Risk factors associated with mortality in individuals with type 2 diabetes following an episode of severe hypoglycaemia. Results from a randomised controlled trial.
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ABSTRACT: Background
Severe hypoglycaemia may pose significant risk to individuals with type 2 diabetes (T2D), and evidence surrounding strategies to mitigate this risk is lacking.Methods
Data was re-analysed from a previous randomised controlled trial studying the impact of nurse-led intervention on mortality following severe hypoglycaemia in the community. A Cox-regression model was used to identify baseline characteristics associated with mortality and to adjust for differences between groups. Kaplan-Meier curves were created to demonstrate differences in outcome between groups across different variables.Results
A total of 124 participants (mean age = 75, 56.5% male) were analysed. In univariate analysis, Diabetes Severity Score (DSS), age and insulin use were baseline factors found to correlate to mortality, while HbA1C and established cardiovascular disease showed no significant correlations. Hazard ratio favoured the intervention (0.68, 95% CI: 0.38-1.19) and in multivariate analysis, only DSS demonstrated a relationship with mortality. Comparison of Kaplan-Meier curves across study groups suggested the intervention is beneficial irrespective of HbA1c, diabetes severity score or age.Conclusion
While DSS predicts mortality following severe community hypoglycaemia in individuals with T2D, a structured nurse-led intervention appears to reduce the risk of death across a range of baseline parameters.
SUBMITTER: Pearson SM
PROVIDER: S-EPMC8801660 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aims/hypothesisSeveral pathophysiological mechanisms would suggest a causal link between hypoglycaemia and cardiovascular death; conversely, current knowledge would not support a causal relationship with other causes of death. To clarify the nature and the magnitude of the association between hypoglycaemia and death, we investigated the 5 year mortality risks for cardiovascular disease, cancer and other causes in individuals with type 2 diabetes admitted to hospital for a severe hypoglycaemic episode.MethodsWe defined in the UK Clinical Practice Research Datalink database a prevalent cohort of adults with type 2 diabetes diagnosed between 1 January 1998 and 1 January 2011 (index date), with available linkage to the Office for National Statistics (ONS) and the Hospital Episode Statistics (HES). A hospital admission reporting hypoglycaemia as the underlying cause was identified before the index date in the HES; date and underlying cause of death were obtained from the ONS. We quantified the 5 year risk of cause-specific death in people with and without admission to hospital for severe hypoglycaemia, adjusting for potential confounders and accounting for competing risk.ResultsOf the 74,610 subjects included in the cohort, 388 (0.5%) were admitted at least once for a severe hypoglycaemic episode; subjects admitted were older, with higher HbA1c and a greater prevalence of multimorbidity. During a median follow-up of 7.1 years, 236 (60.8%) and 18,539 (25.0%) deaths occurred in subjects with and without a previous severe hypoglycaemia, respectively. Non-cardiovascular causes accounted for 71% of all deaths in both subjects with and without hypoglycaemia. In a 60-year-old person with severe hypoglycaemia, the 5 year absolute risk of death, adjusted for age, sex, ethnicity, systolic blood pressure, total cholesterol, HbA1c, BMI, eGFR, smoking status, alcohol consumption and deprivation (Townsend score), was 6.6%, 1.1% and 13.1% for cardiovascular, cancer and other causes, respectively, while the 5 year absolute risk difference compared with a subject without severe hypoglycaemia was 4.7% (95% CI 1.0, 8.3) for cardiovascular, -1.4% (-4.1, 1.4) for cancer and 11.1% (6.1, 16.1) for other causes of death. Results were consistent in models further adjusted for medications and comorbidities (myocardial infarction, stroke, peripheral artery disease, heart failure, atrial fibrillation, cancer), with sulfonylurea and insulin associated with increased mortality rates (from cause-specific hazard ratio of 1.06 [95% CI 0.99, 1.14] for cancer death with use of sulfonylurea to 1.42 [1.29, 1.56] for cardiovascular death with use of insulin). Results were robust to missing data.Conclusions/interpretationThe results of this study indicate severe hypoglycaemia as a marker of, rather than causally linked to, an increased risk of long-term mortality. Regardless of the nature of the association, a severe hypoglycaemic episode represents a strong negative prognostic factor in patients with type 2 diabetes. Graphical abstract.
