A case series of diabetic ketoacidosis associated with SGLT2 inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are increasingly initiated as treatment for type 2 diabetes due to favourable cardiorenal characteristics. However, studies have identified an increased risk of diabetic ketoacidosis (DKA). We carried out a retrospective, case-based study at East and North Herts NHS Trust between February 2018 and December 2020. Fifteen cases of SGLT2i associated DKA were identified in people with presumed type 2 diabetes;33.3% were classed as euglycaemic DKA with a blood glucose of <11mmol/L. All cases were associated with a significant precipitating factor including diarrhoea, vomiting, reduced oral intake and sepsis. One case was related to COVID-19. Two people were subsequently found to have raised islet autoantibodies suggesting type 1 diabetes or latent autoimmune diabetes in adults. It is important that awareness of SGLT2i associated DKA is raised among users and health care practitioners, including the recognition of euglycaemic DKA. Sick day rules should be emphasised and reiterated at clinical encounters. Non-specialists in primary care, oncology and in perioperative settings should be empowered to advocate for temporary withdrawal and there should be readier access to blood ketone monitoring when required. When SGLT2i associated DKA occurs, due consideration should be given to evaluate the diabetes classification and investigate the circumstances of the event. Copyright © 2023 John Wiley & Sons.Copyright © 2023 John Wiley & Sons, Ltd.

Clinical evolution of patients with AF and diabetes mellitus in the COVID-19 pandemic. REFADI Registry

Introduction and objectives: To analyze the evolution of patients with atrial fibrillation (AF) and diabetes in the mid-term follow-up during the COVID-19 pandemic and to describe its impact on this population. Method(s): Multicenter and prospective registry that included patients with AF and diabetes attended in cardiology clinics. A multivariate analysis was performed to determine the variables associated with the occurrence of clinical events and mortality. Recruitment was performed in February-December 2019. Result(s): The evolution of 633 patients, 96,2% of those included in the REFADI registry with a median follow-up of 835 days was analyzed (mean age 73.8 +/- 8.5 years, 54.3% male, CHA2DS2-VASc 4,34 +/- 1,4, HAS-BLED 2,47 +/- 0,96) were analyzed. The proportion of anticoagulated patients remained constant (95.6% vs 94.5%;P = .24). There was a decrease in the prescription of vitamin K antagonists (from 31.4% to 19.7%;P < .01), and an increase in the use of direct anticoagulants (from 62.0% to 70.3%;P < .01). During the follow-up there was an increase in the prescription of SGLT2 inhibitors (from 20.0% to 25.5%;P < .01) and GLP1 agonists (from 4.2% to 9.1%;P < .01). During this period, 17.2% of patients died, the majority from cardiovascular causes, 6.4% from COVID-19, 2.8% from stroke, and 1.8% from hemorrhage. Older age, lower ejection fraction, lower hemoglobin levels, and especially lower direct anticoagulants prescription were associated with mortality. Conclusion(s): Patients with AF and diabetes have a high thromboembolic risk and a high risk of developing complications, especially of cardiovascular origin.Copyright © 2023 Sociedad Espanola de Cardiologia

Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: A randomized cross-over clinical study.

AIM: To evaluate the albuminuria-lowering effect of dapagliflozin, exenatide, and the combination of dapagliflozin and exenatide in patients with type 2 diabetes and microalbuminuria or macroalbuminuria. METHODS: Participants with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of more than 30 ml/min/1.73m2 and an urinary albumin: creatinine ratio (UACR) of more than 3.5 mg/mmol and 100 mg/mmol or less completed three 6-week treatment periods, during which dapagliflozin 10 mg/d, exenatide 2 mg/wk and both drugs combined were given in random order. The primary outcome was the percentage change in UACR. Secondary outcomes included blood pressure, HbA1c, body weight, extracellular volume, fractional lithium excretion and renal haemodynamic variables as determined by magnetic resonance imaging. RESULTS: We enrolled 20 patients, who completed 53 treatment periods in total. Mean percentage change in UACR from baseline was -21.9% (95% CI: -34.8% to -6.4%) during dapagliflozin versus -7.7% (95% CI: -23.5% to 11.2%) during exenatide and -26.0% (95% CI: -38.4% to -11.0%) during dapagliflozin-exenatide treatment. No correlation was observed in albuminuria responses between the different treatments. Numerically greater reductions in systolic blood pressure, body weight and eGFR were observed during dapagliflozin-exenatide treatment compared with dapagliflozin or exenatide alone. Renal blood flow and effective renal plasma flow (ERPF) did not significantly change with either treatment regimen. However, all but four and two patients in the dapagliflozin and dapagliflozin-exenatide groups, respectively, showed reductions in ERPF. The filtration fraction did not change during treatment with dapagliflozin or exenatide, and decreased during dapagliflozin-exenatide treatment (-1.6% [95% CI: -3.2% to -0.01%]; P = .048). CONCLUSIONS: In participants with type 2 diabetes and albuminuria, treatment with dapagliflozin, exenatide and dapagliflozin-exenatide reduced albuminuria, with a numerically larger reduction in the combined dapagliflozin-exenatide treatment group.

