SGLT2 Inhibitor-Associated Ketoacidosis vs Type 1 Diabetes-Associated Ketoacidosis.
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ABSTRACT:
SUBMITTER: Umapathysivam MM
PROVIDER: S-EPMC10949093 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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SGLT2 Inhibitor-Associated Ketoacidosis vs Type 1 Diabetes-Associated Ketoacidosis.
Umapathysivam Mahesh M MM Morgan Bethany B Inglis Joshua M JM Meyer Emily E Liew Danny D Thiruvenkatarajan Venkatesan V Jesudason David D
JAMA network open 20240304 3
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Project description:Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial. We searched the FDA Adverse Event Reporting System (FAERS) for reports of acidosis in patients treated with canagliflozin, dapagliflozin, or empagliflozin (from the date of each drug's FDA approval until May 15, 2015). We compared the number of SGLT2 inhibitor-related reports to reports of acidosis in patients treated with the 2 most commonly used DPP4 inhibitors: sitagliptin and saxagliptin. We estimated relative risks of acidosis by relating the number of reports to cumulative drug sales (a surrogate for patient exposure). FAERS contained 259 reports of acidosis (including 192 reports of ketoacidosis) for SGLT2 inhibitors compared with 477 reports of acidosis for DPP4 inhibitors (including 71 reports of ketoacidosis). Based on estimated patient exposure, the overall risk of developing acidosis was ~14-fold higher for SGLT2 inhibitors. Among 51 SGLT2 inhibitor-related reports with quantifiable metabolic information, 20 cases occurred in patients with type 1 diabetes (T1D), 25 in type 2 diabetes (T2D), and 6 in patients with unspecified type of diabetes. After excluding patients with T1D and focusing on patients identified as having T2D, we estimate that SGLT2 inhibitors were associated with ~7-fold increase in developing acidosis. Seventy-one percent had euglycemic ketoacidosis. Our results support the FDA's warning that SGLT2 inhibitors lead to ketoacidosis, as evidenced by an increased reporting rate for acidosis above that in a comparator population treated with DPP4 inhibitors.
| S-EPMC5950709 | biostudies-literature
Project description:Diabetes Mellitus continues to be a major non- communicable disease with global burden of 366 million at present and projected to increase to 439 to 552 million by 2030, India being the hub of diabetes. Sodium glucose transporter 2 (SGLT2) inhibitors presents a new class of anti-diabetic drugs having an insulin-independent mechanism that offers a considerable advantage of increasing urinary glucose excretion without inducing hypoglycemia and promoting weight loss due to loss of 300 to 400kcal/day, Canagliflozin being the 1(st) successful candidate of this group and became the first SGLT2 inhibitor to be FDA approved on March 29, 2013. In various clinical trials, it has shown promising results in controlling glycemia, causing weight loss, reducing systolic and diastolic BP and cardiovascular risk. There are some safety concerns associated with its use e.g. genital mycotic infections, increased urination, urinary tract infection and hyperkalemia, which need to be carefully addressed while using this drug.
| S-EPMC3978932 | biostudies-other
Project description:BACKGROUND AND OBJECTIVE: As of December 2017, 20 diabetic ketosis (DK)/diabetic ketoacidosis (DKA) cases associated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) had been reported to the Health Sciences Authority (HSA), Singapore. We aimed to provide a detailed analysis of the profile of these cases. METHODS:As part of the emerging safety issue monitoring, the HSA followed up on SGLT2i-associated DK/DKA cases with the reporters to obtain the missing and/or supplementary information. Descriptive statistics were employed to summarise the data collected, while the Mann-Whitney test was employed to evaluate the differences between typical and euglycaemic DKA cases as well as between genders. RESULTS:All cases led to hospitalisation but were non-fatal. Where reported, the majority (71-85%) of DK/DKA cases occurred within 180 days of SGLT2i therapy initiation and involved female patients and/or patients with long-standing type 2 diabetes mellitus (T2DM). Apart from the difference in blood glucose levels, no differences in the profile between the typical and euglycaemic DKA cases were noted. Known precipitating factors were identified in all cases. Acute illnesses, particularly infections and abscesses, were the most commonly reported precipitating factors, followed by insulin dose reduction/cessation. CONCLUSIONS:Based on the profile of the reported cases, it is imperative to maintain clinical vigilance for DK/DKA, especially during the first 6 months of SGLT2i treatment and more so in female patients and/or patients with long-standing T2DM. Prompt evaluation and management of underlying precipitating factors is also important to assess and mitigate the risk of developing DK/DKA during treatment with SGLT2i.
| S-EPMC6592972 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.
