Epidemiology of heart failure in diabetes: a disease in disguise

Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016–October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al’s risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment. Registration PROSPERO ID CRD42022368035. Graphical Abstract Supplementary Information The online version contains peer-reviewed but unedited supplementary material including a slideset of the figures for download, which is available to authorised users at 10.1007/s00125-023-06068-2.


Search strategy, study selection, data extraction and quality assessment
We conducted a systematic search in Medline and Embase for papers published from 2016 to 20 October 2022.Since our review is an update of the reviews published by Bouthoorn et al. (1,2) we used a comparable search strategy (ESM Methods: Search strategies).The protocol for this review was registered in the International Prospective Register of Systematic Reviews, the PROSPERO database, under number: CRD42022368035 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=368035).
Studies published in English and Dutch were considered.Letters, editorials, case reports, practical guidelines and animal or laboratory studies were excluded.Studies using data from the population at large, as well as hospital populations were included, but reported and analyzed separately.If multiple studies were based on the same study population, we selected the study with the largest population for data extraction.

Definition of study outcome
1. Prevalence of left ventricular diastolic dysfunction in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.a. LVDD was defined as an ejection fraction of ⩾45-50% and diastolic abnormalities on echocardiography such as an E/A ratio < 0.75 or >1.50, E/e' ratio > 13 and left atrial (LA) volume index > 34 mL/m2.2. Prevalence of HFpEF in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.a. HFpEF was defined as having an ejection fraction of ⩾45-50% and clinical symptoms and signs suggestive of HF (i.e.shortness of breath, fatigue, pulmonary congestion and/or peripheral edema) and objective evidence of diastolic dysfunction measured with echocardiography 3. Prevalence of left ventricular systolic dysfunction in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.a. LVSD was defined as an ejection fraction of <50% and systolic abnormalities on echocardiography.4. Prevalence of HFrEF in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.a. HFrEF was defined as having an ejection fraction of <50% and clinical symptoms and signs suggestive of HF (i.e.shortness of breath, fatigue, pulmonary congestion and/or peripheral edema) Participants/population Screening and selection was done independently, and consensus was used to resolve disagreement.There were no automation tools used in the screening and selection process.
In agreement with the reviews published by Bouthoorn et al. (1,2), a methodological quality assessment (risk of bias assessment) of the included studies was performed (one author, A.G.H.), which was based on the risk of bias tool of Hoy et al. (3), using signaling questions to identify potential problems in the design, conduct and analysis of a study.Signaling questions were scored separately (low or high risk of bias) and an overall score of bias (low: =< 1 points of high risk, medium: 2-3 points of high risk, high: >3 points of high risk) was given to each included study.Studies were assessed by one author (A.G.H.), but a selection (25%) was performed in twofold with an excellent agreement for data extraction (absolute agreement 98%) and a good agreement for risk of bias (absolute agreement on final score: 74%, compared to an expected 72% reported by Hoy et al. in the validation process.No automation tools were used.

Data synthesis and analysis
Data extraction included: first author's name, publication year, study design, study population and population characteristics, relevant selection criteria (in and exclusion), number of participants (%male), age, duration of type 2 diabetes, method of diagnosing HF/ventricular dysfunction, number of patients with LVDD/LVSD and/or HFpEF/HFrEF, total number of participants in study population.Since prevalence estimates are based on cross sectional data, only baseline cross-sectional data was taken into account during the data extraction process.
Individual study prevalence and the corresponding 95% confidence intervals (CIs) were calculated for all included studies.To perform meta-analysis, the prevalence data was logit transformed in order to make the data follow a normal distribution.A transformation is needed to stabilize the variance in a meta-analysis on prevalence data (4).We used the automated tool embedded in the R package 'meta' to perform the (back)transformation.A random-effects model was used to obtain pooled estimates (with the corresponding 95% CI) of the logit-transformed prevalence data, as this model takes the between-study heterogeneity into account better than a fixed-effects model.Continuity correction (0.5%) was used in studies reporting a prevalence of zero (only used to calculate individual study results).Heterogeneity was assessed using the I2 statistic.The pooled prevalence estimate was calculated for all the included studies and separately for studies concerning the general population and hospital population.If we could not recalculate prevalence estimates or if only figures with no absolute numbers were reported, studies were not included in the meta-analysis.Results of the meta-analysis are presented as forest plots showing prevalence proportions with the corresponding 95% CIs for each study and the overall random-effects pooled estimate.All statistical analyses were performed in R using the 'meta' package version 6.5-0 (CRAN -Package meta (r-project.org).Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

INTRODUCTION
Yes, supplementary materials (page 2-3) and 'updated systematic review' section manuscript Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Yes, supplementary materials (page 2-3) and 'updated systematic review' section manuscript Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Yes, supplementary materials (page 2-3) 10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

Section and Topic
Item # Checklist item Location where item is reported Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Yes, supplementary materials (page 2-3) and 'updated systematic review' section manuscript Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.
Yes, in methods in both the main paper ('updated systematic review' section) as in supplementary materials (page 2-3) (prevalence/incidence and 95% confidence interval) Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

N.A.
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

N.A.
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.Yes, supplementary materials (page 3) 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Yes, supplementary materials (page 3) 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).
Yes, supplementary materials (page 3) and 'updated systematic review' section manuscript 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.Yes, page 'updated systematic review' section manuscript

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).N.A.

