Severe hypoglycaemia and absolute risk of cause-specific mortality in individuals with type 2 diabetes: a UK primary care observational study

Abstract Aims/hypothesis Several 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. Methods We 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. Results Of 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/interpretation The 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.

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A review of mortality in type 2 diabetes mellitus

Diabetes Mellitus ◽

10.14341/dm6846 ◽

2015 ◽

Vol 18 (4) ◽

pp. 12-21 ◽

Cited By ~ 3

Author(s):

Nailya Sayfullaevna Asfandiyarova

Keyword(s):

Type 2 Diabetes ◽

Causes Of Death ◽

Severe Hypoglycaemia ◽

Microvascular Complications ◽

Antiplatelet Agents ◽

Diabetic Coma ◽

Intensive Glucose Control ◽

Risk Of Death ◽

Increased Risk

The morbidity and mortality associated with type 2 diabetes have increased over recent years. The causes of death include cardiovascular disease, cancer, infection, kidney disease and diabetic coma. Risk factors for death are a sedentary lifestyle, obesity, smoking, sex, age, duration and severity of diabetes, macro- and microvascular complications and hyper- and hypoglycaemic states. Adequate glycemic control and moderate exercise along with the use of antiplatelet agents (e.g. aspirin), statins, antihypertensives and metformin can reduce mortality. Intensive glucose control was associated with an increased risk of severe hypoglycaemia and death, and surgical intervention increased the risk of death.

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A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study

Diabetologia ◽

10.1007/s00125-021-05556-7 ◽

2021 ◽

Author(s):

Simon R. Heller ◽

Milan S. Geybels ◽

Ahmed Iqbal ◽

Lei Liu ◽

Lily Wagner ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Severe Hypoglycaemia ◽

Cardiovascular Death ◽

Cardiovascular Outcomes ◽

Post Hoc Analysis ◽

Increased Risk ◽

All Cause Mortality ◽

Post Hoc

Abstract Aims/hypothesis Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. Methods LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. Results We demonstrate that there is an association between NSHEs (2–11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2–11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). Conclusions/interpretation The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. Trial registration ClinicalTrials.gov (NCT01179048). Graphical abstract

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Life-course trajectories of weight and their impact on the incidence of type 2 diabetes

Scientific Reports ◽

10.1038/s41598-021-91910-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Diego Yacamán-Méndez ◽

Ylva Trolle-Lagerros ◽

Minhao Zhou ◽

Antonio Monteiro Ponce de Leon ◽

Hrafnhildur Gudjonsdottir ◽

...

Keyword(s):

Type 2 Diabetes ◽

Life Course ◽

Risk Ratio ◽

Absolute Risk ◽

Early Adulthood ◽

Normal Weight ◽

Overweight And Obesity ◽

Increased Risk ◽

Incident Cases

AbstractAlthough exposure to overweight and obesity at different ages is associated to a higher risk of type 2 diabetes, the effect of different patterns of exposure through life remains unclear. We aimed to characterize life-course trajectories of weight categories and estimate their impact on the incidence of type 2 diabetes. We categorized the weight of 7203 participants as lean, normal or overweight at five time-points from ages 7–55 using retrospective data. Participants were followed for an average of 19 years for the development of type 2 diabetes. We used latent class analysis to describe distinctive trajectories and estimated the risk ratio, absolute risk difference and population attributable fraction (PAF) associated to different trajectories using Poisson regression. We found five distinctive life-course trajectories. Using the stable-normal weight trajectory as reference, the stable overweight, lean increasing weight, overweight from early adulthood and overweight from late adulthood trajectories were associated to higher risk of type 2 diabetes. The estimated risk ratios and absolute risk differences were statistically significant for all trajectories, except for the risk ratio of the lean increasing trajectory group among men. Of the 981 incident cases of type 2 diabetes, 47.4% among women and 42.9% among men were attributable to exposure to any life-course trajectory different from stable normal weight. Most of the risk was attributable to trajectories including overweight or obesity at any point of life (36.8% of the cases among women and 36.7% among men). The overweight from early adulthood trajectory had the highest impact (PAF: 23.2% for woman and 28.5% for men). We described five distinctive life-course trajectories of weight that were associated to increased risk of type 2 diabetes over 19 years of follow-up. The variability of the effect of exposure to overweight and obesity on the risk of developing type 2 diabetes was largely explained by exposure to the different life-course trajectories of weight.

