Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19

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Abstract

OBJECTIVE

To determine the association between prescription of SGLT2 inhibitors (SGLT2is) and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes (T2D) hospitalized with COVID-19.

RESEARCH DESIGN AND METHODS

This was a retrospective cohort study based on secondary analysis of data from a large nationwide audit from a network of 40 centers in the U.K. with data collection up to December 2020. The study was originally designed to describe risk factors associated with adverse outcomes among people with diabetes who were admitted to hospital with COVID-19. The primary outcome for this analysis was DKA on or during hospital admission. The secondary outcome was mortality. Crude, age-sex adjusted, and multivariable logistic regression models were used to generate odds ratios (ORs) and 95% CIs for people prescribed SGLT2i compared with those not prescribed SGLT2i.

RESULTS

The original national audit included 3,067 people with T2D who were admitted to hospital with COVID-19, of whom 230 (7.5%) were prescribed SGLT2is prior to hospital admission. The mean age of the overall cohort was 72 years, 62.3% were men, and 34.9% were prescribed insulin. Overall, 2.8% of the total population had DKA and 35.6% of people in the study died. The adjusted odds of DKA were not significantly different between those prescribed SGLT2is and those not (OR 0.56; 95% CI 0.16–1.97). The adjusted odds of mortality associated with SGLT2is were similar in the total study population (OR 1.13; 95% CI 0.78–1.63), in the subgroup prescribed insulin (OR 1.02; 95% CI 0.59–1.77), and in the subgroup that developed DKA (OR 0.21; 95% CI 0.01–8.76).

CONCLUSIONS

We demonstrate a low risk of DKA and high mortality rate in people with T2D admitted to hospital with COVID-19 and limited power, but no evidence, of increased risk of DKA or in-hospital mortality associated with prescription of SGLT2is.

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Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study

Emma Barron, Chirag Bakhai, Partha Kar … (2020)

Summary Background Although diabetes has been associated with COVID-19-related mortality, the absolute and relative risks for type 1 and type 2 diabetes are unknown. We assessed the independent effects of diabetes status, by type, on in-hospital death in England in patients with COVID-19 during the period from March 1 to May 11, 2020. Methods We did a whole-population study assessing risks of in-hospital death with COVID-19 between March 1 and May 11, 2020. We included all individuals registered with a general practice in England who were alive on Feb 16, 2020. We used multivariable logistic regression to examine the effect of diabetes status, by type, on in-hospital death with COVID-19, adjusting for demographic factors and cardiovascular comorbidities. Because of the absence of data on total numbers of people infected with COVID-19 during the observation period, we calculated mortality rates for the population as a whole, rather than the population who were infected. Findings Of the 61 414 470 individuals who were alive and registered with a general practice on Feb 16, 2020, 263 830 (0·4%) had a recorded diagnosis of type 1 diabetes, 2 864 670 (4·7%) had a diagnosis of type 2 diabetes, 41 750 (0·1%) had other types of diabetes, and 58 244 220 (94·8%) had no diabetes. 23 698 in-hospital COVID-19-related deaths occurred during the study period. A third occurred in people with diabetes: 7434 (31·4%) in people with type 2 diabetes, 364 (1·5%) in those with type 1 diabetes, and 69 (0·3%) in people with other types of diabetes. Unadjusted mortality rates per 100 000 people over the 72-day period were 27 (95% CI 27–28) for those without diabetes, 138 (124–153) for those with type 1 diabetes, and 260 (254–265) for those with type 2 diabetes. Adjusted for age, sex, deprivation, ethnicity, and geographical region, compared with people without diabetes, the odds ratios (ORs) for in-hospital COVID-19-related death were 3·51 (95% CI 3·16–3·90) in people with type 1 diabetes and 2·03 (1·97–2·09) in people with type 2 diabetes. These effects were attenuated to ORs of 2·86 (2·58–3·18) for type 1 diabetes and 1·80 (1·75–1·86) for type 2 diabetes when also adjusted for previous hospital admissions with coronary heart disease, cerebrovascular disease, or heart failure. Interpretation The results of this nationwide analysis in England show that type 1 and type 2 diabetes were both independently associated with a significant increased odds of in-hospital death with COVID-19. Funding None.

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Practical recommendations for the management of diabetes in patients with COVID-19

Stefan R. Bornstein, Francesco Rubino, Kamlesh Khunti … (2020)

Summary Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20–50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups.

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Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes : A Meta-analysis

Darren K McGuire, Weichung Shih, Francesco Cosentino … (2020)

This meta-analysis uses data from patients with type 2 diabetes from 6 outcomes trials to investigate the association of sodium-glucose cotransporter 2 inhibitors with cardiovascular- and kidney disease–related outcomes. Question Is the effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular- and kidney-related outcomes similar across the class of medications overall and by the presence or absence of prevalent cardiovascular and chronic kidney disease? Findings Results from a meta-analysis of 6 outcomes trials of 4 SGLT2 inhibitors suggest an associated reduction in risk of major adverse cardiovascular events and heterogeneity of cardiovascular death. The greatest magnitude of benefit was for reduction in risk for hospitalization for heart failure (HHF) and kidney disease progression, with estimates of HHF risk outcome the most consistent observation across the trials. Meaning These findings suggest that SGLT2 inhibitors have some heterogeneity of associations with outcomes for cardiovascular death, with consistency of favorable HHF and kidney disease outcomes across the class. Importance Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain. Objective To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes. Data Sources A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020. Study Selection One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials. Data Extraction and Synthesis Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model. Main Outcomes and Measures Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials. Results Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I 2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I 2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death ( P = .62 for interaction), HHF ( P = .26 for interaction), or kidney outcomes ( P = .73 for interaction). Conclusions and Relevance In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.