| S-EPMC7476909 | biostudies-literature
Project description:Isobutyryl-CoA Dehydrogenase Deficiency (IBDD) is an inherited disorder of valine metabolism caused by mutations in ACAD8. Most reported patients have been diagnosed through newborn screening programmes due to elevated C4-carnitine levels and appear clinically asymptomatic. One reported non-screened patient had dilated cardiomyopathy and anaemia at the age of two years. We report a 13 month old girl diagnosed with IBDD after developing hypoglycaemic encephalopathy (blood glucose 1.9 mmol/l) during an episode of rotavirus-induced gastroenteritis. Metabolic investigations demonstrated an appropriate ketotic response (free fatty acids 2594 ?mol/l, 3-hydroxybutyrate 3415 ?mol/l), mildly elevated plasma lactate (3.4 mmol/l), increased C4-carnitine on blood spot and plasma acylcarnitine analysis and other metabolic abnormalities secondary to ketosis. After recovery, C4-carnitine remained increased and isobutyrylglycine was detected on urine organic acid analysis. Free carnitine was normal in all acylcarnitine samples. IBDD was confirmed by finding a homozygous c.845C > T substitution in ACAD8. The patient was given, but has not used, a glucose polymer emergency regimen and after ten years' follow-up has had no further episodes of hypoglycaemia nor has she developed cardiomyopathy or anaemia. Psychomotor development has been normal to date. Though we suspect IBDD did not contribute to hypoglycaemia in this patient, patients should be followed-up carefully and glucose polymer emergency regimens may be indicated if recurrent episodes of hypoglycaemia occur.
| S-EPMC5198737 | biostudies-literature
Project description:Aims/hypothesisThe double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.MethodsIn DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.ResultsThere was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.Conclusions/interpretationThe results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.Trial registrationClinicalTrials.gov NCT01959529.
| S-EPMC6002964 | biostudies-literature
Project description:ObjectiveTo determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.DesignRetrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics.ParticipantsPatients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control.Outcome measuresSymptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.Results10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.ConclusionSymptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.Trial registrationNCT00000620.
| S-EPMC2803744 | biostudies-literature
Project description:Background 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. Methods 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 I2 statistic, pooled relative risks (RRs) and 95% confidence intervals (CI) were obtained using random-effects models. Results After 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 (RR 1.42, 95%CI 1.21-1.68), CVD-induced death (RR 1.59, 95% CI 1.24-2.04), and all-cause mortality (RR 1.68, 95% CI 1.49-1.90) compared to euglycaemic patients with significant heterogeneity. Conclusion 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.
| S-EPMC10461564 | biostudies-literature
Project description:AimTo investigate whether an increased bolus: basal insulin ratio (BBR) with liver-targeted bolus insulin (BoI) would increase BoI use and decrease hypoglycaemic events (HEv).Patient population and methodsWe enrolled 52 persons (HbA1c 6.9% ± 0.12%, mean ± SEM) with type 1 diabetes using multiple daily injections. Hepatic-directed vesicle (HDV) was used to deliver 1% of peripheral injected BoI to the liver. A 90-day run-in period was used to introduce subjects to unblinded continuous glucose monitoring and optimize standard basal insulin (BaI) (degludec) and BoI (lispro) dosing. At 90 days, BoI was changed to HDV-insulin lispro and subjects were randomized to an immediate 10% or 40% decrease in BaI dose.ResultsAt 90 days postrandomization, total insulin dosing was increased by ~7% in both cohorts. The -10% and -40% BaI cohorts were on 7.7% and 13% greater BoI with 6.9% and 30% (P = .02) increases in BBR, respectively. Compared with baseline at randomization, nocturnal level 2 HEv were reduced by 21% and 43%, with 54% and 59% reductions in patient-reported HEv in the -10% and -40% BaI cohorts, respectively.ConclusionsOur study shows that liver-targeted BoI safely decreases HEv and symptoms without compromising glucose control. We further show that with initiation of liver-targeted BoI, the BBR can be safely increased by significantly lowering BaI dosing, leading to greater BoI usage.