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Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs

Cardiac Failure Review ◽

10.15420/cfr.2018.44.1 ◽

2019 ◽

Vol 5 (1) ◽

pp. 27-30 ◽

Cited By ~ 3

Author(s):

Thomas A Zelniker ◽

Eugene Braunwald

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Renal Failure ◽

Cardiovascular Death ◽

Cardiovascular Outcomes ◽

Sodium Glucose Cotransporter ◽

Increased Risk ◽

Patients With Diabetes ◽

Glucagon Like Peptide 1

Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

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Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial

10.21203/rs.3.rs-47847/v2 ◽

2020 ◽

Author(s):

Antonio Ceriello ◽

Anne Pernille Ofstad ◽

Isabella Zwiener ◽

Stefan Kaspers ◽

Jyothis George ◽

...

Keyword(s):

Type 2 Diabetes ◽

Standard Deviation ◽

Cox Regression ◽

Glucose Variability ◽

Cardiovascular Death ◽

Baseline Risk ◽

Increased Risk ◽

Outcome Trial ◽

Hba1c Variability

Abstract Background: Glucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin’s cardiovascular death reductions.Methods: In total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment.Results: HbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g.an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615.Conclusions: HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin’s reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability.ClinicalTrials.gov number, NCT01131676

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Estimated glucose disposal rate and risk of stroke and mortality in type 2 diabetes: a nationwide cohort study

Cardiovascular Diabetology ◽

10.1186/s12933-021-01394-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Alexander Zabala ◽

Vladimer Darsalia ◽

Marcus Lind ◽

Ann-Marie Svensson ◽

Stefan Franzén ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cohort Study ◽

Cox Regression ◽

Glucose Disposal ◽

Risk Of Death ◽

Increased Risk ◽

Estimated Glucose Disposal Rate ◽

Glucose Disposal Rate

Abstract Background and aims Insulin resistance contributes to the development of type 2 diabetes (T2D) and is also a cardiovascular risk factor. The aim of this study was to investigate the potential association between insulin resistance measured by estimated glucose disposal rate (eGDR) and risk of stroke and mortality thereof in people with T2D. Materials and methods Nationwide population based observational cohort study that included all T2D patients from the Swedish national diabetes registry between 2004 and 2016 with full data on eGDR and categorised as following: < 4, 4–6, 6–8, and ≥ 8 mg/kg/min. We calculated crude incidence rates and 95% confidence intervals (CIs) and used multiple Cox regression to estimate hazard ratios (HRs) to assess the association between the risk of stroke and death, according to the eGDR categories in which the lowest category < 4 (i.e., highest grade of insulin resistance), served as a reference. The relative importance attributed of each factor in the eGDR formula was measured by the R2 (± SE) values calculating the explainable log-likelihoods in the Cox regression. Results A total of 104 697 T2D individuals, 44.5% women, mean age of 63 years, were included. During a median follow up-time of 5.6 years, 4201 strokes occurred (4.0%). After multivariate adjustment the HRs (95% CI) for stroke in patients with eGDR categories between 4–6, 6–8 and > 8 were: 0.77 (0.69–0.87), 0.68 (0.58–0.80) and 0.60 (0.48–0.76), compared to the reference < 4. Corresponding numbers for the risk of death were: 0.82 (0.70–0.94), 0.75 (0.64–0.88) and 0.68 (0.53–0.89). The attributed relative risk R2 (± SE) for each variable in the eGDR formula and stroke was for: hypertension (0.045 ± 0.0024), HbA1c (0.013 ± 0.0014), and waist (0.006 ± 0.0009), respectively. Conclusion A low eGDR (a measure of insulin resistance) is associated with an increased risk of stroke and death in individuals with T2D. The relative attributed risk was most important for hypertension.

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Fasting C-Peptide Levels and Death Resulting From All Causes and Breast Cancer: The Health, Eating, Activity, and Lifestyle Study

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.4752 ◽

2011 ◽

Vol 29 (1) ◽

pp. 47-53 ◽

Cited By ~ 88

Author(s):

Melinda L. Irwin ◽

Catherine Duggan ◽

Ching-Yun Wang ◽

Ashley Wilder Smith ◽

Anne McTiernan ◽

...

