Since the initial COVID-19 outbreak in China, much attention has focused on people with diabetes because of poor prognosis in those with the infection. Initial reports were mainly on people with type ...2 diabetes, although recent surveys have shown that individuals with type 1 diabetes are also at risk of severe COVID-19. The reason for worse prognosis in people with diabetes is likely to be multifactorial, thus reflecting the syndromic nature of diabetes. Age, sex, ethnicity, comorbidities such as hypertension and cardiovascular disease, obesity, and a pro-inflammatory and pro-coagulative state all probably contribute to the risk of worse outcomes. Glucose-lowering agents and anti-viral treatments can modulate the risk, but limitations to their use and potential interactions with COVID-19 treatments should be carefully assessed. Finally, severe acute respiratory syndrome coronavirus 2 infection itself might represent a worsening factor for people with diabetes, as it can precipitate acute metabolic complications through direct negative effects on β-cell function. These effects on β-cell function might also cause diabetic ketoacidosis in individuals with diabetes, hyperglycaemia at hospital admission in individuals with unknown history of diabetes, and potentially new-onset diabetes.
New-Onset Diabetes in Covid-19 Rubino, Francesco; Amiel, Stephanie A; Zimmet, Paul ...
New England Journal of Medicine,
08/2020, Letnik:
383, Številka:
8
Journal Article, Publication
Recenzirano
Odprti dostop
Diabetes is associated with an increased risk of severe Covid-19. New-onset diabetes and metabolic complications of preexisting diabetes, including diabetic ketoacidosis and hyperosmolarity, for ...which very high doses of insulin are warranted, have been observed in patients with Covid-19. This letter discusses these issues.
Summary Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. ...If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycemia in type 2 ...diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the health care system, and physical activity behaviors, including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.
Certain chronic comorbidities, including diabetes, are highly prevalent in people with coronavirus disease 2019 (COVID-19) and are associated with an increased risk of severe COVID-19 and mortality. ...Mild glucose elevations are also common in COVID-19 patients and associated with worse outcomes even in people without diabetes. Several studies have recently reported new-onset diabetes associated with COVID-19. The phenomenon of new-onset diabetes following admission to the hospital has been observed previously with other viral infections and acute illnesses. The precise mechanisms for new-onset diabetes in people with COVID-19 are not known, but it is likely that a number of complex interrelated processes are involved, including previously undiagnosed diabetes, stress hyperglycemia, steroid-induced hyperglycemia, and direct or indirect effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the β-cell. There is an urgent need for research to help guide management pathways for these patients. In view of increased mortality in people with new-onset diabetes, hospital protocols should include efforts to recognize and manage acute hyperglycemia, including diabetic ketoacidosis, in people admitted to the hospital. Whether new-onset diabetes is likely to remain permanent is not known, as the long-term follow-up of these patients is limited. Prospective studies of metabolism in the setting of postacute COVID-19 will be required to understand the etiology, prognosis, and treatment opportunities.
The development of basal insulin analogues has reduced the risk of hypoglycaemia in insulin-treated individuals with type 2 diabetes. Insulin degludec and insulin glargine 300 U/ml (glargine U300) ...represent an evolution of basal insulin analogues, both of them reducing the risk of hypoglycaemia as compared with that associated with glargine U100. However, whether degludec and glargine U300 are equivalent with respect to glycaemic control and risk of hypoglycaemia remains to be fully ascertained. In the CONCLUDE trial, 1609 individuals with type 2 diabetes were randomised to either degludec 200 U/ml (degludec U200) or glargine U300. In this issue of
Diabetologia
(
https://doi.org/10.1007/s00125-019-05080-9
) the investigators report that during the maintenance period, HbA
1c
improved to a similar extent in the two groups with no significant difference in the rate of overall hypoglycaemia (the primary endpoint of the study), while rates of nocturnal symptomatic and severe hypoglycaemia (secondary endpoints) were lower with degludec U200 than with glargine U300. These results, although of great interest to the clinician, need to be carefully interpreted as they cannot be considered as conclusive. First, the primary endpoint was not met and, therefore, analyses of secondary endpoints remain exploratory. Even assuming that degludec is superior to glargine in reducing the risk of hypoglycaemia, the mechanism(s) accounting for such an advantage remain elusive and potential differences in pharmacokinetics and pharmacodynamics difficult to appreciate because of methodological issues. The study design had to be amended because of lack of reliability of the glucometers initially used in the trial, particularly in the low blood glucose ranges, so the potential implications of these changes in the subsequent conduct of the trial cannot be excluded. Finally, comparison with the BRIGHT trial, the only other available head-to-head study, is complicated by differences between the two studies in the primary endpoint (HbA
1c
reduction vs reduction of the risk of hypoglycaemia), study population (insulin-experienced vs insulin-naive) and concomitant glucose-lowering medications. In spite of all this, CONCLUDE teaches us an important lesson regarding the need, particularly in the clinical setting, to monitor the reliability of the glucometers the diabetic individual uses to adjust his/her insulin dose. Insufficient precision or inappropriate use of the glucometer can easily offset any minute advantage a new insulin can offer with respect to glycaemic control and risk of hypoglycaemia.
Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials ...is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin's protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.
Evidence relating to the impact of COVID-19 in people with diabetes (PWD) is limited but continuing to emerge. PWD appear to be at increased risk of more severe COVID-19 infection, though evidence ...quantifying the risk is highly uncertain. The extent to which clinical and demographic factors moderate this relationship is unclear, though signals are emerging that link higher BMI and higher HbA
to worse outcomes in PWD with COVID-19. As well as posing direct immediate risks to PWD, COVID-19 also risks contributing to worse diabetes outcomes due to disruptions caused by the pandemic, including stress and changes to routine care, diet, and physical activity. Countries have used various strategies to support PWD during this pandemic. There is a high potential for COVID-19 to exacerbate existing health disparities, and research and practice guidelines need to take this into account. Evidence on the management of long-term conditions during national emergencies suggests various ways to mitigate the risks presented by these events.
Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been ...definitively assessed in a cardiovascular outcomes trial.
Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m
were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis).
Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m
. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing.
SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.
To explore whether at-admission hyperglycemia is associated with worse outcomes in patients hospitalized for coronavirus disease 2019 (COVID-19).
Hospitalized COVID-19 patients (
= 271) were ...subdivided based on at-admission glycemic status:
) glucose levels <7.78 mmol/L (NG) (
= 149 55.0%; median glucose 5.99 mmol/L range 5.38-6.72),
) known diabetes mellitus (DM) (
= 56 20.7%; 9.18 mmol/L 7.67-12.71), and
) no diabetes and glucose levels ≥7.78 mmol/L (HG) (
= 66 24.3%; 8.57 mmol/L 8.18-10.47).
Neutrophils were higher and lymphocytes and PaO
/FiO
lower in HG than in DM and NG patients. DM and HG patients had higher D-dimer and worse inflammatory profile. Mortality was greater in HG (39.4% vs. 16.8%; unadjusted hazard ratio HR 2.20, 95% CI 1.27-3.81,
= 0.005) than in NG (16.8%) and marginally so in DM (28.6%; 1.73, 0.92-3.25,
= 0.086) patients. Upon multiple adjustments, only HG remained an independent predictor (HR 1.80, 95% CI 1.03-3.15,
= 0.04). After stratification by quintile of glucose levels, mortality was higher in quintile 4 (Q4) (3.57, 1.46-8.76,
= 0.005) and marginally in Q5 (29.6%) (2.32, 0.91-5.96,
= 0.079) vs. Q1.
Hyperglycemia is an independent factor associated with severe prognosis in people hospitalized for COVID-19.
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