Cardiovascular autonomic neuropathy in diabetes: an update with a focus on management.

Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.

Risk of diabetic retinopathy and diabetic macular oedema with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database.

AIMS/HYPOTHESIS: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. METHODS: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. RESULTS: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). CONCLUSIONS/INTERPRETATION: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies.

The prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review.

AIMS/HYPOTHESIS: Cardiac autonomic neuropathy (CAN) is independently associated with silent myocardial ischaemia, major cardiovascular events, myocardial dysfunction and cardiovascular mortality. Several studies have highlighted the increased prevalence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose). Considering the exponential rise of prediabetes, we aimed to determine the prevalence of CAN through a systematic literature review. METHODS: This systematic review was registered with PROSPERO (CRD42019125447). An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Cochrane databases. Published full text, English language articles that provide CAN prevalence data of studies in individuals with prediabetes and aged over 18 years were included. Prevalence data for normal glucose tolerance and diabetes were also extracted from the selected articles, if present. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using a critical appraisal tool. RESULTS: Database searches found 4500 articles; subsequently, 199 full text articles were screened, 11 of which fulfilled the inclusion criteria (4431 total participants, 1730 people with prediabetes, 1999 people with normal glucose tolerance [NGT] and 702 people with predominantly type 2 diabetes). Six of the selected studies reported definite CAN prevalence data (9-39%). Only a single large population-based study by Ziegler et al (KORA S4 study, 1332 participants) determined definite CAN based on two or more positive autonomic function tests (AFTs), with a mean prevalence of 9% in all prediabetes groups (isolated impaired glucose tolerance 5.9%; isolated impaired fasting glucose 8.1%; impaired fasting glucose plus impaired glucose tolerance 11.4%), which was higher than NGT (4.5%). This study is most likely to provide a reliable population-specific estimate of CAN in prediabetes. There was a higher than expected prevalence of CAN in prediabetes (9-38%) when compared with normal glucose tolerance (0-18%) within the same studies (n = 8). There was a wide prevalence of possible CAN based on one positive AFT (n = 5). There was heterogeneity between the studies with variations in the definition of CAN, methodology and characteristics of the populations, which likely contributed to the diversity of prevalence estimates. The overall risk of bias was low. CONCLUSIONS/INTERPRETATION: There is a higher than expected prevalence of CAN in prediabetes. Early detection of CAN in prediabetes through population screening needs careful consideration in view of the excess morbidity and mortality risk associated with this condition. Graphical abstract.

Frozen Blastocyst Embryo Transfer: Comparison of Protocols and Factors Influencing Outcome.

BACKGROUND: Various factors, including treatment protocols, can influence the outcomes of frozen embryo transfers (FETs). The study objectives were to compare different endometrial preparation protocols of FET cycles and to evaluate the factors, including the endometrial thickness (ET), that affect outcomes. METHODS: This observational cohort study involved 5037 women undergoing FETs at eight tertiary clinics in the UK between January 2016 and March 2019. The endometrial preparation protocols used were natural cycle (NC-FETs), artificial hormone support cycle with oestradiol valerate but without pituitary downregulation (AC-FETs) and artificial hormone support cycle with agonist downregulation (ACDR-FETs). RESULTS: The mean (±SD) ages across NC-FET, AC-FET and ACDR-FET groups were 36.5 (±4.2), 35.9 (±5.0) and 36.4(±4.9) years, respectively. LBRs were comparable (40.7%, 175/430; 36.8%, 986/2658; and 36.7%, 716/1949, respectively) across the three groups. Clinical pregnancy, implantation, multiple pregnancies, miscarriage and ectopic pregnancy rates were also similar. In the regression analysis of variables including age, duration of infertility, number of embryos transferred, protocol type and endometrial thickness, age was the only significant predictor of LBRs, although its predictive ability was poor (AUC: 0.55). With the overall LBR of the study population being 37.1%, the post-test probability of a live birth at an ET of <5 mm was 0%, and at 5-5.9, 6-6.9, 7-7.9 and 8-8.9 mm, the probabilities were 16.7%, 33.8%, 36.7% and 37.7%, respectively. The LBR remained above 35% up to the 14-14.9 mm range and then declined gradually to 23% for the 17-25 mm range. CONCLUSIONS: The FET outcomes were similar for the three protocols used for endometrial preparation. The protocol type and endometrial thickness were not predictive of FET outcomes; age was the only predictive variable, despite its low predictive ability.

Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: a meta-analysis.

We aimed to determine the prognostic association between cardiac autonomic neuropathy (CAN) and cardiovascular disease events (CVE) and mortality in type 1 and type 2 diabetes through a systematic review and meta-analysis. This systematic review and meta-analysis was registered with PROSPERO (CRD42020216305) and was conducted with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological criteria. CAN was defined on the basis of 1 (early/possible CAN) or ≥2 (definite CAN) positive autonomic function tests as per the Toronto Consensus guidelines. Studies included those with prospective CVE or mortality data. Methodological variables/risk of bias were assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions) and RoB-2 (Risk-Of-Bias tool for randomized trials) appraisal tools. Electronic database searches yielded 18 467 articles; 84 articles were screened full-text, 26 articles fulfilled the inclusion criteria for quantitative synthesis. Sixteen studies from patients with (n=2875) and without (n=11 722) CAN demonstrated a pooled relative risk (RR) of 3.16 (95%CI 2.42 to 4.13; p<0.0001) of future CVE in favour of CAN. Nineteen studies provided all-cause mortality data from patients with (n=3679) and without (n=12 420) CAN, with a pooled RR of 3.17 (95%CI 2.11 to 4.78; p<0.0001) in favour of CAN. The risk of both future CVE and mortality was higher in type 1 compared with type 2 diabetes and with a definite CAN (vs possible CAN) diagnosis. Three studies were considered to have risk of serious bias. This study confirms the significant association between CAN and CVE and all-cause mortality. The implementation of population-based CAN screening will identify a subgroup with disproportionately higher cardiovascular and mortality risk that will allow for earlier targeted intervention.

Correction to: Cardiac Autonomic Neuropathy in Obesity, Metabolic Syndrome and Prediabetes: A Narrative Review.

The authors of the article would like to amend the article title to 'Cardiac Autonomic Neuropathy in Obesity, Metabolic Syndrome and Prediabetes: A Narrative Review'.

Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.

Cardiac autonomic neuropathy (CAN) is a major complication of type 1 and type 2 diabetes mellitus (T1DM and T2DM). The increased morbidity, cardiovascular and all-cause mortality associated with CAN is established from numerous epidemiological studies. However, CAN is increasingly recognised in people with prediabetes (pre-DM) and the metabolic syndrome (MetS) with a reported prevalence up to 11% and 24% respectively. CAN is associated with components of MetS including hypertension and obesity, predating hyperglycaemia. The aetiology of CAN is multifactorial and there is a reciprocal relationship with insulin resistance and MetS. Obstructive sleep apnoea (OSA) is also associated with CAN possibly through MetS and an independent mechanism. An estimated global prevalence of the impaired glucose tolerance (IGT) form of pre-DM of 587 million people by 2045 means CAN will become a major clinical problem. CAN is independently associated with silent myocardial ischaemia, major cardiovascular events, myocardial dysfunction and cardiovascular mortality. Screening for CAN in pre-DM using risk scores with analysis of heart rate variability (HRV) or Sudoscan is important to allow earlier treatment at a reversible stage. The link between obesity and CAN highlights the therapeutic potential of lifestyle interventions including diet and physical activity to reverse MetS and prevent CAN. Weight loss achieved using these dietary and exercise lifestyle interventions improves the sympathetic and parasympathetic HRV indices of cardiac autonomic function. Further research is needed to identify high-risk populations of people with pre-DM or obesity that might benefit from targeted pharmacotherapy including metformin, sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) analogues. Bariatric surgery also improves HRV through weight loss which might also prevent CAN in severe obesity. This article reviews the literature on CAN in obesity, pre-DM and MetS, to help determine a rationale for screening, early intervention treatment and formulate future research questions in this highly prevalent condition.