| S-EPMC4160579 | biostudies-literature
Project description:IntroductionCardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications.MethodsType 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.).ResultsDAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment.ConclusionsThese data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.
| S-EPMC8853531 | biostudies-literature
Project description:Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; however, concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion. The mechanisms behind these alterations are unknown. Here we show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. Treatment with a loop diuretic, furosemide, under insulinopenic conditions replicates the effect of dapagliflozin and causes ketoacidosis. Furthermore, the effects of SGLT2 inhibition to promote ketoacidosis are independent from hyperglucagonemia. Taken together these data in rats identify the combination of insulinopenia and dehydration as a potential target to prevent euglycemic ketoacidosis associated with SGLT2i.
| S-EPMC6358621 | biostudies-literature
Project description:ObjectiveBased on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes.MethodsThis is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients' management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week.ResultsWe enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups.ConclusionThe CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.
| S-EPMC9940379 | biostudies-literature
Project description:BackgroundSodium glucose cotransporter 2 (SGLT2) inhibitors improve clinical outcomes in several populations including type 2 diabetes (T2D), chronic renal insufficiency, and heart failure (HF). However, limited data exist on their effects on atrial fibrillation (AF).MethodsWe conducted a retrospective cohort study using the National Health Insurance Service database. A total of 4,771 patients with T2D and AF who were newly prescribed SGLT2 inhibitors or DPP4 inhibitors were selected and matched in a 1:2 ratio by propensity score with 37 confounding variables. We assessed the effect of SGLT2 inhibitors on the composite outcome of either HF hospitalization or death.ResultsOver a median follow-up of 31 months, patients on SGLT2 inhibitors were associated with a lower risk of hospitalizations for HF or mortality compared to those on DPP4 inhibitors (HR 0.61; 95% CI 0.44-0.85; P = 0.004). SGLT2 inhibitor use was also associated with a lower risk of mortality (HR 0.61; 95% CI 0.39-0.94; P = 0.025) and CV mortality (HR 0.43; 95% CI 0.21-0.86; P = 0.018), but not of MI (HR 1.22 [95% CI 0.72-2.09]; P = 0.461) or stroke (HR 1.00 [95% CI 0.75-1.33]; P = 0.980). The incidence of hospitalizations for HF, although statistically insignificant, tended to be lower in the SGLT2 inhibitor group (HR 0.63 [95% CI 0.39-1.02]; P = 0.062).ConclusionIn a nationwide cohort of patients with T2D and AF, SGLT2 inhibitor was associated with a lower risk of mortality, which may suggest that SGLT2 inhibitors may be considered as the first-line antidiabetic medication in patients with T2D and AF.
| S-EPMC11805423 | biostudies-literature
Project description:IntroductionEvidence for dual antidiabetic therapy in type 2 diabetes mellitus patients with cirrhosis is limited. This study compared 5-year mortality, composite hepatic decompensation risk, and hepatocellular carcinoma occurrence in patients with diabetes and cirrhosis who were either on metformin monotherapy or on dual metformin and sodium-glucose co-transporter-2 inhibitor (SGLT2-I) therapy.MethodsThis retrospective study used the TriNetX Research Network to identify propensity score-matched patients treated with either metformin or dual metformin and SGLT2-I therapy. Our outcomes were all-cause mortality, a composite of hepatic decompensation events, and hepatocellular carcinoma (HCC) occurrence over 5 years. We estimated hazard ratios within each cohort with 95% confidence intervals (CI) and Kaplan-Meier estimates for time-to-event distributions with Log-rank tests. We were able to stratify our cohorts by age, sex, race, and ethnicity. We further investigated a subset of diabetic patients with cirrhosis due to MASH.ResultsIn our propensity score-matched cohorts of type 2 diabetes patients with cirrhosis, those on dual metformin and SGLT2-I therapy had decreased risk for mortality (HR 0.57, 95%CI 0.41-0.81), reduced composite risk of becoming decompensated (HR 0.63, 95%CI 0.43-0.93) and less than half the risk for developing HCC (HR 0.43, 95%CI 0.21-0.88) compared to those on mono metformin therapy. We did not find a difference between mono or dual therapy treatment for mortality, decompensation, or HCC risks in the subset of patients with MASH cirrhosis.ConclusionDual metformin and SGLT2-I treatment in type 2 diabetes patients with cirrhosis are associated with improved mortality and hepatic complications.
| S-EPMC10731715 | biostudies-literature
Project description:BackgroundSenescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway.MethodsTo elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4.ResultsThe therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i.ConclusionsCollectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function.
| S-EPMC11619200 | biostudies-literature