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Biomedicines Dec 2023Almost a quarter of a millennium after the discovery of an acidic substance in sour milk by Swedish chemist Carl Wilhelm Scheele and more than 100 years after the... (Review)
Review
Almost a quarter of a millennium after the discovery of an acidic substance in sour milk by Swedish chemist Carl Wilhelm Scheele and more than 100 years after the demonstration of a tight connection between this lactic acid and tissue hypoxia in shock, we are still surrounded by false beliefs and misunderstandings regarding this fascinating molecule. Common perceptions of lactate, the conjugate base of lactic acid, as a plain waste product of anaerobic metabolism and a marker of cellular distress could not be further from the truth. Lactate is formed and utilized continuously by our cells, even under fully aerobic conditions, in large quantities, and although marked hyperlactatemia is always a red flag in our patients, not all these conditions are life-threatening and vice versa-not all critically ill patients have hyperlactatemia. Lactate also does not promote acidosis by itself; it is not toxic, nor is it a metabolic renegade. On the contrary, it has many beneficial properties, and an interpretation of hyperlactatemia might be trickier than we tend to think. The aim of this article is to debunk some of the deeply rooted myths regarding this fascinating molecule.
PubMed: 38137413
DOI: 10.3390/biomedicines11123192 -
Renal Failure Dec 2023The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to... (Meta-Analysis)
Meta-Analysis Review
Comparative safety of sodium-glucose co-transporter 2 inhibitors in elderly patients with type 2 diabetes mellitus and diabetic kidney disease: a systematic review and meta-analysis.
The safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with diabetic kidney disease (DKD) is still controversial. This study aimed to analyze the safety of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus (T2DM) and DKD. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to March 2023. Randomized controlled trials (RCTs) were included. Data including patient characteristics and interesting outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean difference (MD) with 95% CIs, respectively. A total of 14 RCTs with 59874 participants were finally included. There were 38,252 males (63.9%) and 21,622 females (36.1%). The patients' mean age was > 64.6 years. SGLT2 inhibitors could delay the further decline of estimated glomerular filtration rate (eGFR) when eGFR ≥ 60 ml/min/1.73m (MD: 2.36; 95%CI [1.15-3.57]). SGLT2 inhibitors in elderly patients with eGFR < 60 ml/min/1.73m (RR: 0.86; 95%CI [0.67-1.11]) may have a relatively increased risk of acute kidney injury compared to eGFR ≥ 60 ml/min/1.73m. SGLT2 inhibitors increased the incidence of genital mycotic infections (RR: 3.47; 95%CI [2.97-4.04]) and diabetic ketoacidosis (RR: 2.25; 95%CI [1.57-3.24]). Except for genital mycotic infections and diabetic ketoacidosis, other adverse reactions were few, indicating that SGLT2 inhibitors are relatively safe for elderly patients with T2DM and DKD. Safety and renoprotection may be diminished when SGLT2 inhibitors are used in elderly patients with eGFR < 60 ml/min/1.73m.
Topics: Male; Female; Humans; Aged; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Diabetic Nephropathies; Diabetic Ketoacidosis; Diabetes Mellitus, Type 2; Symporters; Glucose; Sodium; Hypoglycemic Agents
PubMed: 37246403
DOI: 10.1080/0886022X.2023.2217287 -
Diabetologia Oct 2023Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1...
AIMS/HYPOTHESIS
Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes.
METHODS
We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy.
RESULTS
We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA (-2.6 mmol/mol [-0.2%] with SGLT2i and -5.4 mmol/mol [-0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m vs -7.2 ml/min per 1.73 m, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort.
CONCLUSIONS/INTERPRETATION
Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Sodium-Glucose Transporter 2 Inhibitors; Retrospective Studies; Insulin; Diabetic Ketoacidosis; Renal Insufficiency, Chronic; Glucagon-Like Peptide 1; Glucose; Glucagon-Like Peptide-1 Receptor
PubMed: 37505282
DOI: 10.1007/s00125-023-05975-8 -
Ugeskrift For Laeger Sep 2023Diabetic ketoacidosis (DKA) in children with severe hypertriglyceridaemia (S-HTG) is infrequent. This case report presents a seven-year-old girl without a family history...
