Hypoglycaemia has been linked to an increased risk of cardiac arrhythmias by causing autonomic and metabolic alterations, which may be associated with detrimental outcomes in individuals with diabetes(IWD), such as cardiovascular diseases (CVDs) and mortality, especially in multimorbid or frail people. However, such relationships in this population have not been thoroughly investigated. For this reason, we conducted a systematic review and meta-analysis.2 statistic, pooled relative risks (RRs) and 95% confidence intervals (CI) were obtained using random-effects models.Relevant papers published on PubMed, Embase, Cochrane, Web of Knowledge, Scopus, and CINHAL complete from inception to December 22, 2022 were routinely searched without regard for language. All of the selected articles included odds ratio, hazard ratio, or relative risk statistics, as well as data for estimating the connection of hypoglycaemia with cardiac arrhythmia, CVD-induced death, or total death in IWD. Regardless of the heterogeneity assessed by the IAfter deleting duplicates and closely evaluating all screened citations, we chose 60 studies with totally 5,960,224 participants for this analysis. Fourteen studies were included in the arrhythmia risk analysis, and 50 in the analysis of all-cause mortality. Hypoglycaemic patients had significantly higher risks of arrhythmia occurrence , CVD-induced death , and all-cause mortality  compared to euglycaemic patients with significant heterogeneity.Hypoglycaemic individuals are more susceptible to develop cardiac arrhythmias and die, but evidence of potential causal linkages beyond statistical associations must await proof by additional specifically well planned research that controls for all potential remaining confounding factors. Diabetes, a non-communicable disease, is a serious public health concern worldwide. More than half a billion people (536.6 million) aged 20-79 were predicted to develop diabetes mellitus (DM) in 2021, with roughly 90% having type 2 DM (T2DM) (Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality in this populace . NumerouFor these reasons, our aim was to assess if hypoglycaemia affects the risk of arrhythmia or mortality in IWD.Two separate reviewers searched PubMed, EMBASE, Wiley Cochrane Central Register of Controlled Trials(CENTRAL), Web of knowledge, Scopus and CINAHL complete up to December 22, 2022 as per applicable recommendations . Any dispost-hoc analysis or sub-analysis of randomised controlled trials (p-h/sa of RCTs); (ii) focusing on the relationship of any hypoglycaemia with arrhythmias or CVD-induced death or overall death in IWD, and reporting risk or prevalence or incidence of arrhythmias  for IWD with hypoglycaemia as compared with euglycaemia, and (iii) standardized mortality or incidence ratio (SMR or SIR), or incidence rate ratio (IRR), or odds ratios (OR), or hazard ratio (HR), or relative risk (RR), as well as pertinent relevant raw data for recalculation are all used to report effect estimates. Exclusion criteria were as follows: (I) emphasizing the connection of hypoglycaemia with adverse outcomes such as arrhythmias- or CVD-caused death or all-cause mortality in non-diabetic people; (II) case report, quasiexperiment (in which subjects are not assigned at random), editorial, remark, review, letter or unpublished study; (III) only published as abstract or conference proceeding. Diabetes studies that did not provide such estimations were also omitted. When a site-specific dataset was published multiple times, the study with the newest t publication or the largest sample size was generally picked.The inclusion criteria were: (i) observational studies (OSs) , Data were collected about the research , participants (mean age and the gender), analysis strategy , effect size , as well as pertinent raw data for recalculation.Two researchers independently assessed the quality of each p-h/sa of RCT and enrolled study based on cohort or case-control design utilizing the 9-star Newcastle-Ottawa Scale (NOS) . A ratin2 statistic was used to determine the fraction of variability between studies because of heterogeneity between studies, and with I2 values greater than 50%, 25-50%, and less than 25%, was classified as high, medium, and low respectively  whereas the analysis period, respectively. OR, or RR with 95% confidence interval (CI) was used to summarize dichotomous outcomes. ORs are comparable to RRs since the absolute risk of arrhythmias or death is minimal in these populations and the two indices provide equivalent RR estimates . The I2 ectively . The iteively , diurnal differences , severity of hypoglycaemia , clarity of diabetes , and type of arrhythmia . For all-cause mortality analysis, subgroup analyses were conducted with sample size, country/region , study population , hypoglycaemia episode , clarity of diabetes, study design , severity of