Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial.

BACKGROUND: The effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients. METHODS: This is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment. RESULTS: A total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48-68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8-12) days. Neutralising antibody titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference -3.7%, 95% CI -18.8-11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups. CONCLUSIONS: CP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone.

Diabetes Insipidus after Vasopressin Withdrawal: A Scoping Review.

Objectives: The objective of this study is to synthesize the current literature about the relationship between the occurrence of diabetes insipidus (DI), its diagnosis criteria, and management after withdrawal of vasopressin (VP) in critically ill. Data sources: This scoping review followed the recommendations of Preferred Reporting Items for Systematic Review and Meta-Analyses for Scoping Review (PRISMA-ScR). The search literature was conducted in MEDLINE and EMBASE databases, until March 2022. A manual search was also conducted in order to include articles that were not identified in the initial search performed in the databases. Study selection and data extraction: The selection of studies and extraction of data were carried out in a paired and independent manner. There was no restriction regarding the language of publication of the included manuscripts. Data synthesis: The analysis included 17 studies (16 case reports and one retrospective cohort). All studies used VP, with a median time of drug infusion of 48 hours (IQR: 16-72) and DI incidence of 1.53%. The diagnosis of DI was based on diuresis output and concomitant hypernatremia or changes in serum sodium concentration, with median time to symptoms onset after discontinuation of VP of 5 hours (IQR: 3-10). The treatment of DI consisted mainly of fluid management and the use of desmopressin. Conclusions: DI after VP withdrawal was present in 51 patients described in 17 studies, but diagnosis and management varied among each report. Using the available data, we propose a diagnosis suggestion and a flowchart for managing patients with DI after withdrawal of VP in the Intensive Care Unit. Multicentric collaborative research is urgently needed to obtain more quality data on this topic. How to cite this article: Pérsico RS, Viana MV, Viana LV. Diabetes Insipidus after Vasopressin Withdrawal: A Scoping Review. Indian J Crit Care Med 2022;26(7):846-852.

Caloric Adequacy in the First Week of Mechanically Ventilated Patients has No Impact on Long-term Daily Life Activities.

AIM AND OBJECTIVE: The aim and objective of this study is to test the effect of an optimized caloric supply in the first week of intensive care unit (ICU) stay in mechanically ventilated patients on the ability to perform their activities of daily living (ADL) in the long-term. MATERIALS AND METHODS: A prospective observational study comparing patients who achieved an adequate caloric target (≥80%) vs those whose target was inadequate (<80%). The primary outcome under study is the instrumental ADL (IADL) scale after 6 months of discharge. RESULTS: Ninety-two patients were evaluated in the ICU and 50 were alive at 6 months. Follow-up was lost for 3 patients and 47 patients were evaluated at ICU and after 6 months. Thirty-four patients reached the energetic target and 13 did not reach it. There was no significant variation in IADL. CONCLUSION: The energy adequacy in the first week of hospitalization was achieved by most survivors; however, this conduct does not seem to have influenced the ability to perform ADL after 6 months of discharge. HOW TO CITE THIS ARTICLE: Dariano AP, Couto CFL, Rubin BA, Viana MV, Friedman G. Caloric Adequacy in the First Week of Mechanically Ventilated Patients has No Impact on Long-term Daily Life Activities. Indian J Crit Care Med 2020;24(12):1206-1212.

Delayed medical emergency team calls and associated outcomes.

OBJECTIVE: To determine whether there was an association between delayed medical emergency team calls and mortality after a medical emergency team review. DESIGN: This was a prospective observational study. SETTING: A university-affiliated tertiary referral hospital in Porto Alegre, Brazil. PATIENTS: All patients were reviewed by the medical emergency team from July 2008 to December 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,481 calls for 1,148 patients. Delayed medical emergency team calls occurred for 246 patients (21.4%). The criterion associated with delay was typically the same criterion for the subsequent medical emergency team call. Physicians had a greater prevalence of delayed medical emergency team calls (110 of 246 [44.7%]) than timely medical emergency team calls (267 of 902 [29.6%]; p < 0.001). The mortality at 30 days after medical emergency team review was higher among patients with delayed medical emergency team activation (152 [61.8%]) than patients receiving timely medical emergency team activation (378 [41.9%]; p < 0.001). In a multivariate analysis, delayed medical emergency team calls remained significantly associated with higher mortality. CONCLUSIONS: Delayed medical emergency team calls are common and are independently associated with higher mortality. This result reaffirms the concept and need for a rapid response system.

