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Effectiveness of ketoacidosis prevention campaigns at diagnosis of type 1 diabetes in children: A systematic review and meta-analysis.
Cherubini, V, Marino, M, Carle, F, Zagaroli, L, Bowers, R, Gesuita, R
Diabetes research and clinical practice. 2021;:108838
Abstract
AIM: To determine if diabetes awareness campaigns are an effective intervention to reduce diabetes ketoacidosis at diagnosis of type 1 diabetes in children and youth. METHODS Search strategies included PubMed, Scopus, CINAHL and WOS electronic databases, hand search of select journals and a grey literature search "Google" search to include all relevant information. Studies included community-based interventions focused on children younger than 18 years old. The difference in the frequency of DKA was measured in two separate comparisons; before and after perform awareness campaigns in the same area, and between areas with and without intervention campaigns. RESULTS Of 1136 records identified, 14 studies were eligible for the analysis. The first group of 12 studies measured DKA at diagnosis, before (n = 6548 individuals) and after (n = 4931 individuals) the awareness campaigns. The pooled difference was a reduction of 7.20% (95%CI: 0.99-13.41). The second group of four studies measured the difference in an area with no intervention (n = 338 individuals) and in an area with an awareness campaign (n = 187 individuals). The pooled difference in DKA was 35.71% (95%CI: 5.81-65.61). CONCLUSIONS This review demonstrated that DKA awareness campaigns are effective to reduce DKA among children and adolescents with type 1 diabetes and the core components that explain why these campaigns are effective. Back to top.
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2.
Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis: An Example of Complementary Evidence for Rare Adverse Events.
Alkabbani, W, Pelletier, R, Gamble, JM
American journal of epidemiology. 2021;(8):1572-1581
Abstract
Evidence from observational studies may be considered complementary to that of randomized controlled trials (RCTs), particularly when assessing rare outcomes of drug therapies. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic agents that have been linked to an increased risk of diabetic ketoacidosis (DKA). We conducted a systematic review and separately meta-analyzed data from RCTs (n = 18; 2013-2019) and cohort studies (n = 7; 2017-2020) to assess the consistency of the magnitude of association between SGLT-2 inhibitors and DKA risk. We illustrate the strengths and weaknesses of the 2 designs. Results from RCTs and observational studies consistently showed almost a doubling in the risk of DKA among patients using an SGLT-2 inhibitor as compared with placebo or an active comparator. In a random-effects model, the pooled relative risk was 2.08 (95% confidence interval (CI): 1.28, 3.40) from placebo-controlled RCTs and 0.82 (95% CI: 0.25, 2.68) from active-comparator RCTs. The pooled adjusted hazard ratio from observational studies was 1.74 (95% CI: 1.28, 2.38). Notably, the 2 designs complement each other in several domains, including external and internal validity and power. This demonstrates a need for more comprehensive evidence when assessing rare adverse events for both sources.
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Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis.
Donnan, JR, Grandy, CA, Chibrikov, E, Marra, CA, Aubrey-Bassler, K, Johnston, K, Swab, M, Hache, J, Curnew, D, Nguyen, H, et al
BMJ open. 2019;(1):e022577
Abstract
OBJECTIVE To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies. DESIGN We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs). INTERVENTION SGLT2 inhibitors, compared with placebo or active comparators. PRIMARY OUTCOMES Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations. RESULTS We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture. CONCLUSIONS Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear. PROSPERO REGISTRATION NUMBER CRD42016038715.
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Incidence of Diabetic Ketoacidosis of New-Onset Type 1 Diabetes in Children and Adolescents in Different Countries Correlates with Human Development Index (HDI): An Updated Systematic Review, Meta-Analysis, and Meta-Regression.
Große, J, Hornstein, H, Manuwald, U, Kugler, J, Glauche, I, Rothe, U
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2018;(3):209-222
Abstract
Type 1 diabetes mellitus (T1DM) is usually diagnosed by insulin deficiency at a young age. Diabetic ketoacidosis (DKA) represents a severe complication occurring before the first diagnosis of T1DM. Actually, the data situation is still unsettled in assessing the current state of diagnosis. This study summarizes the latest rates of DKA of new-onset T1DM in children and adolescents in different countries available over the last five years. Different T1DM-related, geographical and socioeconomic moderators are suitable to explain the heterogeneity of observed DKA rates. A systematic literature search using PubMed, EMBASE*, and MedLine* (*via OVID) was conducted to extract worldwide DKA rates covering publications from April 2011 to May 2016. We define DKA consistently by pH<7.3 or bicarbonate<15 mmol/l. We identified 34 suitable studies covering DKA rates in 25 countries. Overall DKA rates were compared to earlier studies to identify a temporal trend. We further applied a random effects meta-analysis and used meta-regression to reveal moderators of DKA rate heterogeneity. This review evaluating 34 studies includes 47 000 children and adolescents in total. DKA rates varied from 14.7% (Denmark) to 79.8% (Saudi Arabia). DKA rates are still high but a decline can also be recognized. The meta-regression shows that latitude (p<0.000) and human development index (HDI) (p<0.000) are moderators of DKA rates. The frequency of DKA rates occurrence varies widely for different countries. Both latitude and HDI partially explain the observed heterogeneity, while other moderators such as density of physicians showed no obvious correlation.
