Dapagliflozin for inpatient hyperglycemia in cardiac surgery patients with type 2 diabetes: randomised controlled trial (Dapa-Hospital trial).

AIMS: To examine the efficacy and safety of dapagliflozin in the treatment of hyperglycemia in cardiac surgery patients with type 2 diabetes (T2D). METHODS: Cardiac surgery patients with T2D (n = 250) were randomly assigned (1:1) to receive dapagliflozin plus basal-bolus insulin (DAPA group) or basal-bolus insulin alone (INSULIN group) in the early postoperative period. The primary outcome was mean difference in daily blood glucose (BG) concentrations between groups. The major safety outcomes were the occurrence of severe ketonemia/diabetic ketoacidosis (DKA) and hypoglycemia. All analyses were performed according to the intention-to-treat principle. RESULTS: The median age of the patients was 61 years (range, 55-61), and 219 (87.6%) were men. Overall, the randomization blood glucose was 165 mg/dL (SD, 37) and glycated hemoglobin was 7.7% (SD, 1.4). There were no differences in mean daily BG concentrations (149 vs. 150 mg/dL), mean percentage of readings within target BG of 70-180 mg/dL (82.7% vs. 82.5%), total daily insulin dose (mean, 39 vs. 40 units/day), number of daily insulin injections (median, 3.9 vs. 4), length of hospital stay (median, 10 vs. 10 days), or hospital complications (21.6% vs. 24.8%) between the DAPA and INSULIN groups. The mean plasma ketone levels were significantly higher in the DAPA group than in the INSULIN group at day 3 (0.71 vs. 0.30 mmol/L) and day 5 (0.42 vs. 0.19 mmol/L) of randomization. Six patients in the DAPA group developed severe ketonemia, but no patient developed DKA. There were no differences in the proportion of patients with BG < 70 mg/dL (9.6% vs. 7.2%) between the two groups. CONCLUSION: Dapagliflozin complementary to basal-bolus insulin does not improve glycemia further over and above the basal-bolus insulin alone in hospitalized cardiac surgery patients. Dapagliflozin significantly increases plasma ketones levels. Safety of dapagliflozin in hospitalized patients needs further investigation. Trial registration ClinicalTrials.gov NCT05457933.

NOD-like receptors in the pathogenesis of metabolic (dysfunction)-associated fatty liver disease: Therapeutic agents targeting NOD-like receptors.

BACKGROUND AND AIMS: In metabolic (dysfunction)-associated fatty liver disease (MAFLD), activation of inflammatory processes marks the transition of simple steatosis to steatohepatitis, which can further evolve to advanced fibrosis or hepatocellular carcinoma. Under the stress of chronic overnutrition, the innate immune system orchestrates hepatic inflammation through pattern recognition receptors (PRRs). Cytosolic PRRs that include NOD-like receptors (NLRs) are crucial for inducing inflammatory processes in the liver. METHODS: A literature search was performed with Medline (PubMed), Google Scholar and Scopus electronic databases till January 2023, using relevant keywords to extract studies describing the role of NLRs in the pathogenesis of MAFLD. RESULTS: Several NLRs operate through the formation of inflammasomes, which are multimolecular complexes that generate pro-inflammatory cytokines and induce pyroptotic cell death. A multitude of pharmacological agents target NLRs and improve several aspects of MAFLD. In this review, we discuss the current concepts related to the role of NLRs in the pathogenesis of MAFLD and its complications. We also discuss the latest research on MAFLD therapeutics functioning through NLRs. CONCLUSIONS: NLRs play a significant role in the pathogenesis of MAFLD and its consequences, especially through generation of inflammasomes, such as NLRP3 inflammasomes. Lifestyle changes (exercise, coffee consumption) and therapeutic agents (GLP-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, obeticholic acid) improve MAFLD and its complications partly through blockade of NLRP3 inflammasome activation. New studies are required to explore these inflammatory pathways fully for the treatment of MAFLD.

Efficacy and safety of degludec U100 versus glargine U300 for the early postoperative management of patients with type 2 diabetes mellitus undergoing coronary artery bypass graft surgery: A non-inferiority randomized trial.