Impact of ß-hydroxy-ß-methylbutyrate (HMB) in critically ill patients on the endocrine axis - A post-hoc cohort study of the HMB-ICU trial.

BACKGROUND: ß-hydroxy-ß-methylbutyrate (HMB) might improve muscle function and maintain its mass in critically ill patients. We aimed to investigate whether the administration of HMB influenced the plasma levels of growth hormone (GH)/insulin-like growth factor-1 (IGF-1), C-peptide, and 25-OH vitamin-D. METHODS: Post-hoc analysis of the study HMB-ICU, a randomized, placebo-controlled double-blind trial. INCLUSION CRITERIA: Intensive care unit (ICU) patients depending on mechanical ventilation on day 3 with functional gastrointestinal tract. Patients were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on, for 30 days. Blood samples were collected on days 4 and 15. We determined the GH, C-peptide, 25-OH vitamin-D, and IGF-1. Statistics by ANCOVA. RESULTS: Blood samples of 26 patients were available on day 4, and 23 on day 15. While age and severity of disease did not differ, diabetes was more frequent in the HMB group (p = 0.041), and obesity was more frequent in the placebo group (p = 0.021). Glucose intake, blood glucose (BG) and amount of insulin to maintain blood glucose between 6 and 8 mM did not differ between groups. There was no difference between groups for C-peptide, GH, IGF-1, and 25-OH vitamin-D. IGF-1 increased significantly from day 4-15 (p = 0.026) in both groups. CONCLUSION: Subject to possible insufficient power of the study, we did not reach conclusive results. HMB intervention does not affect significantly the plasma concentrations of insulin, GH/IGF axis activity, C-peptide, and 25-OH vitamin-D. GOV IDENTIFIER: NCT03628365.

Functional assessment and mortality in underweight critically ill patients one year after hospital discharge: A prospective cohort study.

BACKCGROUND & AIMS: There in no data regarding outcomes after hospital discharge for underweight critically ill patients. This study aimed to assess long-term survival and functional capacity in underweight critically ill patients. MATERIALS & METHODS: Prospective observational study that included underweight critically ill patients (BMI <20 kg/cm2) followed-up one year after hospital discharge. To assess functional capacity, we interviewed patients or caregivers and performed Katz index (KI) and Lawton scale. Patients were divided into two groups: (1) poor functional capacity, if the patient had less points than the median of the Katz and IADL score, and (2) good functional capacity, if at least one score was above the median. Extremely low weight defined as less than 45 kg. RESULTS: We assessed the vital status of 103 patients. Mortality was 38.8% (median 362 [136, 422] days of follow-up). We interviewed 62 patients or proxies. No difference was observed between survivors and non-survivors regarding weight and BMI at intensive care unit admission and nutritional therapy received in the first days of intensive care admission. Patients with poor functional capacity had lower admission weight (43.9 vs 52 ± 7.9 kg, p < 0.001) and BMI (17 ± 2.1 vs 18.2 ± 1.8 kg/cm2, p = 0.028). In a multivariate logistic regression, weight under 45 kg was independently associated with poor functional capacity (OR = 13.6, 95%CI, 3.7 to 66.5) CONCLUSION: Underweight critically ill patients have high mortality and a persistent functional impairment, the last being more important in extremely low weight. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov number NCT03398343.

Females have a different metabolic response to critical illness, measured by comprehensive amino acid flux analysis.