Diabetic ketoacidosis (DKA) in children with severe hypertriglyceridaemia (S-HTG) is infrequent. This case report presents a seven-year-old girl without a family history of dyslipidaemia with moderate DKA, lipaemic plasma, retinal lipaemia, and P-triglyceride 185 mmol/l. The course was uneventful on standard treatment and lipids normalized. She had abdominal pain but no biochemical or ultrasound evidence of pancreatitis. S-HTG affected laboratory analysis; CO2 could not be analyzed, and there was haemolysis and uncertain electrolyte results with P-Na+ 125 mmol/l, i.e. pseudo hyponatraemia, despite ultracentrifugation.
Topics: Female; Humans; Child; Diabetic Ketoacidosis; Hyperlipidemias; Hypertriglyceridemia; Pancreatitis; Triglycerides; Diabetes Mellitus
PubMed: 37873990
DOI: No ID Found -
International Journal of Molecular... Feb 2024Diets can influence the body's acid-base status because specific food components yield acids, bases, or neither when metabolized. Animal-sourced foods yield acids and... (Review)
Review
Diets can influence the body's acid-base status because specific food components yield acids, bases, or neither when metabolized. Animal-sourced foods yield acids and plant-sourced food, particularly fruits and vegetables, generally yield bases when metabolized. Modern diets proportionately contain more animal-sourced than plant-sourced foods, are, thereby, generally net acid-producing, and so constitute an ongoing acid challenge. Acid accumulation severe enough to reduce serum bicarbonate concentration, i.e., manifesting as chronic metabolic acidosis, the most extreme end of the continuum of "acid stress", harms bones and muscles and appears to enhance the progression of chronic kidney disease (CKD). Progressive acid accumulation that does not achieve the threshold amount necessary to cause chronic metabolic acidosis also appears to have deleterious effects. Specifically, identifiable acid retention without reduced serum bicarbonate concentration, which, in this review, we will call "covert acidosis", appears to cause kidney injury and exacerbate CKD progression. Furthermore, the chronic engagement of mechanisms to mitigate the ongoing acid challenge of modern diets also appears to threaten health, including kidney health. This review describes the full continuum of "acid stress" to which modern diets contribute and the mechanisms by which acid stress challenges health. Ongoing research will develop clinically useful tools to identify stages of acid stress earlier than metabolic acidosis and determine if dietary acid reduction lowers or eliminates the threats to health that these diets appear to cause.
Topics: Animals; Bicarbonates; Acid-Base Equilibrium; Diet; Acidosis; Renal Insufficiency, Chronic
PubMed: 38397012
DOI: 10.3390/ijms25042336 -
Frontiers in Endocrinology 2023The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons. (Comparative Study)
Comparative Study Meta-Analysis
Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUNDS
The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons.
METHODS
This network meta-analysis (NMA) was performed to compare the safety of nine SGLT-2 inhibitors in patients with type 2 diabetes (T2DM). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for studies published in English before August 30, 2022. Published and unpublished randomized controlled trials (RCTs) comparing the safety of individual SGLT-2 inhibitors in patients with T2DM were included. A Bayesian NMA with random effects model was applied. Subgroup and sensitivity analyses were performed. The quality of the evidence was evaluated using the Confidence in Network Meta-Analysis framework.
RESULTS
Nine SGLT-2 inhibitors were evaluated in 113 RCTs (12 registries) involving 105,293 adult patients. Reproductive tract infections (RTIs) were reported in 1,967 (4.51%) and 276 (1.01%) patients in the SGLT-2 inhibitor and placebo groups, respectively. Furthermore, pollakiuria was reported in 233 (2.66%) and 45 (0.84%) patients, respectively. Compared to placebo, a significantly higher risk of RTIs was observed with canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotagliflozin, but not with luseogliflozin and ipragliflozin, regardless of gender. An increased risk of pollakiuria was observed with dapagliflozin [odds ratio (OR) 10.40, 95% confidence interval (CI) 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97). Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of urinary tract infections (UTIs). Instead, the included SGLT-2 inhibitors had a protective effect against acute kidney injury (AKI). No significant differences were found for hypovolemia, renal impairment or failure, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia between the SGLT-2 inhibitor and the placebo groups.
CONCLUSION
In patients with T2DM, dapagliflozin was associated with an increased risk of RTIs, pollakiuria, and UTIs. Empagliflozin increased the risk of RTIs and pollakiuria. Remogliflozin increased the risk of UTIs. None of the SGLT-2 inhibitors showed a significant difference from the placebo for hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia. The findings guide the selection of SGLT-2 inhibitors for patients with T2DM based on the patient's profiles to maximize safety.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42022334644.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fractures, Bone; Hypoglycemia; Hypovolemia; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37701900
DOI: 10.3389/fendo.2023.1238399