Keyword(s):

Breast Cancer ◽

Type 2 Diabetes ◽

Cox Regression ◽

Treatment Strategies ◽

Breast Cancer Diagnosis ◽

C Peptide ◽

Risk Of Death ◽

Increased Risk ◽

Health Eating

Purpose To examine the association between serum C-peptide, a marker of insulin secretion, measured 3 years after a breast cancer diagnosis, and death resulting from all causes and breast cancer. Patients and Methods This was a prospective, observational study of 604 women enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or December 31, 2006, whichever came first. The hazard ratio (HR) for all deaths and deaths owing to breast cancer and 95% CIs for the HR were estimated using multivariable stratified Cox regression analyses. Results Among women without type 2 diabetes, fasting C-peptide levels were associated with an increased risk of death resulting from all causes and from breast cancer. A 1-ng/mL increase in C-peptide was associated with a 31% increased risk of any death (HR = 1.31; 95% CI, 1.06 to 1.63; P = .013) and a 35% increased risk of death as a result of breast cancer (HR = 1.35; 95% CI, 1.02 to 1.87, P = .048). Associations between C-peptide levels and death as a result of breast cancer were stronger in certain subgroups, including women with type 2 diabetes, women with a body mass index less than 25 kg/m2, women diagnosed with a higher stage of disease, and women whose tumors were estrogen receptor positive. Conclusion Treatment strategies to reduce C-peptide levels in patients with breast cancer, including dietary-induced weight loss, physical activity, and/or use of insulin-lowering medications, should be explored.

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Retinal Vascular Measures from Diabetes Retinal Screening Photographs and Risk of Incident Dementia in Type 2 Diabetes: A GoDARTS Study

10.1101/2020.11.15.20230490 ◽

2020 ◽

Author(s):

Alexander SF Doney ◽

Aditya Nar ◽

Yu Huang ◽

Emanuele Trucco ◽

Tom MacGillivray ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fractal Dimension ◽

Competing Risk ◽

Imaging Biomarkers ◽

Prevention Strategies ◽

Risk Of Death ◽

Increased Risk ◽

Patients With Diabetes ◽

Reduced Risk

AbstractObjectivePatients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk.Research Design and MethodsRVMs were obtained from 6,111 patients in the GoDARTS bioresource using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer’s dementia (AD) and vascular dementia (VD). We used Cox’s proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated.ResultsIncreased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction.ConclusionsConventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies.

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Association of Baseline HbA1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

Diabetes Care ◽

10.2337/dc21-1744 ◽

2022 ◽

Author(s):

Avivit Cahn ◽

Stephen D. Wiviott ◽

Ofri Mosenzon ◽

Erica L. Goodrich ◽

Sabina A. Murphy ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Events ◽

Cox Regression ◽

Cardiovascular Death ◽

Atherosclerotic Cardiovascular Disease ◽

Baseline Hba1c ◽

Renal Outcomes ◽

Increased Risk ◽

Hba1c Levels

OBJECTIVE Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models. RESULTS In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06–1.19], 1.08 [1.04–1.13], and 1.17 [1.11–1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05). CONCLUSIONS Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%.

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Glycemic Control and Risk of Sepsis and Subsequent Mortality in Type 2 Diabetes

10.2337/figshare.16775743 ◽

2021 ◽

Author(s):

Anca Balintescu ◽

Marcus Lind ◽

Mikael Andersson Franko ◽

Anders Oldner ◽

Maria Cronhjort ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Analysis ◽

Cox Regression ◽

Cubic Spline ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Increased Risk

Objective To investigate the nature of the relationship between HbA1c and sepsis among individuals with type 2 diabetes and to assess the association of sepsis and all-cause mortality in such patients. Research design and methods We included 502,871 individuals with type 2 diabetes recorded in the Swedish National Diabetes Register and used multivariable Cox regression and restricted cubic spline analyses to assess the association between time-updated HbA1c values and sepsis occurrence between January 1, 2005 and December 31, 2015. The association between sepsis and death was examined using multivariable Cox regression analysis. Result Overall, 14,534 (2.9%) patients developed sepsis during the study period. On multivariable Cox regression analysis, compared with an HbA1c of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was 1.15 (95% CI 1.07-1.24) for HbA1c <43 mmol/mol (6.1%); 0.93 (0.87-0.99) for HbA1c 53-62 mmol/mol (7.0-7.8%); 1.05 (0.97-1.13) for HbA1c 63-72 mmol/mol (7.9-8.7%); 1.14 (1.04-1.25) for HbA1c 73-82 mmol/mol (8.8-9.7%); and 1.52 (1.37-1.68) for HbA1c >82 mmol/mol (9.7%). In the cubic spline model, a reduction of the adjusted risk was observed within the lower HbA1c range until 53 mmol/mol (7.0%), with a hazard ratio of 0.78 (0.73-0.82) per standard deviation, and increased thereafter (P for non-linearity <0.001). As compared to patients without sepsis, the adjusted hazard ratio for death among patients with sepsis was 4.16 (4.03-4.30). Conclusions In a nationwide cohort of individuals with type 2 diabetes, we found a U-shaped association between HbA1c and sepsis and a four-fold increased risk of death among those developing sepsis.

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