Relationship Between Lipohypertrophy, Glycemic Control, and Insulin Dosing: A Systematic Meta-Analysis.

Background: Lipohypertrophy is a common complication in patients with diabetes receiving insulin therapy. There is a lack of consensus regarding how much lipohypertrophy affects diabetes management. Our study aimed to assess the potential correlation between lipohypertrophy and glycemic control, as well as insulin dosing in patients with diabetes. Methods: We performed a systematic review followed by a meta-analysis to collect data about glycemic control and insulin dosing in diabetic patients with and without lipohypertrophy. To identify relevant studies published in English, we searched medical databases (MEDLINE/PubMed, Embase, and CENTRAL) from 1990 to January 20, 2023. An additional hand-search of references was performed to retrieve publications not indexed in medical databases. Results of meta-analyses were presented either as prevalence odds ratios (pORs) or mean differences (MDs) with 95% confidence intervals (95% CIs). This study was registered on PROSPERO (CRD42023393103). Results: Of the 5540 records and 240 full-text articles screened, 37 studies fulfilled the prespecified inclusion criteria. Performed meta-analyses showed that patients with lipohypertrophy compared with those without lipohypertrophy were more likely to experience unexplained hypoglycemia (pOR [95% CI] = 6.98 [3.30-14.77]), overall hypoglycemia (pOR [95% CI] = 6.65 [1.37-32.36]), and glycemic variability (pOR [95% CI] = 5.24 [2.68-10.23]). Patients with lipohypertrophy also had higher HbA1c (MD [95% CI] = 0.55 [0.23-0.87] %), and increased daily insulin consumption (MD [95% CI] = 7.68 IU [5.31-10.06]). Conclusions: These results suggest that overall glycemic control is worse in patients with lipohypertrophy than in those without this condition.

Energy and cost efficiency of Bitcoin mining endeavor.

The main aim of the study is to analyze BTC mining's efficiency under current market conditions (December 2021), including soaring energy prices produced from many different sources in different geographical locations. After a thorough analysis of initial assumptions concerning the (1) price of mining machine with associated components and its effective amortization period, (2) difficulty and the hash rate of the BTC network, (3) BTC transaction fees, and (4) energy costs from various sources, we have found that currently, BTC mining is not profitable, except for some rare cases. The main reason for this phenomenon is the fast and unpredictable increase of difficulty of the BTC network over time which results in decreasing participation of already purchased mining machines in the BTC network hash rate. The research is augmented with a detailed sensitivity analysis of mining efficiency to initial parameters assumptions, which allows observing that the conditions for BTC mining to be efficient and profitable are very challenging.

NPWT in diabetic foot wounds-a systematic review and meta-analysis of observational studies.

PURPOSE: Negative-pressure wound therapy (NPWT) is an adjunct modality in diabetic foot ulcerations (DFUs). Randomized controlled trials (RCTs) have shown its advantage over standard approaches; however, data from observational studies remain scarce.We performed a systematic review of observational non-RCTs evaluating NPWT efficacy and safety in patients with DFU. METHODS: Electronic databases were searched for observational studies involving NPWT. The results of single-arm studies were presented as percentages of patients with the outcome of interest. A meta-analysis of comparative studies provided point estimates of outcomes. Continuous outcomes were reported as either weighted or standardized mean differences and dichotomous data as relative risks (RR). RESULTS: The search identified 16 relevant observational studies, 12 single-arm, and 4 comparative, reporting on a total of 18,449 patients with DFU, of whom 1882 were managed with NPWT. In the NPWT-treated patients, ulcers were larger (average size range 6.6-27.9 cm2), as compared with controls (≤3 cm2). The pooled results showed healing and major amputation in 51% and 5% of NPWT patients, respectively. The meta-analysis of comparative studies revealed lower risk of major amputation [RR = 0.23 (0.07; 0.80)] in NPWT-treated patients. The pooled results for healing rate and risk of any amputation were inconclusive due to large between-study heterogeneity. Overall, 6 deaths out of 158 patients were reported, none of them related to NPWT. Serious adverse events occurred in 6% of patients on NPWT. CONCLUSIONS: This systematic review of observational studies provided supportive evidence that NWPT is an efficient and safe adjunct treatment in the management of DFUs.