AIMS: To compare the efficacy and safety of degludec U100 versus glargine U300 for the early postoperative management of patients with type 2 diabetes mellitus (T2D) undergoing coronary artery bypass graft (CABG) surgery. METHODS: A total of 239 patients were randomly assigned (1:1) to receive a basal-bolus regimen in the early postoperative period using degludec U100 (n = 122) or glargine U300 (n = 117) as basal and glulisine before meals. The primary outcome was mean differences between groups in their daily BG concentrations. The major safety outcome was the occurrence of hypoglycemia. RESULTS: There were no differences in mean daily BG concentrations (157 vs. 162 mg/dl), mean percentage of readings within target BG of 70-180 mg/dl (74% vs. 73%), daily basal insulin dose (19 vs. 21 units/day), length of stay (median [IQR]: 9 vs. 9 days), or hospital complications (21.3% vs. 21.4%) between treatment groups. There were no differences in the proportion of patients with BG <70 mg/dl (15.6% vs. 23.1%) or <54 mg/dl (1.6% vs. 4.3%) between degludec-100 and glargine-300 groups. CONCLUSIONS: Treatment with degludec U100 is as effective and safe as glargine U300 for the early postoperative hospital management of patients with T2D undergoing CABG.

Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease.

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is characterized by the accumulation of lipids in the liver (steatosis). In predisposed individuals, liver steatosis can progress to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MAFLD is complex and incompletely understood, involving various steatogenic, pro-inflammatory, and fibrogenic processes. Hyperactivation of the innate immune system through hepatic toll-like receptors (TLRs) contributes to the pathogenesis of MAFLD. Products of intestinal microbiota and danger signals from damaged hepatocytes constitute key ligands of TLRs that promote MAFLD. Most TLRs promote development and progression of MAFLD by induction of pro-inflammatory and pro-fibrogenic cytokines. Several nutraceutical and therapeutic agents improve MAFLD partly through the inhibition of hepatic TLRs. Herein, we review the available literature on hepatic TLR expression and signaling; crosstalk between gut microbiota and hepatic TLRs; and the contribution of TLRs to the pathogenesis of MAFLD. We also highlight implications for therapeutic approaches for MAFLD based on modulation of TLR signaling.

Non-alcoholic fatty liver disease-related fibrosis and sarcopenia: An altered liver-muscle crosstalk leading to increased mortality risk.

In the last few decades, the loss of skeletal muscle mass and function, known as sarcopenia, has significantly increased in prevalence, becoming a major global public health concern. On the other hand, the prevalence of non-alcoholic fatty liver disease (NAFLD) has also reached pandemic proportions, constituting the leading cause of hepatic fibrosis worldwide. Remarkably, while sarcopenia and NAFLD-related fibrosis are independently associated with all-cause mortality, the combination of both conditions entails a greater risk for all-cause and cardiac-specific mortality. Interestingly, both sarcopenia and NAFLD-related fibrosis share common pathophysiological pathways, including insulin resistance, chronic inflammation, hyperammonemia, alterations in the regulation of myokines, sex hormones and growth hormone/insulin-like growth factor-1 signaling, which may explain reciprocal connections between these two disorders. Additional contributing factors, such as the gut microbiome, may also play a role in this relationship. In skeletal muscle, phosphatidylinositol 3-kinase/Akt and myostatin signaling are the central anabolic and catabolic pathways, respectively, and the imbalance between them can lead to muscle wasting in patients with NAFLD-related fibrosis. In this review, we summarize the bidirectional influence between NAFLD-related fibrosis and sarcopenia, highlighting the main potential mechanisms involved in this complex crosstalk, and we discuss the synergistic effects of both conditions in overall and cardiovascular mortality.

Role of diabetologists in the management of nonalcoholic fatty liver disease: Primary prevention and screening/management of fibrosis and cirrhosis.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a common condition, especially among individuals with type 2 diabetes (T2D). Presence of T2D increases the risk of progression of simple steatosis to more severe liver conditions, such as nonalcoholic steatohepatitis (NASH) and fibrosis (NASH-fibrosis). Since majority of patients with T2D are managed by diabetologists (including physicians and endocrinologists), their roles in the management of coexisting NAFLD are not well defined, partly due to lack of unambiguous guidelines. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till January 2022, using relevant keywords (nonalcoholic fatty liver disease and diabetologist; screening of NASH; management of NASH) to extract relevant studies describing prevention and screening of NAFLD/NASH, especially in people with T2D. RESULTS: Diabetologists have two main roles for the management of patients with T2D and coexisting NAFLD. The most important role is to prevent the development of NASH-fibrosis in patients with simple steatosis (primary prevention). This can be achieved by reinforcing the importance of lifestyle measures, and by early use of glucose-lowering agents with beneficial effects on the liver. The second important role of diabetologists is to screen all patients with T2D for liver fibrosis and compensated cirrhosis, and provide appropriate referral for timely management of complications (secondary prevention). CONCLUSION: Diabetologists can play a central role in mitigating the epidemic of NAFLD in individuals with T2D. However, diabetologists need to be aware about their roles in NASH-fibrosis prevention and screening. Furthermore, longitudinal studies should explore the role of newer glucose-lowering drugs in the primary prevention of NASH-fibrosis in individuals with coexisting T2D and simple steatosis.