A study of glycemic perturbations following two doses of COVID-19 vaccination for patients with diabetes: the impacts of vaccine type and anti-diabetes drugs.

BACKGROUND: Glycemic monitoring has become critical during the COVID-19 pandemic because of poor prognosis in diabetes. Vaccines were key in reducing the spread of infection and disease severity but data were lacking on effects on blood sugar levels. The aim of the current study was to investigate the impact of COVID-19 vaccination on glycemic control. METHODS: We performed a retrospective study of 455 consecutive patients with diabetes who completed two doses of COVID-19 vaccination and attended a single medical center. Laboratory measurements of metabolic values were assessed before and after vaccination, while the type of vaccine and administrated anti-diabetes drugs were analyzed to find independent risks associated with elevated glycemic levels. RESULTS: One hundred and fifty-nine subjects received ChAdOx1 (ChAd) vaccines, 229 received Moderna vaccines, and 67 received Pfizer-BioNtech (BNT) vaccines. The average HbA1c was raised in the BNT group from 7.09 to 7.34% (P = 0.012) and non-significantly raised in ChAd (7.13 to 7.18%, P = 0.279) and Moderna (7.19 to 7.27%, P = 0.196) groups. Both Moderna and BNT groups had around 60% of patients with elevated HbA1c following two doses of COVID-19 vaccination, and the ChAd group had only 49%. Under logistic regression modeling, the Moderna vaccine was found to independently predict the elevation of HbA1c (Odds ratio 1.737, 95% Confidence interval 1.12-2.693, P = 0.014), and sodium-glucose co-transporter 2 inhibitor (SGLT2i) was negatively associated with elevated HbA1c (OR 0.535, 95% CI 0.309-0.927, P = 0.026). CONCLUSIONS: Patients with diabetes might have mild glycemic perturbations following two doses of COVID-19 vaccines, particularly with mRNA vaccines. SGLT2i showed some protective effect on glycemic stability. Hesitancy in having vaccinations should not be indicated for diabetic patients with respect to manageable glycemic change. TRIAL REGISTRATION: Not applicable.