hypoglycaemia, follow-up duration , and methods for effect estimate extraction . Any quantifiable source of heterogeneity was identified through sensitivity analysis by excluding each study individually.Publication bias was examined using Begg’s and Egger’s tests when at least five studies were available for analysis, as well as by visually inspecting the asymmetry of funnel plots of estimated effects against standard errors . Any pubFrom the 51,794 articles discovered through a systematic search, 137 were selected for further analysis Figure 1Apart from 10 studies on multinational origins, other origins were mentioned developed countries or regions in 46 articles, and developing countries in 4 articles. More than 50% studies (34/60) reported severe hypoglycaemia. Sixteen articles reported IWD with comorbidities or at high risk of CVD. Definitions of hypoglycaemia varied widely and were mostly based on blood glucose concentration or the presence of symptoms necessitating the assistance of another individual or medical help. Ten, 46, and 15 articles presented data on arrhythmia risk only, all-cause mortality only, and CVD death only, respectively, and four studies reported data on both arrhythmia and all-cause mortality risk.For cardiac arrhythmia analysis, quality analysis showed about 7 of 11 cohort studies and one case-control study were of high methodological quality, with ≥7 NOS scores  , but there was evident heterogeneity between studies (Ip<0.001) Figure 2The pooled RRs were essentially uniform regardless of the sample size , severity of hypoglycaemia , noctural hypoglycaemia (P=0.012), type of arrhythmia , T2DM (P =0.001), or total diabetes (P<0.001) Figure 32 = 97.1%; P<0.001; Fifty studies reported a link between hypoglycemia and overall death in IWD. In a random-effects model, the pooled RR was 1.68  with severe heterogeneity  nor visual inspection revealed significant publication bias  from 15 relevant studies found that hypoglycemic versus euglycaemic IWD had a 59% significantly higher risk  in susceptibility to CVD-caused death. A random-effects model exhibiting substantial heterogeneity , carries a greater proarrhythmic risk than euglycemia or hyperglycemia, as also observed in this study. The proarrhythmic mechanisms of hypoglycaemia, especially SH, may be various . Low gluEven though the overall pooled RR suggests a 42% substantially higher likelihood of cardiac arrhythmia in hypoglycemic patients over euglycaemia patients, around 57% (8/14) recruited studies report no significant link between hypoglycemia and cardiac arrhythmia. There can be several reasons for this null result. First, the antagonistic autonomic nerve responses are a fundamental mechanism underlying the harmful effect of SH, but can be diminished in patients with long-standing diabetes, long follow-up, or established cardiovascular risks –97. ConsAs for the mortality analysis, we did not aim to prove causality, but did highlight the associations between hypoglycemia and death. Due to pre-existing comorbidities, CVD-induced death usually accounted for the majority of deaths in the diabetes group. The relationship between hypoglycaemia and cardiovascular events is bidirectional in accordance with previous studies , 86. FirSecondly, hypoglycaemia or SH is a plausible indicator instead of a direct cause of an elevated risk of unfavorable clinical outcomes, which reflects the influence of concomitant illnesses in addition to unmeasured or incompletely defined confounding variables  that indThe mechanisms that relate SH to non-cardiovascular fatalities remain unknown , 54. SH Subgroup analyses were performed so as to clarify whether the incidence of cardiac arrhythmia or all-cause death differed among relevant characteristics. In the trials with T2DM patients, preliminary subgroup analysis revealed a substantial increase in overall death risk among hypoglycemic versus euglycaemic individuals. Because T1DM patients are frequently younger than T2DM patients, they have less risk factors for death. Despite this, SH is more likely to attack T1DM patients, raising the risk of arrhythmia. SH is more likely to assault T1DM patients, increasing the risk of arrhythmia. This is not the case, and the underlying reason is unknown . In termNo review or meta-analysis can avoid heterogeneity of OS due to the lack of standardisation of method for clarifying cases, study design and time, classification of endpoints, and the amount of inter-study confounding that has been adjusted. For example, definitions of hypoglycaemia differ greatly. In spite of the sensitivity testing, we were unable to account for the greatest between-study heterogeneity in the outcome of cardiac arrhythmia and death. Therefore, these results need confirmation from more research. Furthermore, the statistical methodologies used in p-h/sa of RCTs and OSs did not adequately address the influence