BACKGROUND: The trajectory from healthy to critical illness is influenced by numerous factors, including metabolism, which differs substantially between males and females. Whole body protein breakdown is substantially increased in critically ill patients, but it remains unclear whether there are sex differences that could explain the different health outcomes. Hence, we performed a secondary analysis of a study, where we used a novel pulse isotope method in critically ill and matched healthy males and females. METHODS: In 51 critically ill ICU patients (26 males, 15 females) and 49 healthy controls (36 males and 27 females), we assessed their general and disease characteristics and collected arterial(ized) blood in the postabsorptive state after pulse administration of 8 ml of a solution containing 18 stable AA tracers. In contrast to the original study, we now fitted the decay curves and calculated non-compartmental whole body amino acid production (WBP) and compartmental measurements of metabolism, including intracellular amino acid production. We measured amino acid enrichments and concentrations by LC-MS/MS and derived statistics using AN(C)OVA. RESULTS: Critically ill males and females showed an increase in the WBP of many amino acids, including those related to protein breakdown, but females showed greater elevations, or in the event of a reduction, attenuated reductions. Protein breakdown-independent WBP differences remained between males and females, notably increased glutamine and glutamate WBP. Only severely ill females showed a lower increase in WBP of many amino acids in comparison to moderately ill females, suggesting a suppressed metabolism. Compartmental analysis supported the observations. CONCLUSIONS: The present study shows that females have a different response to critical illness in the production of several amino acids and changes in protein breakdown, observations made possible using our innovative stable tracer pulse approach. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Specific nutrition and metabolic characteristics of critically ill patients with persistent COVID-19.

BACKGROUND: Little is known about metabolic and nutrition characteristics of patients with coronavirus disease 2019 (COVID-19) and persistent critical illness. We aimed to compare those characteristics in patients with PCI and COVID-19 and patients without COVID-19 infection (non-CO)-primarily, their energy balance. METHODS: This is a prospective observational study including two consecutive cohorts, defined as needing intubation for >10 days. We collected demographic data, severity scores, nutrition variables, length of stay, and mortality. RESULTS: Altogether, 104 patients (52 per group) were included (59 ± 14 years old [mean ± SD], 75% men) between July 2019 and May 2020. SAPSII, Nutrition Risk Screening (NRS) score, proportion of obese patients, duration of intubation (18.2 ± 11.7 days), and mortality rates were similar. Patients with COVID-19 (vs non-CO) had lower SOFA scores (P = 0.013) and more frequently needed prone position (P < 0.0001) and neuromuscular blockade (P < 0.0001): lengths of ICU (P = 0.03) and hospital stays were shorter (P < 0.0001). Prescribed energy targets were below those of the ICU protocol. The energy balance of patients with COVID-19 was significantly more negative after day 10. Enteral nutrition (EN) started earlier (P < 0.0001). During the first 10 days, COVID-19 patients received more lipid (propofol sedation) and less protein. Higher admission C-reactive protein (P = 0.002) decreased faster (P < 0.001). Whereas intestinal function was characterized by constipation in both groups during the first 10 days, diarrhea was less common in patients with COVID-19 thereafter. CONCLUSION: Compared with non-CO patients, COVID-19 patients were not more obese, had lower SOFA scores, and were fed more rapidly with EN, because of a more normal gastrointestinal function possibly due to fewer non-respiratory organ failures: their energy balances were more negative after the first 10 days. Propofol sedation reduced protein delivery.

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.

The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Impact of ß-hydroxy-ß-methylbutyrate (HMB) on muscle loss and protein metabolism in critically ill patients: A RCT.