Another Cause of DKA in T2DM in COVID-19 Pandemic

Background: 47-year Emirati female, has history of T2DM since age of 39. Her overall diabetes poorly controlled with HbA1C of 8.6% (69 mmol/mol IFCC) on Empagliflozin 10 mg OD over the last 2 years well tolerated. NO micro- or macrovascular complications of her diabetes. No other significant medical history apart from hypertension she is taking Amlodipine 10 mg OD for it with good control. She has presented twice to the hospital 24 hours apart. 1st Visit to ER in our Hospital with fever epigastric pain discharged on Ciprofloxacin suspected gastroenteritis with PPI and sent home. Approximately, 24 hours later she presented again with same symptoms namely fever and epigastric pain but this time associated with diarrhea and nausea for last 20 hours. There was no shortness of Breath or cough. This time she has been admitted to isolating room giving suspicion of COVID-19. Vital signs as following: Temp 38.5 HR 105, BP 135/65 mmHg O2 Sats 96%. on RA. On examination, she was conscious, oriented to time place person. No signs of dehydration. abdomen soft non tender, Chest good air entry no added sound. Hear S1-S2 no murmurs. HRCT has been done at ER. HRCT shows wide spread area of multifocal ground glass opacification are seen in both lungs most of them shows peripheral sub-pleural distribution Around small size consolidation are seen within the ground glass opacification, CT findings are in favour of possibility of COVID-19. Result(s): Blood test as following On admission, FBC was normal, with Hb 13.2, WBC 8.0, Plt 388 cellX 10/ul, U/Es: S.NA 132, s.K 4.2 mmo/l, s. Creatinine normal (58 umol/L -NR 49-90 umol/L) LFTs, Amylase and lipase normal, LDH mild elevation 304 U/L (NR 81-234), Very low Phosphate 03 mmol/L (NR 0.87-1.45), D-Dimer 0.6 mg/L (NR 0.0- 0.5), Corrected Calcium normal, S. Ferritin was 242 ug/L (NR 8.00- 388.00 ug/L), Urinalysis Protein =1 and 4+ ketones, CRP was normal 1 mg/dl ( increased to 214 mg/ l 3rd day) before it goes done 41 mg/L on 7th day of admission. Giving the pandemic of COVID 19 and according to MOHAP Criteria for presenting symptoms. This lady underwent HRCT and COVID19 test by Nasal Swab. Meanwhile, Her Venous Blood gas shows sever metabolic acidosis pH 7.107, PCO2 12.90, PCO2 69.10 On RA, BC 8.9, BE -25.5. Blood sugar 13.2 mmol/L with Urinary Ketones of 4+. Patient has put on DKA Protocol according to our Hospital DKA protocol in addition Stopped her SGLT2 and start on Lantus as a basal. She has put on Scale C (which is the higher scale with infusion about 10 units per hour, for about 96 hours (i.e. 4 days till the blood sugar back to normal for Ketones to disappear, her acidosis didn't improve 1st 24 hours till we give her 1.26% of 500 ml of Sodium Bicarbonate over 6 hours. COVID 19 Test back after 72 hours with positive results. Once out of DKA Diabetes team has stopped her Lantus a stared-on Humalog mix 50% 25 unit TDS. Meanwhile, she has received the following medications waiting for COVID 19 test. Treated with Favipiravir 1600 mg BD for 1 day and 600 mg BD, Start Tazocin 4.5 (stopped after 3 days) Metronidazole, and with prophylactic dose of Clexane. The Hydroxychloroquine hasn't started as Prolong QTC has been notice). Discussion(s): This patient presentation with DKA is another example how COVID- 19 could be a reason for DKA, though SGLT2 could be another cause of her presentation, however the huge insulin requirement and unusual prolong DKA status even with sever acidosis is making COVID-19 more likely causing her presentation It. Conclusion(s): We report this case to highlight the fact DKA - and in fact sever resistant DKA need prolong treatment can happen to Patient with T2DM and COVID 19 positive, and special attention to be paid (with early referral to the diabetes team) if the patient already on SGLT2. And we recommend that to have low threshold to start investigation and treatment as early as possible, regardless the type of Diabetes these patient might have.

High-Dose Liraglutide and SGLT2 Inhibitor: A Promising Combination.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists are important drugs in our armamentarium of treatment for Type 2 diabetes mellitus (DM). In addition to their glucose-lowering effects, they have effects on weight, other metabolic diseases and perhaps most importantly, a cardioprotective and reno-protective effect. Liraglutide is a long-acting GLP-1 agonist which was originally used at 1.8 mg daily for the treatment of DM. However, high-dose liraglutide-liraglutide 3 mg daily, has been demonstrated to be a safe and effective treatment for obesity, with or without DM. In this manuscript, I present two patients who had unusual responses to combination therapy with high-dose liraglutide and SGLT2 inhibitor-marked and/or rapid improvement in glycemic control and weight loss. Drawing from the observations in both cases, I discuss the complementary mechanisms of actions of both drugs, review the clinical effects of combination therapy and distil them into clinical pearls of practical utility for the physician. Given the "clash of the two pandemics" of obesity and COVID-19 and the burgeoning rates of obesity which loom in the near horizon, this is most timely.

Heart failure: an update from the last years and a look at the near future.

In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium-lowering agents may counteract hyperkalaemia and facilitate renin-angiotensin-aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre-specified meta-analysis of major randomized controlled trials, sodium-glucose co-transporter-2 inhibitors reduced all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM-HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66-1.02; P = 0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article.