of unmeasured confounding components regarding overall effect estimation. The origins of variability were attributed to differences in study populations and exposure, according to sensitivity analyses.Some of the significant strengths of this meta-analysis include the detailed retrieval plan with Cochrane procedures, the broad search approach, the relatively large sample size, and the capacity to investigate the link between hypoglycemia and cardiac arrhythmia or death. Nevertheless, this study has some limitations. First, the avoidance of unreported reports can have influenced our findings. Second, there is also a wide range of exposure, including severe hypoglycemia and any hypoglycemia. Third, the analyses employed for arrhythmia source research have drawbacks as well. Some studies have presented incident rate ratios for arrhythmias, implying that an increased risk applies to the whole research group whereas, in fact, only a few individuals who are extremely vulnerable may be impacted . Fourth,In summary, hypoglycemia, as opposed to euglycaemia, is associated with a higher risk of cardiac arrhythmia and mortality. Nevertheless, evidence of potential causal linkages beyond statistical associations must await proof by additional specifically well planned research that controls for all potential remaining confounding factors, including a unified definition of hypoglycemia  as recomThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.XW and GL conceived the conception and design of the study, the search of the relevant literature, the extraction and analysis of data, and the drafting and revision of the final manuscript. SZ and FZ interpreted the analysed data, reviewed the manuscript critically, and contributed to its drafting. The final manuscript was read and approved by all authors.


Do vegetarian diets improve the cardiometabolic profile of people with or at high risk of cardiovascular diseases (CVDs)?1c by 0.25%, and body weight by 3.4 kg. The GRADE assessment showed a moderate level of evidence for low-density lipoprotein cholesterol and hemoglobin A1c reduction.In this meta-analysis of 20 randomized clinical trials (with 1878 participants) with an average 6 months of intervention, vegetarian diets were associated with significant improvements in low-density lipoprotein cholesterol by 6.8 mg/dL, hemoglobin AThese results suggest that consuming a vegetarian diet may modestly but significantly improve cardiometabolic outcomes beyond standard pharmacological therapy in individuals at high risk of CVDs, highlighting the potential protective and synergistic effects of vegetarian diets for the primary prevention of CVD. This systematic review and meta-analysis examines 20 clinical trials of various vegetarian diets for improved outcomes for patients with major cardiometabolic risk factors. Plant-based diets are known to improve cardiometabolic risk in the general population, but their effects on people at high risk of cardiovascular diseases (CVDs) remain inconclusive.1c (HbA1c), systolic blood pressure (SBP), and body weight in people with or at high risk of CVDs.To assess the association of vegetarian diets with major cardiometabolic risk factors, including low-density lipoprotein cholesterol (LDL-C), hemoglobin AThis meta-analysis was registered before the study was conducted. Systematic searches performed included Embase, MEDLINE, CINAHL, and CENTRAL from inception until July 31, 2021.1c or SBP were included. Of the 7871 records screened, 29  met inclusion criteria.Eligible randomized clinical trials (RCTs) that delivered vegetarian diets in adults with or at high risk of CVDs and measured LDL-C, HbA1c, SBP, and body weight. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool.Two reviewers independently extracted data including demographics, study design, sample size, and diet description, and performed risk of bias assessment. A random-effects model was used to assess mean changes in LDL-C, HbA1c, and SBP; secondary outcomes were changes in body weight and energy intake.Mean differences between groups in changes (preintervention vs postintervention) of LDL-C, HbA1c, and body weight by 6.6 mg/dL , 0.24% , and 3.4 kg , respectively, but the association with SBP was not significant . The GRADE assessment showed a moderate level of evidence for LDL-C and HbA1c reduction.Twenty RCTs involving 1878 participants  were included, and mean duration of intervention was 25.4 weeks . Four studies targeted people with CVDs, 7 focused on diabetes, and 9 included people with at least 2 CVD risk factors. Overall, relative to all comparison diets, meta-analyses showed that consuming vegetarian diets for an average of 6 months was associated with decreased LDL-C, HbA1c and body weight beyond standard therapy in individuals at high risk of CVDs. Additional high-quality trials are warranted to further elucidate the effects of