Gut microbiota and related metabolites in the pathogenesis of nonalcoholic steatohepatitis and its resolution after bariatric surgery.

Nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the rising prevalence of obesity, leading to major health and socioeconomic consequences. To date, the most effective therapeutic approach for NAFLD is weight loss. Accordingly, bariatric surgery (BS), which produces marked reductions in body weight, is associated with significant histopathological improvements in advanced stages of NAFLD, such as nonalcoholic steatohepatitis (NASH) and liver fibrosis. BS is also associated with substantial taxonomical and functional alterations in gut microbiota, which are believed to play a significant role in metabolic improvement after BS. Interestingly, gut microbiota and related metabolites may be implicated in the pathogenesis of NAFLD through diverse mechanisms, including specific microbiome signatures, short chain fatty acid production or the modulation of one-carbon metabolism. Moreover, emerging evidence highlights the potential association between gut microbiota changes after BS and NASH resolution. In this review, we summarize the current knowledge on the relationship between NAFLD severity and gut microbiota, as well as the role of the gut microbiome and related metabolites in NAFLD improvement after BS.

Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges.

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world's population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.

Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism.

Severe hypercalcemia is a medical emergency that requires immediate and aggressive management. Primary hyperparathyroidism (PHPT) often causes severe hypercalcemia. Volume resuscitation, parenteral salmon calcitonin, and administration of intravenous bisphosphonates are common measures used to stabilize patients. However, the use of these measures is inadequate in several patients and may even be contraindicated in individuals with renal insufficiency or severe systemic illness. This study demonstrated the efficacy and safety of denosumab in patients with severe hypercalcemia due to PHPT, when immediate surgery was not feasible. We present four patients with severe hypercalcemia due to PHPT. Immediate surgery was not feasible because the patients had severe systemic illness, such as seizures and altered sensorium (case 1); acute severe pancreatitis (cases 2 and 3); or coronavirus disease 2019 pneumonia (case 4). Intravenous normal saline and parenteral salmon calcitonin were inadequate for controlling hypercalcemia. Intravenous bisphosphonates were avoided because of severe systemic illness in all cases and impaired renal function in three cases. Denosumab was administered to control hypercalcemia and allow the stabilization of patients for definitive surgical management. Following denosumab administration, serum calcium levels normalized, and general condition improved in all patients. Three patients underwent parathyroidectomy after two weeks and another patient after eight weeks. The use of denosumab for the management of severe hypercalcemia due to PHPT is efficacious and safe in patients when immediate surgical management is not feasible due to severe systemic illness.

Prevalence of clinically relevant liver fibrosis due to nonalcoholic fatty liver disease in Indian individuals with type 2 diabetes.

BACKGROUND AND AIM: Type 2 diabetes (T2D) in associated with higher prevalence and worse outcomes of nonalcoholic fatty liver disease (NAFLD). However, data regarding the prevalence of clinically relevant liver fibrosis (CRLF) in Indian individuals with T2D are scarce. We investigated the prevalence of, and factors associated with, CRLF in Indians with T2D. METHODS: We conducted a prospective study of 601 consecutive adults with T2D. Steatosis was diagnosed using ultrasonography. Liver stiffness measurement (LSM) by transient elastography of ≥8.0 kPa was taken as cutoff suggesting CRLF. Individuals with LSM > 13.0 kPa underwent dynamic magnetic resonance imaging (MRI) of liver for detecting changes consistent with cirrhosis. RESULTS: The prevalence of steatosis was 84.2%. Higher body mass index (BMI, P = 0.022), alanine aminotransferase (ALT; P = 0.001), and lower high-density lipoprotein (HDL; P = 0.002) were independent factors associated with steatosis. The prevalence of CRLF was 28.2%. Higher BMI (P = 0.001), aspartate aminotransferase (AST; P < 0.0001), gamma-glutamyl transpeptidase (GGT; P < 0.0001), and concomitant hypertension (P = 0.03) were independent factors associated with CRLF. Elevated ALT and AST (≥40 units/L) levels were present in 70.6 and 51.6% individuals with CRLF, respectively. Thirty-one (7.2%) individuals had LSM > 13.0 kPa. Among them, 25 individuals underwent dynamic MRI of liver, which revealed features consistent with cirrhosis in 18 patients. CONCLUSION: CRLF, an established risk factor for cirrhosis and overall mortality, affects at least one out of four (25%) Indians with T2D. These results support screening of all patients with T2D and NAFLD for liver fibrosis.