The effect of SGLT2 inhibitors, GLP1 agonists, and their sequential combination on cardiometabolic parameters: A randomized, prospective, intervention study.

BACKGROUND: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We aim to compare the effect of empagliflozin, liraglutide and their sequential combination on arterial stiffness indices in patients with type 2 diabetes (T2D). METHODS: This was a randomized single blind study evaluating the effect of empagliflozin vs liraglutide in adult patients with T2D. Patients were randomized to liraglutide titrated gradually to 1.8 mg or empagliflozin 25 mg in 1:1 ratio. Three months later empagliflozin was added to the liraglutide group, and liraglutide was added to the empagliflozin group. Patients were assessed with non-invasive tests for arterial stiffness (i.e., carotid-femoral PWV and AIx of aortic pressure) at baseline, 3-month and 9-month visits (final visit was extended for 3 months from the initial design due to Covid 19 pandemic). The primary outcome was the between-group difference of PWV change (ΔPWV) and ΔAIx at 3 months. Secondary outcomes included the between-group difference of ΔPWV and ΔAIx at 9 months, as well as the ΔPWV and ΔAIx between baseline and 9-month visit when total study population was assessed. RESULTS: A total of 62 patients with T2D (30 started liraglutide; 32 empagliflozin, mean age 63 years, 25 % with established cardiovascular disease) participated in the study. We failed to show any significant between-group differences of ΔPWV and ΔΑΙx at 3 and 9 months, as well as between-group difference of ΔPWV and ΔAIx for the total study population between baseline and 9-month visit. In contrast, systemic vascular resistance and lipoprotein(a) levels improved, showing better results with liraglutide than empagliflozin. Favorable effects were also observed on body weight, body mass index, body and visceral fat, blood pressure, HbA1c, and uric acid levels. CONCLUSION: No evidence of a favorable change in arterial stiffness indices was seen with empagliflozin or liraglutide or their combination in this study. Well-designed powerful studies are needed to address any potential effects on arterial stiffness in selected populations.

Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis.

BACKGROUND: Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. METHODS: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p < .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p < .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p < .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p < .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p < .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p = .04). CONCLUSIONS: AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

The Impact of COVID-19 Lockdown on Patients with Type 2 Diabetes Mellitus: A Brief Report.

BACKGROUND: The Italian population's habits changed dramatically during the "COVID- 19 lockdown" due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. v Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). METHODS: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. RESULTS: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed frombaseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. CONCLUSION: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

Pre-admission use of sodium glucose transporter-2 inhibitor (SGLT-2i) may significantly improves Covid-19 outcomes in patients with diabetes: A systematic review, meta-analysis, and meta-regression.

AIMS: This study aims to examine the effectiveness of using sodium glucose transporter-2 inhibitor (SGLT-2i) before hospital admission on Covid-19 outcomes in diabetic patients. METHODS: A literature search was conducted using specific keywords until October 24th, 2022 on 4 databases: Medline, Scopus, Cochrane Library, and ClinicalTrials.gov. All articles regarding SGLT-2i in diabetic patients with Covid-19 were included in the study. Outcomes in this study were calculated using random-effect models to generate pooled odds ratio (OR) with 95% confidence intervals (CI). RESULTS: A total of 17 studies were included in the analysis. Our meta-analysis showed that pre-admission use of SGLT-2i was associated with reduced mortality (OR 0.69; 95 %CI: 0.56 - 0.87, p = 0.001, I2 = 91 %) and severity of Covid-19 (OR 0.88; 95 %CI: 0.80 - 0.97, p = 0.008, I2 = 13 %). This benefit of SGLT-2i on Covid-19 mortality was not significantly affected by patient's factors such as age (p = 0.2335), sex (p = 0.2742), hypertension (p = 0.2165), heart failure (p = 0.1616), HbA1c levels (p = 0.4924), metformin use (p = 0.6617), duration of diabetes (p = 0.7233), and BMI (p = 0.1797). CONCLUSIONS: This study suggests that SGLT-2i as glucose lowering treatment in patients with diabetes has a positive effect on Covid-19 outcomes, therefore can be considered as an antidiabetic drug of choice, especially during the Covid-19 pandemic. Short Title: SGLT-2i in diabetes and Covid-19. REGISTRATION DETAILS: CRD42022369784.