healthy plant-based diets in people with CVDs.In this study, consuming a vegetarian diet was associated with significant improvements in LDL-C, HbA Much of this is attributable to the failed implementation of prevention strategies to comprehensively address modifiable risk factors in individuals at risk.4 The 2021 dietary guidelines of the American Heart Association emphasize the importance of dietary patterns rich in minimally processed plant foods, fish and seafood, and low-fat dairy products.5 Different forms of vegetarian diets, which exclude meat and sometimes also eggs and dairy, are becoming increasingly popular because of their health and environmental benefits.6 Diabetes organizations recommend the consumption of well-balanced vegetarian diets in line with the vast evidence supporting their beneficial effects in preventing type 2 diabetes and some of its metabolic complications.9Poor diet is mechanistically linked to an elevated risk of CVD morbidity and mortality.11 but little is known on their effectiveness in patients with or at high risk of CVDs. Moreover, metabolic outcomes among different vegetarian diets  were not investigated thoroughly,14 with little control for key confounders, such as energy restriction,16 physical activity,15 and medication changes.12Accumulating data from meta-analyses of randomized clinical trials (RCTs) suggest a role of vegetarian diets in the primary prevention of CVDs in the general population,18 For example, Glenn et al17 combined evidence from 7 cohort studies and found that a vegetarian diet was not associated with CVD mortality, with the evidence graded as very low due to indirectness and imprecision. An observational study found that individuals may choose to follow vegetarian diets because of perceived health benefits; these individuals may also present fewer adverse health behaviors , and the findings can be affected by these confounders.18 In general, findings from observational studies provide less strength of evidence, as they cannot rule out residual confounding, and a causal relationship cannot be established.19 Thus, our meta-analysis aims to fill in this gap, with subgroup analyses controlling for energy restriction, physical activity, medication use, and the type of control diet.To the best of our knowledge, no meta-analysis of RCTs has been conducted to investigate the association of vegetarian diets with outcomes among people with CVD—indeed, research here has primarily focused on observational studies.CRD42021218348) before the study was conducted. Institutional review board approval and informed consent were not required as this was a secondary analysis of deidentified data. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the AMSTAR-2 checklist20 for this study.This systematic review and meta-analysis was registered with PROSPERO  (eTable 1 in 1c (HbA1c), or systolic blood pressure (SBP) were included. Of the 7871 records screened, 29  met inclusion criteria. Two reviewers  independently extracted data including demographics, study design, sample size, and diet description, and performed risk of bias assessment.Eligible RCTs delivered vegetarian diets in adults with or at high risk of CVDs and measured low-density lipoprotein cholesterol (LDL-C), hemoglobin A1c, and SBP. The secondary outcomes are changes in body weight, and energy intake. The meta package of R version 1.4.1717 21 was used to perform meta-analysis and meta-regression.22 A random-effects model was used, implemented using the metacont function for mean differences. We estimated the overall pooled effect size based on inverse-variance weighting using a restricted maximum likelihood estimator for the among-study heterogeneity.23 Confidence intervals are at the 95% level and estimated based on a standard-normal distribution . The total heterogeneity was quantified as τ2 . The statistical significance for heterogeneity was assessed by a modified Q test, which used the Farebrother method to obtain the distribution of Q values, as recommended for mean differences by Kulinskaya et al.24 We evaluated the overall certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool.The primary outcomes are the mean differences between groups in changes (preintervention vs postintervention) in LDL-C, HbA49 Studies were conducted in the US,52 Asia,40 Europe,49 or New Zealand,53 and all published between 1990 and 2021. Sample size ranged from 13 to 291 participants , and mean duration of intervention was 25.4 weeks .Of the 7871 records screened, 29 articles  were included . Reasons52 of which 3 applied the Ornish diet.52 This diet is a very low-fat (less than 10% energy from fat), lacto-ovo-vegetarian diet that excludes all animal proteins except for nonfat dairy products and egg whites . We therefore conducted a sensitivity analysis excluding Ornish et al45 and the effect size remained statistically