Continuous subcutaneous insulin infusion vs multiple daily injections in pregnant women with type 1 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Randomised controlled trials (RCTs) have shown an advantage of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) in the general type 1 diabetes mellitus (T1DM) population. RCT data on T1DM management in pregnancy remain limited. OBJECTIVE: We performed a systematic review of both RCTs and non-RCTs evaluating CSII vs MDI in T1DM-complicated pregnancy. STUDY DESIGN: Electronic databases were searched for studies comparing CSII with MDI in T1DM-complicated pregnancy. METHODS: A meta-analysis provided point estimates with 95% confidence intervals (CI). Continuous outcomes were reported as weighted mean differences (WMD) or standardised mean differences (SMD), and dichotomous data as relative risk (RR). RESULTS: The search identified 47 studies, including 43 non-RCTs, reporting on 7824 pregnancies. The meta-analysis showed a lower HbA1c level with CSII vs MDI in the first trimester (WMD: -0.45%; 95%CI: -0.62, -0.27). This difference decreased in subsequent trimesters. Compared to MDI, therapy with CSII resulted in higher gestational weight gain (GWG) (WMD: 1.02 kg; 95%CI: 0.41, 1.62), and lower daily insulin dose requirements in the first (SMD: -0.46; 95%CI: -0.68, -0.24) and subsequent trimesters. Moreover, infants from the CSII group were more likely to be large for gestational age (LGA) (RR: 1.16; 95%CI: 1.07, 1.24) and less likely to be small for gestational age (SGA) (RR: 0.66; 95%CI: 0.45; 0.97). CONCLUSIONS: In T1DM-complicated pregnancy, CSII compared to MDI therapy resulted in better first trimester glycaemic control; this difference decreased in subsequent trimesters. CSII therapy was associated with lower insulin requirements, higher GWG and altered risk for infants being LGA and SGA.

Adrenal suppression by inhaled corticosteroids in patients with asthma: A systematic review and quantitative analysis.

BACKGROUND: Inhaled corticosteroids used for treating persistent asthma can suppress adrenal cortisol secretion. This inhibition of endogenous cortisol secretion is an important marker of systemic steroid activity. Although meta-analyses have demonstrated a dose-dependent suppression of cortisol by inhaled corticosteroids, regardless of inhaler type, the impact of novel freon-free inhaled corticosteroid preparations has not been reviewed. OBJECTIVE: The aim of this study was to synthesize all currently available studies on novel inhaled corticosteroid preparations, including ciclesonide, beclomethasone dipropionate, budesonide, and fluticasone propionate. In particular, we aimed to compare the effect of ciclesonide on cortisol suppression with other existing preparations. METHODS: We carried out a systematic review of the medical data bases on cortisol suppression in patients due to inhaled corticosteroids. A multivariate regression model was used to determine dose-dependent relationships between each inhaled corticosteroid and cortisol suppression with respect to age, type of inhaler, and study design. RESULTS: From analysis of 64 studies identified in the review, the strongest dose-response urinary cortisol suppression was observed in patients treated with beclomethasone (8.4% per 100 µg; p = 0.029), followed by fluticasone (3.2% per 100 µg; p < 0.001), and budesonide (3.1% per 100 µg; p = 0.001). No significant urinary cortisol suppression was associated with ciclesonide treatment (1.8% per 100 µg; p = 0.267). Although ciclesonide did not affect cortisol levels, this appeared to be due to its unique pharmacokinetic properties rather than the use of a novel formulation. CONCLUSION: Our findings indicated that the introduction of novel freon-free delivery technologies for inhaled corticosteroids had not eliminated adverse adrenal suppression of cortisol secretion.

Clinical efficacy and safety of insulin aspart compared with regular human insulin in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis.