Low skeletal muscle mass is associated with liver fibrosis in individuals with type 2 diabetes and nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Type 2 diabetes (T2D) and low skeletal muscle mass (SMM) are associated with increased risk of nonalcoholic fatty liver disease (NAFLD). However, data regarding the association between low SMM and NAFLD-related liver fibrosis in individuals with T2D are scarce. Therefore, we aimed to investigate the association between low SMM and liver fibrosis in individuals with T2D and NAFLD. METHODS: Controlled attenuation parameter (CAP) of ≥ 248 dB/m was taken as cutoff suggesting NAFLD. Clinically relevant liver fibrosis and advanced liver fibrosis were defined as liver stiffness measurement (LSM) by transient elastography (TE) of ≥ 8.0 and ≥ 9.6 kPa, respectively. SMM was measured using dual energy X-ray absorptiometry (DEXA). Low SMM was defined as appendicular SMM index of < 7.0 kg/m2 for men and < 5.4 kg/m2 for women. RESULTS: Of the 487 consecutive patients with T2D, 366 (75.1%) had NAFLD. Among individuals with NAFLD, 118 (32.2%) and 64 (17.5%) had clinically relevant liver fibrosis and advanced liver fibrosis, respectively. Low SMM was diagnosed in 78 (21.3%) individuals with NAFLD. Patients with low SMM were older (56.1 vs 52.8 years) and had longer duration of diabetes (10.3 vs 8.1 years). Low SMM was an independent risk factor associated with clinically relevant liver fibrosis (P = 0.002) and advanced liver fibrosis (P ≤ 0.0001). Associations between low SMM and clinically relevant- and advanced liver fibrosis were maintained even after sequential adjustment for confounding variables through the multivariate regression analysis. CONCLUSIONS: Low SMM is independently associated with liver fibrosis in individuals with T2D and NAFLD.

Effectiveness of diabetes education including insulin injection technique and dose adjustment through telemedicine in hospitalized patients with COVID-19.

AIMS: To study the feasibility of diabetes education through telemedicine in patients with diabetes mellitus (DM) hospitalized for coronavirus disease 2019 (COVID-19) management. METHODS: This was a prospective study of 100 patients with DM who were admitted in a COVID isolation ward for management of COVID-19. Patients managed with multiple subcutaneous insulin injections were eligible. During teleconsultation, diabetes education including insulin injection technique was given by a diabetes educator via a phone call (audio and video) during hospitalization. They were also re-assessed after 2 weeks of discharge from the hospital via teleconsultation or in-person. RESULTS: Out of 100 patients, 72.0% had prior history of diabetes while 28.0% were newly diagnosed. The median age of our cohort was 56 years and median duration of diabetes was 7.0 years. Telemedicine as a mode of consult for diabetes education was accepted by 96.0% of patients during hospitalization. At 2 weeks' follow-up, 77.0% patients were following insulin instructions correctly and were satisfied with this mode of consultation. CONCLUSION: Diabetes education using telemedicine as a technology is feasible, acceptable, and effective in the management of most patients with DM. Telemedicine appears to be an effective way to replace routine visits in special situations.

Glycemic parameters in patients with new-onset diabetes during COVID-19 pandemic are more severe than in patients with new-onset diabetes before the pandemic: NOD COVID India Study.

BACKGROUND AND AIMS: It is not known if new onset diabetes during Coronavirus-19 disease (COVID-19; NOD COVID) is phenotypically or biochemically different than new onset diabetes before COVID-19 (NOD). METHODS: All adults diagnosed with new onset diabetes from during the time of COVID-19 were compared with new onset diabetes prior to COVID-19 from two tertiary care hospitals in Chennai and Delhi. RTPCR test for SARS-CoV-2 virus was done as appropriate, and COVID-19 antibody test was done in all other NOD COVID patients. RESULT: A total of 555 patients with new onset diabetes were included in the study (282 NOD and 273 NOD COVID patients). Patients with NOD COVID had higher fasting and post prandial blood glucose and glycated hemoglobin levels vs. NOD patients. Both the groups had high average body mass index; ∼28 kg/m2. Interestingly, fasting C-peptide levels were significantly higher in the NOD COVID group vs. NOD group. There was no difference in C-peptide levels or glycemic parameters between the COVID-19 antibody positive and negative NOD COVID cases. CONCLUSION: Individuals who were diagnosed with diabetes during COVID-19 epidemic (NOD COVID) do not significantly differ from those diagnosed before COVID-19 in symptomatology, phenotype, and C-peptide levels but they had more severe glycemia.