Certainty assessment
15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.Yes, page 'updated systematic review' section manuscript

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

Eligibility criteria Specify the inclusion and exclusion criteria for the review. Yes
Information sources Specify the information sources (e.g.databases, registers) used to identify studies and the date when each was last searched.

Yes
Risk of bias Specify the methods used to assess risk of bias in the included studies.Yes

Synthesis of results
Specify the methods used to present and synthesise results.Yes

Included studies
Give the total number of included studies and participants and summarise relevant characteristics of studies.Yes

Synthesis of results
Present results for main outcomes, preferably indicating the number of included studies and participants for each.If metaanalysis was done, report the summary estimate and confidence/credible interval.If comparing groups, indicate the direction of the effect (i.e. which group is favoured).

Limitations of evidence
Provide a brief summary of the limitations of the evidence included in the review (e.g.study risk of bias, inconsistency and imprecision).

Yes
Not specified Not specified, but referred to the Redfield definitions (16) normal (0.75 < E/A<1.5 and E/e′ < 10); mild (defined as impaired relaxation without increased filling pressures, E/A ≤ 0.75 and E/e′ < 10); moderate (defined as impaired relaxation associated with moderately elevated filling pressures or pseudonormal filling, 0.75 < E/A < 1.5 and E/e′ ≥ 10); and severe (defined as advanced reduction in compliance or reversible or fixed restrictive filling, E/A > 1. 5

Types of study to be included
Observational studies (cross-sectional and prospective studies), and interventional studies reporting (baseline) prevalences of undiagnosed LVDD/LVSD and/or HFpEF/HFrEF in a certain population Prevalence of undiagnosed HFpEF in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.
1.People with type 2 diabetes, male and female ≥ 18 years old a. defined by one of the following criteria: documentation in medical record, physician's diagnosis, self-reported history, use of anti-diabetic agents and random serum glucose ⩾ 200 mg/dL (or ⩾11.1 mmol/L) or serum fasting glucose ⩾ 126 mg/dL (or ⩾7.0 mmol/L) 2. No restrictions are placed on the study population i. HFpEF was defined as having an ejection fraction of ⩾45% and clinical symptoms and signs suggestive of HF (i.e.shortness of breath, fatigue, pulmonary congestion and/or peripheral edema) and objective evidence of diastolic dysfunction measured with echocardiography c.Prevalence of left ventricular systolic dysfunction in people with type 2 diabetes;Only studies that used echocardiography to establish or confirm the diagnosis are included.i.LVSD was defined as an ejection fraction of <50% and systolic abnormalities on echocardiography.d.Prevalence of HFrEF in people with type 2 diabetes; Only studies that used echocardiography to establish or confirm the diagnosis are included.i.HFrEF was defined as having an ejection fraction of <50% and clinical symptoms and signs suggestive of HF (i.e.shortness of breath, fatigue, pulmonary congestion and/or peripheral edema)From the criteria mentioned above, the following patient, intervention, comparison, outcome (PICO) Rationale 3 Describe the rationale for the review in the context of existing knowledge.
Yes, 'Introduction' and 'updated systematic review' section Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses.Yes, 'Introduction' and 'updated systematic review' sectionMETHODSEligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.Yes, supplementary materials (page 1)Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.

Table 2 : PRISMA checklist for abstracts
manuscript 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.
20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

Table 3 :
Overview of different methods used to diagnose left ventricular diastolic dysfunction in patients with type II diabetes, included in the systematic review and meta-analysis

Table 4 :
American society of echocardiography/European association of cardiovascular imaging, BSA; Body surface area, DT; deceleration time, E; early mitral inflow wave, E/A; early mitral inflow wave / atrial contraction wave, IVRT; isovolumic relaxation time, LA; left atrium, LAVI; left atrial volume index, LV; left ventricle; LVDD; left ventricular diastolic dysfunction; LVEF: left ventricular ejection fraction, PASP; pulmonary artery pressure, TR: tricuspid regurgitation, TDI; tissue doppler imaging ESM Overview of different methods used to diagnose heart failure with preserved ejection fraction in patients with type II diabetes, included in the systematic review and meta-analysis >50% NT-proBNP concentration above the age-specific diagnostic threshold of ≥450pg/mL in age <50 years, ≥900pg/mL in age 50-75 years and ≥1800pg/mL in age >75 years and ejection fraction >50% and LVEF (≥50% to diagnose heart failure with preserved ejection fraction and <50% to diagnose heart failure with reduced ejection fraction) HFpEF was defined as reporting of dyspnea corresponding to the New York Heart Association class II-IV and presence of at least one of the following echocardiographic findings: (a) LVEF >40% and ≤50%, (b) ratio of early diastolic mitral inflow velocity (E) to early diastolic septal annular velocity (e' )(E/e´septal) ≥15, (c) increased left ventricular (mass index (>95 g/cm2 for women and >115 g/cm2 for men), and (d) left atrial volume index >34 American society of echocardiography/European association of cardiovascular imaging, ESC; European society of cardiology, HFpEF; heart failure with preserved ejection fraction, LVEF: left ventricle ejection fraction, NTproBNP; N-terminal pro-B-type natriuretic peptide