Tight versus liberal blood-glucose control in the intensive care unit: special considerations for patients with diabetes

The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

Summary Background Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. Methods We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. Findings Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017–19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48–53 mmol/mol (6·5–7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50–3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47–1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48–53 mmol/mol (HR 1·22 [95% CI 1·15–1·30, p<0·0001] for 59–74 mmol/mol [7·6–8·9%] and 1·36 [1·24–1·50, p<0·0001] for 75–85 mmol/mol [9·0–9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0–29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60–3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53–3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11–2·56, p<0·0001) and 1·60 (1·47–1·75, p<0·0001). Interpretation Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. Funding None.

The optimal target range for blood glucose in critically ill patients remains unclear. Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization. Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.) 2009 Massachusetts Medical Society