PURPOSE: Muscle wasting deteriorates life quality after critical illness and increases mortality. Wasting starts upon admission to intensive care unit (ICU). We aimed to determine whether ß-hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine, can attenuate this process. METHODS: Prospective randomized, placebo-controlled double blind trial. INCLUSION CRITERIA: ICU patients depending on mechanical ventilation on day 3 having a functional gastrointestinal tract. They were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on for 30 days. PRIMARY OUTCOME: magnitude of loss of skeletal muscle area (SMA) of the quadriceps femoris measured by ultrasound at days 4 and 15. SECONDARY OUTCOMES: body composition, change in protein metabolism assessed by amino acids tracer pulse, and global health at 60 days. Data are mean [95% CI]. Statistics by ANCOVA with correction for confounders sex, age and/or BMI. RESULTS: Thirty patients completed the trial, aged 65 [59, 71] years, SAPS2 score 48 [43, 52] and SOFA 8.5 [7.4, 9.7]. The loss of total SMA was 11% between days 4 and 15 (p < 0.001), but not different between the groups (p = 0.86). In the HMB group, net protein breakdown (Δ Estimate HMB-Placebo: -153 [-242, -63]; p = 0.0021) and production of several amino acid was significantly reduced, while phase angle increased more (0.66 [0.09, 1.24]; p = 0.0247), and SF-12 global health improved more (Δ Estimate HMB-Placebo: 27.39 [1.594, 53.19], p = 0.04). CONCLUSION: HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle and better global health. CLINICALTRIALS. GOV IDENTIFIER: NCT03628365.

Comprehensive metabolic amino acid flux analysis in critically ill patients.

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p < 0.00001), and higher CRP (p < 0.0001). Most AA concentrations were lower in ICU patients (p < 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p < 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p < 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Nutritional therapy and outcomes in underweight critically ill patients.

BACKGROUND & AIMS: Critically ill patients with body mass index (BMI) < 20 kg/m2 have worse outcomes than normal/overweight patients possibly because underweight is a marker of malnutrition. To assess the effects of nutrition therapy in this population during the first week of an ICU stay. METHODS: Prospective, 2-centre, observational study. Nutritional evaluations were performed between days 2 and 3 (first) and between days 5 and 7 (second) of ICU admission. In the first evaluation, patients were divided into non-fed (without nutritional support) and early-fed (those already receiving nutritional support) groups. In the second evaluation, patients were divided according to caloric intake (≥or<20 kcal/kg) and protein intake (≥or<1.3 g of protein/kg). RESULTS: Of the 4236 patients screened and 342 were included in the cohort. Mortality was 58.5% (median 21 [11-38.25] days of follow-up). Unadjusted patient survival was worse in the non-fed group than in the early-fed group (HR 1.66; 95%CI, 1.18 to 2.32). There was no difference in mortality between groups after adjusting for the SOFA score on the day of the evaluation. At the second evaluation, unadjusted analysis showed better in-hospital survival in patients with higher caloric (HR0.58; 95%CI, 0.40 to 0.86) and protein intake (HR0.59; 95%CI, 0.42 to 0.82); there was no association between mortality and caloric or protein intake after adjusting for the SOFA score on the day of the evaluation. CONCLUSION: Nutritional therapy in the first week of ICU stay did not affect vital outcome after adjusting for the SOFA score on the day of the evaluation in underweight critically ill patients. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov number NCT03398343.

Metabolic and Nutritional Characteristics of Long-Stay Critically Ill Patients.

BACKGROUND: insufficient feeding is frequent in the intensive care unit (ICU), which results in poor outcomes. Little is known about the nutrition pattern of patients requiring prolonged ICU stays. The aims of our study are to describe the demographic, metabolic, and nutritional specificities of chronically critically ill (CCI) patients defined by an ICU stay >2 weeks, and to identify an early risk factor. METHODS: analysis of consecutive patients prospectively admitted to the CCI program, with the following variables: demographic characteristics, Nutrition Risk Screening (NRS-2002) score, total daily energy from nutritional and non-nutritional sources, protein and glucose intakes, all arterial blood glucose values, length of ICU and hospital stay, and outcome (ICU and 90-day survival). Two phases were considered for the analysis: the first 10 days, and the next 20 days of the ICU stay. STATISTICS: parametric and non-parametric tests. RESULTS: 150 patients, aged 60 ± 15 years were prospectively included. Median (Q1, Q3) length of ICU stay was 31 (26, 46) days. The mortality was 18% at ICU discharge and 35.3% at 90 days. Non-survivors were older (p = 0.024), tended to have a higher SAPSII score (p = 0.072), with a significantly higher NRS score (p = 0.033). Enteral nutrition predominated, while combined feeding was minimally used. All patients received energy and protein below the ICU's protocol recommendation. The proportion of days with fasting was 10.8%, being significantly higher in non-survivors (2 versus 3 days; p = 0.038). Higher protein delivery was associated with an increase in prealbumin over time (r2 = 0.19, p = 0.027). CONCLUSIONS: High NRS scores may identify patients at highest risk of poor outcome when exposed to underfeeding. Further studies are required to evaluate a nutrition strategy for patients with high NRS, addressing combined parenteral nutrition and protein delivery.