significant   , and this reduction is clinically significant of LDL-C . Compare53 were included in the HbA1c meta-analysis  in a mean 6 months of intervention , and the heterogeneity was not statistically significant , with greater effect observed in studies of people with type 2 diabetes   was observed in people following a vegan diet53 even without energy restriction  and the conventional energy-restricted diabetic diet   in studies with no physical activity prescription  in studies that used the intention-to-treat analysis analysis . Overallo −0.18) . A reduc53 were included in the meta-analysis of SBP, and the pooled effect size of vegetarian diets was not statistically significant   6 mm Hg) . Among-s53 were included in the meta-analysis of body weight   were the comparison group. This was consistent with our results that showed how vegetarian diets were associated with greater weight reduction compared with usual diets  than with energy-restricted interventional diet  52 significantly reduced energy intake compared with the usual diet  53 emphasized the consumption of plant-based whole foods  and imprecision (sample size under 400 and mean difference includes zero). In individuals with type 2 diabetes, the certainty of the evidence was rated moderate for a reduction in HbA1c and an increase in SBP. Note that 4 of 6 studies44 included in the GRADE assessment of SBP used active control as the comparison diet. We found low evidence for LDL-C and weight reduction in people with type 2 diabetes. Finally, in people with CVD, the certainty of the evidence was low in LDL-C and SBP reduction. The outcomes and funding sources of included studies are described in eTable 13 and eTable 14 in eTables 8-11 in 55 The results of this meta-analysis demonstrate that consuming a vegetarian diet exerts a modest but significant effect in concomitantly reducing multiple key risk factors, including LDL-C, HbA1c, and body weight, especially in high-risk patients. In population-stratified analysis, the greatest reduction in LDL-C was observed in individuals at high risk of CVD. Vegetarian diets were most effective in glycemic control among people with type 2 diabetes, and led to favorable changes in weight in people at high risk of CVD and in those with type 2 diabetes, suggesting that vegetarian diets might have a synergistic (or at least nonantagonistic) use in potentiating the effects of optimal drug therapy in the prevention and treatment of a range of cardiometabolic diseases.Findings from pharmacological randomized trials of statins, antidiabetic, and antihypertensive drugs have clearly shown that lowering cholesterol, glucose, and blood pressure levels exerts major antiatherosclerotic and nephro-protective effects.56 HbA1c ,16 SBP ,12 and body weight ,10 which is consistent with our findings in terms of LDL-C, HbA1c, and body weight improvement. However, most prior meta-analyses did not stratify populations by disease status,56 type of vegetarian diet,16 nor comparison diet.56 Moreover, important confounders such as energy restriction,56 physical activity,56 or changes in medication use16 were not controlled for. For instance, Yoko et al56 reported a greater improvement in LDL-C, but 7 out of the 17 studies targeted general population, and 5 studies had a duration of less than 8 weeks. To fill in this research gap, our meta-analysis only included mid- to long-term trials  of patients with or at high risk of CVD.To the best of our knowledge, this meta-analysis is the first that generates evidence from RCTs to assess the association of vegetarian diets with outcomes in people affected by CVDs. Previous meta-analyses of RCTs reported a favorable association of vegetarian diets with LDL-C ,58 suggesting that diet quality plays a major role in lowering blood pressure, independent of animal food consumption, as the DASH diet trial demonstrated.59 Different from the general population, most patients included in our study53 took medications to manage their hypertension, hyperglycemia, and/or dyslipidemia at trial enrollment. Eight RCTs53 reported a decrease in medication dose due to intervention effect. Although our results show an overall improvement in LDL-C, HbA1c, and weight, independent of energy restriction, the changes in LDL-C and HbA1c did not reach the clinically significance as per cutoff target. In fact, the use of glucose, lipid, and blood pressure-lowering drugs, and the reduction in medication dosage, may obscure the favorable effect on cardiometabolic outcomes induced by vegetarian diets, implying a larger actual effect size. This hypothesis is supported by 2 RCTs49 in our meta-analysis that required patients not to take medication that could influence cardiometabolic outcomes; these studies significantly improved SBP and LDL-C.Interestingly, we did not observe a significant change in SBP, consistent with the findings of previous