| S-EPMC9546184 | biostudies-literature
Project description:AIM:This study aimed to assess the association between body mass index (BMI) and the development of severe hypoglycaemia in patients with type 2 diabetes (T2D), using nationwide data for the entire South Korean population. METHODS:The association between BMI and severe hypoglycaemia was retrospectively examined from claims and National Health examination data registered between 2002 and 2015. A total of 1,366,692 subjects assigned clinical codes for T2D and prescribed antihypoglycaemic agents were included. The primary outcome was an episode of severe hypoglycaemia after the baseline health examination. RESULTS:A total of 37,682 subjects (2.7%) experienced a new severe hypoglycaemic event during the follow-up period (mean: 8.6 years). An inverse J-shaped association was observed between BMI and severe hypoglycaemic events. The association between low BMI and high risk of severe hypoglycaemia was similar in subjects who had never smoked, did not consume alcohol, did not use insulin and had no major comorbidities, after adjusting for multiple confounding variables. This association was also found to be intensified in men, young people aged 30-49 years, those with major comorbidities and insulin users. CONCLUSION:BMI and severe hypoglycaemia were found to be inversely associated. Thus, those who fall into the category of having low BMI and high risk of severe hypoglycaemia should be warned about the risk of having a hypoglycaemic event and be properly informed about hypoglycaemia to minimize the risk of fatal hypoglycaemia-related outcomes.
| S-EPMC6279604 | biostudies-literature
Project description:AimThis study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial).MethodsIn this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16-week maintenance periods.ResultsFor individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1-40) vs 15 (1-54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively.ConclusionTreatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.
| S-EPMC6618254 | biostudies-literature
Project description:AimTo investigate whether a history of severe hypoglycaemia (SH) or the associated presence of impaired awareness of hypoglycaemia (IAH) is characterized by a pro-inflammatory profile in people with type 1 diabetes.Research design and methodsWe measured circulating inflammatory markers and pro- and anti-inflammatory cytokine production after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) in a well-characterized cohort of individuals with type 1 diabetes (n = 239) and in people without diabetes (n = 56). Data were corrected for confounders by using multivariate linear regression models.ResultsPeople with type 1 diabetes had higher circulating concentrations of high-sensitivity C-reactive protein (hs-CRP; 0.91 [0.36-2.25] vs. 0.52 [0.20-0.98] pg/mL, P < 0.001 and interleukin-18-binding protein (IL-18BP; 1746 [1304-2112] vs. 1381 [1191-1807] pg/mL; P = 0.001) than those without diabetes. In multivariate analysis, only higher hs-CRP concentrations persisted. Neither circulating immune cells nor ex vivo cytokine levels produced by PBMCs in response to an extensive panel of stimuli differed in groups defined by awareness state or a history of SH, apart from elevated IL-18BP in people with, versus those without, history of SH (1524 [1227-1903] vs. 1913 [1459-2408] pg/mL; P < 0.001).ConclusionsIAH or history of SH in people with type 1 diabetes was not associated with altered inflammatory profiles, arguing against chronically elevated inflammatory activity mediating the increased cardiovascular risk associated with hypoglycaemia. The finding of higher circulating concentrations of IL-18BP in individuals with a history of SH requires further investigation.
| S-EPMC7756490 | biostudies-literature
Project description:Aims: To undertake a post-hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes.Materials and methods: The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all-cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all-cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100?units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all-cause mortality were investigated.Results: Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all-cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all-cause mortality).Conclusions: The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all-cause mortality and that, in this high-risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.
| S-EPMC7754351 | biostudies-literature