabetes: a cohort study. Annals of Internal Medicine. 2009;151(12):854–60. pmid:20008761. Language: English. Entry Date: 20101210. Revision Date: 20150711. Publication Type: Journal Article.
- 43. Huang YQ, Gou R, Diao YS, Yin QH, Fan WX, Liang YP, et al. Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy. Journal of Zhejiang University SCIENCE B. 2014;15(1):58–66. https://doi.org/10.1631/jzus.B1300109 pmid:24390745.
- 44. Hunt KJ, Gebregziabher M, Lynch CP, Echols C, Mauldin PD, Egede LE. Impact of diabetes control on mortality by race in a national cohort of veterans. Annals of Epidemiology. 2013;23(2):74–9. https://doi.org/10.1016/j.annepidem.2012.11.002 pmid:23238350.
- 45. Kheirbek RE, Alemi F, Zargoush M. Comparative effectiveness of hypoglycemic medications among veterans. Journal of Managed Care Pharmacy. 2013;19(9):740–4. https://doi.org/10.18553/jmcp.2013.19.9.740 pmid:24156642.
- 46. Lin WH, Hsu CH, Chen HF, Liu CC, Li CY. Mortality of patients with type 2 diabetes in Taiwan: a 10-year nationwide follow-up study. Diabetes Research & Clinical Practice. 2015;107(1):178–86. https://doi.org/10.1016/j.diabres.2014.09.021 pmid:25451891.
- 47. Lynch CP, Gebregziabher M, Zhao Y, Hunt KJ, Egede LE. Impact of medical and psychiatric multi-morbidity on mortality in diabetes: emerging evidence. BMC endocrine disorders. 2014;14:68. https://doi.org/10.1186/1472-6823-14-68 pmid:25138206.
- 48. Martin WG, Galligan J, Simpson S Jr., Greenaway T, Burgess J. Admission blood glucose predicts mortality and length of stay in patients admitted through the emergency department. Internal Medicine Journal. 2015;45(9):916–24. https://doi.org/10.1111/imj.12841 pmid:26109328.
- 49. McEwen LN, Karter AJ, Waitzfelder BE, Crosson JC, Marrero DG, Mangione CM, 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. https://doi.org/10.2337/dc11-2281 pmid:22432119.
- 50. Monami M, Lambertucci L, Lamanna C, Lotti E, Marsili A, Masotti G, et al. Are comorbidity indices useful in predicting all-cause mortality in Type 2 diabetic patients? Comparison between Charlson index and disease count. Aging-Clinical & Experimental Research. 2007;19(6):492–6. pmid:18172372.
- 51. Monami M, Luzzi C, Lamanna C, Chiasserini V, Addante F, Desideri CM, et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes/Metabolism Research Reviews. 2006;22(6):477–82. https://doi.org/10.1002/dmrr.642 pmid:16634115.
- 52. Walker J, Halbesma N, Lone N, McAllister D, Weir CJ, Wild SH, et al. Socioeconomic status, comorbidity and mortality in patients with type 2 diabetes mellitus in Scotland 2004–2011: a cohort study. Journal of Epidemiology & Community Health. 2016;70(6):596–601. https://doi.org/10.1136/jech-2015-206702 pmid:26681293.
- 53. Wang CP, Lorenzo C, Espinoza SE. Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes. Journal of Endocrinology Diabetes & Obesity. 2014;2(2). pmid:25506599.
- 54. Weir DL, McAlister FA, Majumdar SR, Eurich DT. The Interplay Between Continuity of Care, Multimorbidity, and Adverse Events in Patients With Diabetes. Medical care. 2016;54(4):386–93. https://doi.org/10.1097/MLR.0000000000000493 pmid:26807539.
- 55. Wilke T, Mueller S, Groth A, Berg B, Hammar N, Tsai K, et al. Effectiveness of sulphonylureas in the therapy of diabetes mellitus type 2 patients: an observational cohort study. Journal of Diabetes & Matabolic Disorders. 2015;15:28. https://doi.org/10.1186/s40200-016-0251-9 pmid:27486568.