Association of multiple glycemic parameters at intensive care unit admission with mortality and clinical outcomes in critically ill patients.

The aim of the present study was to investigate the association of multiple glycemic parameters at intensive care unit (ICU) admission with outcomes in critically ill patients. Critically ill adults admitted to ICU were included prospectively in the study and followed for 180 days until hospital discharge or death. Patients were assessed for glycemic gap, hypoglycemia, hyperglycemia, glycemic variability, and stress hyperglycemia ratio (SHR). A total of 542 patients were enrolled (30% with preexisting diabetes). Patients with glycemic gap >80 mg/dL had increased need for renal replacement therapy (RRT; 37.7% vs. 23.7%, p = 0.025) and shock incidence (54.7% vs. 37.4%, p = 0.014). Hypoglycemia was associated with increased mortality (54.8% vs. 35.8%, p = 0.004), need for RRT (45.1% vs. 22.3%, p < 0.001), mechanical ventilation (MV; 72.6% vs. 57.5%, p = 0.024), and shock incidence (62.9% vs. 35.8%, p < 0.001). Hyperglycemia increased mortality (44.3% vs. 34.9%, p = 0.031). Glycemic variability >40 mg/dL was associated with increased need for RRT (28.3% vs. 14.4%, p = 0.002) and shock incidence (41.4% vs.31.2%, p = 0.039). In this mixed sample of critically ill subjects, including patients with and without preexisting diabetes, glycemic gap, glycemic variability, and SHR were associated with worse outcomes, but not with mortality. Hypoglycemia and hyperglycemia were independently associated with increased mortality.

The Quality of End-of-Life Care after Limitations of Medical Treatment as Defined by a Rapid Response Team: A Retrospective Cohort Study.

BACKGROUND: Despite the increase in the identification of patients at the end of life after the introduction of rapid response team (RRT), there is doubt as to whether there has been an improvement in the quality of care offered to these patients. Proper end-of-life care is the next expected step after identifying patients who are dying. OBJECTIVE: To evaluate the end-of-life care after limitations of medical treatment (LOMTs) as defined by an RRT. DESIGN: This is a single-center retrospective cohort study at a tertiary teaching hospital in Porto Alegre, Brazil, from July 2014 to July 2016. SETTING/SUBJECTS: We included 242 patients with an LOMT as defined by the RRT. MEASUREMENTS: Outcomes of interest included symptoms and palliative measures after RRT review. RESULTS: During the study period, there were 5396 calls to 2937 patients, representing 126 calls per 1000 hospital discharges. Of these calls, 4.9% (n = 242) resulted in an LOMT. The primary care team agreed with the LOMT decision proposed by the RRT in 91.7% of cases. Regarding end-of-life symptoms, 7.4% and 5.8% of patients presented with intense or moderate pain, respectively, and 62.4% of patients presented dyspnea in the last 48 hours of hospitalization. Less than 15% of patients received attention for their spiritual needs and/or received psychological support. CONCLUSIONS: Our data reinforce the important role of RRTs in the identification of end-of-life patients with clinical deterioration. Despite the increase in the identification of these patients, the quality of end-of-life care needs to be improved.

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

ABSTRACT The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI −0.66 to −0.59) and body weight by 0.60 kg (95% CI −0.64 to −0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.