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Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials.
Monami, M, Nreu, B, Zannoni, S, Lualdi, C, Mannucci, E
Diabetes research and clinical practice. 2017;:53-60
Abstract
AIMS: Diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors (SGLT-2i) is a possible adverse event. In fact, SGLT-2i are capable of stimulating the release of glucagon and ketone re-absorption in the renal tubuli, thus increasing the concentration of ketone bodies. METHODS A Medline search for SGLT2i (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials with a duration of treatment≥12weeks, enrolling patients with type 2 diabetes, and comparing a SGLT2i with placebo or other comparators. The principal outcome was the effect of SGLT2i on ketoacidosis as serious adverse event. RESULTS Out of 72 trials reporting information on DKA, 9 reported at least one event of ketoacidosis; those eight trials enrolled 10,157 and 5396 in SGLT-2 inhibitors and comparator groups, respectively. No signal of increased risk for ketoacidosis was observed for SGLT2 inhibitors as a class (MH-OR [95% CI] 1.14 [0.45-2.88], p=0.78) or as individual molecule. The sensitivity analysis with continuity correction (inputing one event each in drug and comparator arms of each trial with zero events) suggested a reduced incidence of ketoacidosis in patients treated with SGLT-2 inhibitors (MH-OR 0.65 [0.47-0.90]; p=0.01). CONCLUSIONS The results of clinical trials summarized in the present meta-analysis reassure us that, when the drug is properly prescribed, the risk of DKA is negligible.
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[Systematic review with meta-analysis: Subcutaneous insulin glargine coadministration for diabetic ketoacidosis].
Andrade-Castellanos, CA, Colunga-Lozano, LE
Gaceta medica de Mexico. 2016;(6):761-769
Abstract
BACKGROUND The standard treatment of diabetic ketoacidosis involves intravenous infusion of regular insulin until recovery of the episode: this is associated with high costs. Coadministration of insulin glargine from the onset of management may prove beneficial, potentially avoiding rebound hyperglycemia, and hopefully improving the time to resolution of the disease. METHODS We searched MEDLINE, EMBASE, and CENTRAL for randomized controlled trials comparing coadministration of insulin glargine versus standard treatment in patients with diabetic ketoacidosis. To be eligible, studies must assess the efficacy of insulin glargine and report clinically important outcomes. Two reviewers extracted data, assessed risk of bias and summarized strength of evidence using the GRADE approach. RESULTS Four studies (135 participants during hospital follow-up) were included in this review. Low-quality evidence from three trials suggested that subcutaneously administered insulin glargine, in addition to the standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis (MD -4.19 hours; 95% CI: -7.81 to 0.57; p = 0.02). There was neutral difference between the two groups regarding length of hospital stay and hypoglycemic episodes. CONCLUSIONS subcutaneously administered insulin glargine, in addition to standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis, with neutral effects on hypoglycemic episodes.
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Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis.