Glucose Lowering Efficacy and Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitors.

In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter 2 (SGLT2) protein expression and activity contribute to the maintenance of hyperglycemia. By inhibiting these proteins, SGLT2 inhibitors increase urinary glucose excretion (UGE) that leads to fall in plasma glucose concentrations and improvement in all glycemic parameters. Clinical studies have demonstrated that in patients with type 2 diabetes, SGLT2 inhibitors resulted in sustained reductions in glycated hemoglobin (HbA1C), body weight, blood pressure and serum uric acid levels. Interestingly, the cardiovascular (CV) and renal outcome trials revealed the beneficial effects of SGLT2 inhibitors on CV and renal functions. Because the benefits were seen soon after initiation of SGLT2 inhibitors, these observations are explained by effects beyond their glucose lowering capacity. SGLT2 inhibitors also reduce liver fat in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. This chapter describes the basic information about SGLT2 inhibitors, current status of SGLT2 inhibitors in the management of type 2 diabetes and their beneficial effects in addition to glycemic control.

Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism

SUMMARY Severe hypercalcemia is a medical emergency that requires immediate and aggressive management. Primary hyperparathyroidism (PHPT) often causes severe hypercalcemia. Volume resuscitation, parenteral salmon calcitonin, and administration of intravenous bisphosphonates are common measures used to stabilize patients. However, the use of these measures is inadequate in several patients and may even be contraindicated in individuals with renal insufficiency or severe systemic illness. This study demonstrated the efficacy and safety of denosumab in patients with severe hypercalcemia due to PHPT, when immediate surgery was not feasible. We present four patients with severe hypercalcemia due to PHPT. Immediate surgery was not feasible because the patients had severe systemic illness, such as seizures and altered sensorium (case 1); acute severe pancreatitis (cases 2 and 3); or coronavirus disease 2019 pneumonia (case 4). Intravenous normal saline and parenteral salmon calcitonin were inadequate for controlling hypercalcemia. Intravenous bisphosphonates were avoided because of severe systemic illness in all cases and impaired renal function in three cases. Denosumab was administered to control hypercalcemia and allow the stabilization of patients for definitive surgical management. Following denosumab administration, serum calcium levels normalized, and general condition improved in all patients. Three patients underwent parathyroidectomy after two weeks and another patient after eight weeks. The use of denosumab for the management of severe hypercalcemia due to PHPT is efficacious and safe in patients when immediate surgical management is not feasible due to severe systemic illness.

Nonalcoholic fatty liver disease should be considered for treatment allocation in standard management algorithms for type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) often exist together. This is a high-risk population, as presence of T2D promotes the progression of NAFLD to more severe liver pathologies. There are several international guidelines for managing T2D, however guidance for management of NAFLD in individuals with T2D is scarce. In India, there is hardly any screening programme for identification of high-risk NAFLD individuals. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till October 2020, using relevant keywords (nonalcoholic fatty liver disease; NAFLD; nonalcoholic steatohepatitis; NASH screening and management; metabolic associated fatty liver disease) to extract relevant studies describing screening and management strategies of NAFLD/NASH, especially in patients with T2D. RESULTS: An estimated 12.4 million Indian people are living with coexisting T2D and NAFLD-related advanced liver fibrosis, which is a major determinant of liver-related mortality in these individuals. Several studies have reported screening tools for identification of high risk NAFLD patients with coexisting T2D. The emphasis has been laid on the identification of advanced liver fibrosis and cirrhosis, using noninvasive tests at the primary level. For management, lifestyle measures and appropriate glucose-lowering medication have been proposed that help patients with coexisting T2D and NAFLD. Timely referral to specialists is also critical for preventing complications of cirrhosis. CONCLUSIONS: While current management algorithms for T2D include atherosclerotic cardiovascular disease, kidney dysfunction and obesity as co-morbidities to direct appropriate therapies, NAFLD should be considered as additional pathway to select appropriate treatment.