Effect of Empagliflozin and Dapagliflozin on Ambulatory Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Cardiovascular Co-Morbidities: A Prospective, Observational Study.

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

IMPACT OF ANTIDIABETIC DRUGS ON RISK AND OUTCOME OF COVID-19 INFECTION: A REVIEW

Based on many reports, an unmistakable link probably exists between diabetes mellitus and COVID-19. A major predisposing factor determining severity and mortality of COVID-19 is diabetes mellitus, diabetic patients were shown to be at higher risk for developing severe COVID-19 disease than non-diabetics;many recent studies reported a striking prevalence of DM in those diagnosed with COVID-19. Accordingly, antidiabetic drugs can possibly impact the clinical course and / or the outcome of this infection, either by alleviating diabetes-associated symptoms, minimizing its complications, or by mitigating or aggravating COVID-19 disease by effects independent from their direct antidiabetic effects. Several antidiabetic drug classes were shown to have varying effects, like blocking viral entry to cells, as well as having immunomodulatory, anti-inflammatory, antifibrotic, or cardioprotective effects;such effects could prove beneficial for COVID-19 patients. On the other hand, some antidiabetic agents may have adverse effects that aggravate patients’ condition like hypoglycemia, fluid retention, increased weight or lactic acidosis, which require special consideration in patient management. Some of the drugs were found in observational studies to either reduce mortality from COVID-19 or pose no harm, but more solid evidence from clinical trials is still lacking. © 2022, University of Defence, Faculty of Military Health Sciences. All rights reserved.

Euglycemic diabetic ketoacidosis in a patient with type 1 diabetes and SARS-CoV-2 pneumonia: case-report and review of the literature.

OBJECTIVE: Recent publications on Coronavirus Disease-2019 (COVID-19) report that diabetic people with or without co-morbidities are at higher risk of developing severe and/or fatal illnesses. METHOD AND RESULT: We report the first case of a 60-year-old man with a 27-year history of type 1 diabetes mellitus, infected by SARS-CoV-2 presenting with an euglycaemic ketoacidosis and an acute respiratory distress syndrome. CONCLUSION: This case report reminds us of the importance of adjusting more recent glucose-lowering drugs, including sodium-glucose cotransporter 2 inhibitors, in the overall management of type 1 diabetic individuals during the ongoing COVID-19 outbreak. ABBREVIATIONS: COVID-19: Coronavirus disease 2019 (SARS-CoV-2) virus, T1DM: Type 1 diabetes mellitus, T2DM: Type 2 diabetes mellitus, SGLT2i: Sodium-glucose cotransporter 2 inhibitor, DKA: diabetic ketoacidosis, euDKA: euglycaemic diabetic ketoacidosis.

Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial.

BACKGROUND/AIM: DARE-19 (NCT04350593) was a randomized trial studying the effects of dapagliflozin, an SGLT2 inhibitor, in hospitalized patients with COVID-19 pneumonia and cardiometabolic risk factors. The conduct of DARE-19 offered the opportunity to define an innovative and clinically meaningful endpoint in a new disease that would best reflect the known profile of dapagliflozin, accompanied by the statistical challenges of analysis and interpretation of such a novel endpoint. METHODS: Hierarchical composite endpoints (HCEs) are based on clinical outcomes which, unlike traditional composite endpoints incorporate ranking of components according to clinical importance. Design of an HCE requires the clinical considerations specific to the therapeutic area under study and the mechanism of action of the investigational treatment. Statistical aspects for the clinical endpoints include the proper definition of the estimand as suggested by ICH E9(R1) for the precise specification of the treatment effect measured by an HCE. RESULTS: We describe the estimand of the DARE-19 trial, where an HCE was constructed to capture the treatment effect of dapagliflozin in hospitalized patients with COVID-19, and was analyzed using a win odds. Practical aspects of designing new studies based on an HCE are described. These include sample size, power, and minimal detectable effect calculations for an HCE based on the win odds analysis, as well as handling of missing data and the clinical interpretability of the win odds in relation to the estimand. CONCLUSIONS: HCEs are flexible endpoints that can be adapted for use in different therapeutic areas, with win odds as the analysis method. DARE-19 is an example of a COVID-19 trial with an HCE as one of the primary endpoints for estimating a clinically interpretable treatment effect in the COVID-19 setting.