Andrade-Castellanos, CA, Colunga-Lozano, LE, Delgado-Figueroa, N, Gonzalez-Padilla, DA
The Cochrane database of systematic reviews. 2016;(1):CD011281
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Abstract
BACKGROUND Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of uncontrolled diabetes that mainly occurs in individuals with autoimmune type 1 diabetes, but it is not uncommon in some people with type 2 diabetes. The treatment of DKA is traditionally accomplished by the administration of intravenous infusion of regular insulin that is initiated in the emergency department and continued in an intensive care unit or a high-dependency unit environment. It is unclear whether people with DKA should be treated with other treatment modalities such as subcutaneous rapid-acting insulin analogues. OBJECTIVES To assess the effects of subcutaneous rapid-acting insulin analogues for the treatment of diabetic ketoacidosis. SEARCH METHODS We identified eligible trials by searching MEDLINE, PubMed, EMBASE, LILACS, CINAHL, and the Cochrane Library. We searched the trials registers WHO ICTRP Search Portal and ClinicalTrials.gov. The date of last search for all databases was 27 October 2015. We also examined reference lists of included randomised controlled trials (RCTs) and systematic reviews, and contacted trial authors. SELECTION CRITERIA We included trials if they were RCTs comparing subcutaneous rapid-acting insulin analogues versus standard intravenous infusion in participants with DKA of any age or sex with type 1 or type 2 diabetes, and in pregnant women. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data, assessed studies for risk of bias, and evaluated overall study quality utilising the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the I² statistic. We synthesised data using random-effects model meta-analysis or descriptive analysis, as appropriate. MAIN RESULTS Five trials randomised 201 participants (110 participants to subcutaneous rapid-acting insulin analogues and 91 to intravenous regular insulin). The criteria for DKA were consistent with the American Diabetes Association criteria for mild or moderate DKA. The underlying cause of DKA was mostly poor compliance with diabetes therapy. Most trials did not report on type of diabetes. Younger diabetic participants and children were underrepresented in our included trials (one trial only). Four trials evaluated the effects of the rapid-acting insulin analogue lispro, and one the effects of the rapid-acting insulin analogue aspart. The mean follow-up period as measured by mean hospital stay ranged between two and seven days. Overall, risk of bias of the evaluated trials was unclear in many domains and high for performance bias for the outcome measure time to resolution of DKA.No deaths were reported in the included trials (186 participants; 3 trials; moderate- (insulin lispro) to low-quality evidence (insulin aspart)). There was very low-quality evidence to evaluate the effects of subcutaneous insulin lispro versus intravenous regular insulin on the time to resolution of DKA: mean difference (MD) 0.2 h (95% CI -1.7 to 2.1); P = 0.81; 90 participants; 2 trials. In one trial involving children with DKA, the time to reach a glucose level of 250 mg/dL was similar between insulin lispro and intravenous regular insulin. There was very low-quality evidence to evaluate the effects of subcutaneous insulin aspart versus intravenous regular insulin on the time to resolution of DKA: MD -1 h (95% CI -3.2 to 1.2); P = 0.36; 30 participants; 1 trial. There was low-quality evidence to evaluate the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin on hypoglycaemic episodes: 6 of 80 insulin lispro-treated participants compared with 9 of 76 regular insulin-treated participants reported hypoglycaemic events; risk ratio (RR) 0.59 (95% CI 0.23 to 1.52); P = 0.28; 156 participants; 4 trials. For insulin aspart compared with regular insulin, RR for hypoglycaemic episodes was 1.00 (95% CI 0.07 to 14.55); P = 1.0; 30 participants; 1 trial; low-quality evidence. Socioeconomic effects as measured by length of mean hospital stay for insulin lispro compared with regular insulin showed a MD of -0.4 days (95% CI -1 to 0.2); P = 0.22; 90 participants; 2 trials; low-quality evidence and for insulin aspart compared with regular insulin 1.1 days (95% CI -3.3 to 1.1); P = 0.32; low-quality evidence. Data on morbidity were limited, but no specific events were reported for the comparison of insulin lispro with regular insulin. No trial reported on adverse events other than hypoglycaemic episodes, and no trial investigated patient satisfaction. AUTHORS' CONCLUSIONS Our review, which provided mainly data on adults, suggests on the basis of mostly low- to very low-quality evidence that there are neither advantages nor disadvantages when comparing the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin for treating mild or moderate DKA.
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Is subcutaneous administration of rapid-acting insulin as effective as intravenous insulin for treating diabetic ketoacidosis?
Mazer, M, Chen, E
Annals of emergency medicine. 2009;(2):259-63
Abstract
To determine whether intermittent subcutaneous administration of rapid-acting insulin is as effective as intravenous infusion of regular insulin for treating uncomplicated diabetic ketoacidosis, we performed a MEDLINE, EMBASE, and Cochrane Library search, using the key words "subcutaneous insulin AND intravenous insulin AND diabetic ketoacidosis; LIMIT humans and English." We also searched the references in these articles for additional studies. This search yielded a total of 35 articles, 4 of which directly addressed the question at hand. According to this review of the available evidence; subcutaneous administration of rapid-acting insulin analogs such as lispro is as effective and safe as intravenous infusion of regular insulin for the management of uncomplicated diabetic ketoacidosis. In addition, use of insulin analogs may confer an overall cost savings, obviating the need for infusion pumps and ICU admissions in certain institutions. Therefore, it would be safe and effective to use subcutaneously administered rapid-acting insulin analogues instead of intravenous regular insulin infusions for patients with uncomplicated diabetic ketoacidosis.