INTRODUCTION: Prandial insulin is a key component in insulin treatment of type 1 diabetes mellitus (T1DM) and in many patients with type 2 diabetes mellitus (T2DM). The evidence-based data supporting the choice of an insulin preparation are still limited. OBJECTIVES: We performed a systematic review to summarize and update the evidence on relative efficacy and safety of insulin aspart (IAsp) and regular human insulin (RHI) in both types of diabetes. METHODS: Randomized controlled trials comparing IAsp with RHI in patients with either T1DM or T2DM and conducted until May 2013 were retrieved from a systematic search of MEDLINE, EMBASE, and Cochrane Library. RESULTS: Of 16 relevant trials, 11 involved patients with T1DM and 5--with T2DM. In the T1DM population, IAsp, when compared with RHI, provided a greater reduction in hemoglobin A1c (HbA1c) levels (weighted mean difference [WMD], -0.11%; 95% confidence interval [CI], -0.16 to -0.05; WMD, -1.2 mmol/mol; 95% CI, -1.7 to -0.5), and improved postprandial glucose levels following breakfast (WMD, -1.40 mmol/l; 95% CI, -1.72 to -1.07), lunch (WMD, -1.01 mmol/l; 95% CI, -1.61 to -0.41), and dinner (WMD, -0.89 mmol/l; 95% CI, -1.19 to -0.59). The risk of nocturnal hypoglycemia was lower in T1DM patients receiving IAsp (relative risk, 0.76; 95% CI, 0.64-0.91), while no difference was observed for severe hypoglycemia. In T2DM patients, IAsp led to a greater reduction in HbA1c levels (WMD, -0.22%; 95% CI, -0.39 to -0.05; -2.4 mmol/mol, -4.3 to -0.5) and postprandial blood glucose. The risk of overall hypoglycemia and severe adverse effects was comparable between the groups. CONCLUSIONS: IAsp provides better glycemic control when compared with RHI in patients with T1DM and T2DM. Fewer T1DM patients treated with IAsp experienced nocturnal hypoglycemia, while both interventions showed a comparable risk of severe hypoglycemic events in both types of diabetes.

Systematic review and meta-analysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus.

AIMS: A variety of basal insulin preparations are used to treat patients with type 2 diabetes mellitus (T2DM). We aimed to summarize scientific evidence on relative efficacy and safety of insulin glargine (IGlar) and other insulins in T2DM. METHODS: A systematic review was carried out in major medical databases up to December 2012. Relevant studies compared efficacy and safety of IGlar, added to oral drugs (OAD) or/and in combination with bolus insulin, with protamine insulin (NPH) or premixed insulin (MIX) in the same regimen, as well as with insulin detemir (IDet), in T2DM. Target HbA1c level without hypoglycemic events was considered the primary endpoint. RESULTS: Twenty eight RCTs involving 12,669 T2DM patients followed for 12-52 weeks were included in quantitative analysis. IGlar + OAD use was associated with higher probability of reaching target HbA1c level without hypoglycemia as compared to NPH + OAD (RR = 1.32 [1.09, 1.59]) or MIX without OAD (RR = 1.61 [1.22, 2.13]) and similar effect as IDet + OAD (RR = 1.07 [0.87, 1.33]) and MIX + OAD (RR = 1.09 [0.86, 1.38]). IGlar + OAD demonstrated significantly lower risk of symptomatic hypoglycemia as compared to NPH + OAD (RR = 0.89 [0.83, 0.96]), MIX + OAD (RR = 0.75 [0.68, 0.83]) and MIX without OAD(RR = 0.75 [0.68, 0.83]), but not with IDet + OAD (RR = 0.99 [0.90, 1.08]). In basal-bolus regimens, IGlar demonstrated similar proportion of T2DM patients achieving target HbA1c as compared to NPH (RR = 1.14 [0.91, 1.44]) but higher than MIX (RR = 1.26 [1.12, 1.42) or IDet (RR = 1.38 [1.11, 1.72]). The risk of severe hypoglycemia was lower in IGlar than in NPH (RR = 0.77 [0.63, 0.94]), with no differences in comparison with MIX (RR = 0.74 [0.46, 1.20]) and IDet (RR = 1.10 [0.54, 2.25]). IGlar + OAD has comparable safety profile to NPH, with less frequent adverse events leading to treatment discontinuation than MIX + OAD (RR = 0.41 [0.22, 0.76]) and IDet + OAD (RR = 0.40 [0.24, 0.69]). Also severe adverse reactions were less common for IGlar + OAD when compared to MIX + OAD (RR = 0.71 [0.52; 0.98]). CONCLUSION: For the majority of examined efficacy and safety outcomes, IGlar use in T2DM patients was superior or non-inferior to the alternative insulin treatment options.

Efficacy and safety comparison of continuous glucose monitoring and self-monitoring of blood glucose in type 1 diabetes: systematic review and meta-analysis.