- 56. Zelada H, Bernabe-Ortiz A, Manrique H. Inhospital Mortality in Patients with Type 2 Diabetes Mellitus: A Prospective Cohort Study in Lima, Peru. Journal of Diabetes Research. 2016;2016:7287215. https://doi.org/10.1155/2016/7287215 pmid:26788522.
- 57. Escalada J, Liao L, Pan C, Wang H, Bala M. Outcomes and healthcare resource utilization associated with medically attended hypoglycemia in older patients with type 2 diabetes initiating basal insulin in a US managed care setting. Current Medical Research & Opinion. 2016;32(9):1557–65. https://doi.org/10.1080/03007995.2016.1189893 pmid:27173946.
- 58. Li B, Evans D, Faris P, Dean S, Quan H. Risk adjustment performance of Charlson and Elixhauser comorbidities in ICD-9 and ICD-10 administrative databases. BMC health services research. 2008;8:12. pmid:18194561; PubMed Central PMCID: PMC2267188.
- 59. Perkins AJ, Kroenke K, Unutzer J, Katon W, Williams JW Jr., Hope C, et al. Common comorbidity scales were similar in their ability to predict health care costs and mortality. Journal of clinical epidemiology. 2004;57(10):1040–8. pmid:15528055.
- 60. Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. Journal of clinical epidemiology. 2004;57(12):1288–94. pmid:15617955.
- 61. Lynch CP, Gebregziabher M, Echols C, Gilbert GE, Zhao Y, Egede LE. Racial disparities in all-cause mortality among veterans with type 2 diabetes. Journal of general internal medicine. 2010;25(10):1051–6. pmid:20532659; PubMed Central PMCID: PMC2955466.
- 62. Shalev V, Chodick G, Bialik M, Green MS, Heymann AD. In a population-based cohort of diabetes patients, men and women had similar risks for all-cause mortality. Journal of clinical epidemiology. 2007;60(1):86–93. pmid:17161759.
- 63. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr., Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. The New England journal of medicine. 2008;358(24):2545–59. pmid:18539917; PubMed Central PMCID: PMC4551392.
- 64. Cheung NW, Conn JJ, d'Emden MC, Gunton JE, Jenkins AJ, Ross GP, et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Medical Journal of Australia. 2009;191(6):339–44. MEDLINE:pmid:19769558.
- 65. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians. Ann Intern Med. 2018;168(8):569–76. Epub 2018/03/07. pmid:29507945.
- 66. MacMahon S, Collins R. Reliable assessment of the effects of treatment on mortality and major morbidity, II: observational studies. Lancet. 2001;357(9254):455–62. pmid:11273081.
- 67. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. The New England journal of medicine. 2010;363(15):1410–8. pmid:20925543.
- 68. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. Bmj. 2010;340:b4909. pmid:20061358; PubMed Central PMCID: PMC2803744.
- 69. Henderson JN, Allen KV, Deary IJ, Frier BM. Hypoglycaemia in insulin-treated Type 2 diabetes: frequency, symptoms and impaired awareness. Diabetic medicine: a journal of the British Diabetic Association. 2003;20(12):1016–21. Epub 2003/11/25. pmid:14632703.
- 70. Zhu L, Ang LC, Tan WB, Xin X, Bee YM, Goh SY, et al. A study to evaluate the prevalence of impaired awareness of hypoglycaemia in adults with type 2 diabetes in outpatient clinic in a tertiary care centre in Singapore. Therapeutic advances in endocrinology and metabolism. 2017;8(5):69–74. Epub 2017/06/22. pmid:28634533; PubMed Central PMCID: PMCPmc5467801.
- 71. Frontoni S, Di Bartolo P, Avogaro A, Bosi E, Paolisso G, Ceriello A. Glucose variability: An emerging target for the treatment of diabetes mellitus. Diabetes Res Clin Pract. 2013;102(2):86–95. pmid:24128999.
- 72. Piette JD, Kerr EA. The impact of comorbid chronic conditions on diabetes care. Diabetes care. 2006;29(3):725–31. pmid:16505540.
- 73. May C, Montori VM, Mair FS. We need minimally disruptive medicine. Bmj. 2009;339. pmid:19671932
- 74. Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M, et al. The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies. International journal of technology assessment in health care. 2012;28(2):138–44. pmid:22559755.