meta-analyses,60 L-carnitine and choline (precursors of the atherogenic TMAO),61 and branch chain amino acids (promoters of insulin resistance63 and platelet activation via tropomodulin-3 propionylation).64 In our meta-analysis, 12 studies emphasized low-fat content, which may in part contribute to the observed improvement in LDL-C. Depending on their design, these diets may also be high in dietary fiber, sterols, mono- and polyunsaturated fatty acids, potassium, magnesium, phytochemicals, and have lower energy density and lower scores on the glycemic index.66 Indeed, not all vegetarian diets could be considered healthy. For instance, more than one-third of the studies included in our meta-analysis did not emphasize the importance of consuming minimally processed plant-based whole foods. Vegetarian diets, particularly those practiced for ethical reasons or focused on convenience, may contain high levels of so-called empty calories, refined carbohydrates, hydrogenated oils, high-fructose corn syrup, sucrose or artificial sweeteners and salt. We were unable to perform a thorough evaluation of diet quality and adherence for the studies included in our meta-analysis because of limited dietary data  diets can have multiple health benefits, including lower intake of: saturated fat,The strengths of this study included: (1) to our knowledge, this is the first meta-analysis generating evidence of vegetarian diets from RCTs in people with CVDs; (2) we strictly followed a prespecified protocol; (3) we conducted a rigorous search using 4 databases, including trials registries, supplemented by hand searches; (4) we performed comprehensive subgroup analyses to examine people with different disease status and the effect of different vegetarian diets, control diets, energy restriction, physical activity, medication, and analyses method; (5) we contacted authors of included studies to extract unpublished data, and to improve the accuracy of meta-analysis calculations; (6) we used the GRADE approach to assess the overall certainty of the evidence for each cardiometabolic outcome in people with different disease status; and (7) we published the R script for meta-analysis and shared the data set, hence our findings are transparent and reproducible  to vegetarian diets on cardiometabolic health in individuals at high risk of CVD. Seventh, although the detected publication bias was low and we conducted a rigorous search, we cannot rule out the possibility of missing unpublished data. Eighth, only studies published in English and Chinese were included, and trials published in other languages were likely to have been missed  investigated vegetarian diets in patients with CVDs, of which 3 required SD imputation as these could not be obtained from authors. Second, although we conducted comprehensive subgroup analyses, the results could be limited by the relatively small sample sizes (200 participants or less) of the subgroups as reflected by the GRADE assessment. Furthermore, these subgroup analyses did not reach the required sample size to draw solid conclusions, and some of them had high heterogeneity in the pooled estimate. Third, we were not able to assess adherence and diet quality thoroughly due to limited dietary data. Future research should fully document dietary data including energy, macronutrients, micronutrients, and ideally food groups and other relevant information  to allow for a thorough assessment of adherence and diet quality. Fourth, many of the studies included in this meta-analysis emphasized a low-fat diet, and data on the effectiveness of vegetarianism combined with higher or moderate fat intake on cardiometabolic health are limited. Fifth, most of included studies were conducted in Western countries (17 studies) and mostly in the US (14 studies), which could limit the generalizability of our findings to other populations. Past research revealed that the quality of vegetarian diets varied between South Asian and American with vegetarians in the US consistently consuming healthier food groups than South Asian vegetarians.1c and body weight, beyond standard therapy, in patients with or at high risk of CVDs. The greatest improvements in HbA1c and LDL-C were observed in individuals with type 2 diabetes and people at high risk of CVD, highlighting the potential protective and synergistic effects of vegetarian diets for the primary prevention of CVD. Well-designed nutrition clinical trials with comprehensive dietary information are warranted to investigate the full effect of high-quality vegetarian diets in combination with optimal pharmacological therapy in people with CVDs.In summary, our findings contribute important information to the development of clinical guidelines in cardiometabolic risk factors management as they demonstrate that consuming a vegetarian diet was associated with significant reductions in LDL-C, HbA