INTRODUCTION: Self-monitoring of blood glucose (SMBG) is a crucial element of clinical care in type 1 diabetes, but it may not provide adequate glucose control. A newer alternative approach is continuous glucose monitoring (CGM) system, which allows a more thorough metabolic control. However, the results of trials comparing CGM with SMBG are inconsistent. OBJECTIVES: Based on a systematic review and meta-analysis, we aimed to assess the efficacy and safety of various CGM systems compared with SMBG. METHODS: We searched major medical databases up to June 2011 for randomized controlled trials comparing CGM and SMBG in type 1 diabetes. Studies of at least 12-week duration were included. Weighted mean difference (WMD) or standardized mean difference (SMD) was calculated for continuous measures and dichotomous data were expressed as odds ratio (OR) or risk ratio. RESULTS: We identified 14 relevant trials including a total of 1268 type 1 diabetic patients, of whom 670 were randomized to the CGM group and 598 to the SMBG group. Patients using CGM had a greater decrease in hemoglobin A1c (HbA1c) from baseline compared with those using SMBG (WMD -0.26% [-0.34; -0.19]). We found that the magnitude of the effect was similar in the subset of children and adolescents (WMD -0.25% [-0.43; -0.08]) to that in adults (WMD -0.33% [-0.46; -0.2]). Only real-time devices for CGM improved glycemic control (WMD -0.27% [-0.34; -0.19]). The percentage of patients achieving target HbA1c was higher in the CGM group (OR 2.14 [1.41; 3.26]). Pooled results from 4 studies revealed a reduction in hypoglycemic events in the CGM group (SMD -0.32 [-0.52; -0.13]). CONCLUSIONS: CGM, partcicularly its real-time system, has a favorable effect on glycemic control and decreases the incidence of hypoglycemic episodes in both adult and pediatric patients with type 1 diabetes.

Economic analysis of the implementation of guidelines for type 2 diabetes control developed by Diabetes Poland: what increase in costs is justified by clinical results?

INTRODUCTION: Diabetes Poland has recently published guidelines for the treatment of type 2 diabetes. Treatment according to these guidelines is more expensive and requires more involvement of the patient than is the case in current clinical practice. OBJECTIVES: The aim of the study was to assess to what extent the cost of type 2 diabetes treatment according to the Diabetes Poland guidelines may be increased when compared with the cost of the current treatment, so that the introduction of the guidelines remains cost-effective in the Polish setting. PATIENTS AND METHODS: Two hypothetical patients were defined, John and Peter, representing the population of newly diagnosed type 2 diabetic patients. The disease progression was simulated assuming that John is treated according to the current practice and Peter is treated to achieve and maintain the goals defined by Diabetes Poland. The simulation was performed using the CORE model, which has been constructed based on the published scientific evidence and includes more than a dozen of diabetes complications. The model has been widely validated by numerous studies and is broadly used; it enables a reliable estimation of costs and clinical effects associated with diabetes. The parameters of the model were adapted to the Polish conditions. The analysis was conducted in a life-long perspective, discounting of costs/effects was included, and the acceptability threshold was set at 25,511 EUR per quality-adjusted life-year (QALY). RESULTS: The quality-adjusted life expectancy of John will be 0.3 QALY lower than the life expectancy of Peter. The treatment of diabetic complications will be 400 EUR more expensive in the case of John compared with that of Peter. Assuming the willingness to pay at the level of 7500 EUR/QALY, the cost of diabetes treatment of Peter may be 250 EUR higher than that of John's treatment. For the threshold level of 15,000 EUR/QALY, the difference in cost may be 450 EUR, and for the threshold level of 25,000 EUR/QALY - 725 EUR per year. CONCLUSIONS: Treatment according to the guidelines of Diabetes Poland may be cost-effective provided that the additional costs associated with intensification of therapy will not exceed 725 EUR per year.

[Health economics of inhibitor bypassing agents in haemophilia A-activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa)]. / Ekonomika terapii lekami omijajacymi w hemofilii A powiklanej inhibitorem--aktywowane koncentraty zespolu protrombiny (aPCC) a rekombinowany aktywowany czynnik VII (rfVIIa).

UNLABELLED: Haemophilia A is a sex-linked recessive genetic disorder associated with haemorrhagic diathesis due to reduced plasma activity of coagulation factor VIII, i.e., below 50% of the normal value (< 0.5 IU/ ml). The treatment of haemophilia A-Inhibitor patients is bidirectional. Major issues with treatment are inhibitor eradication and control of haemorrhage. The aim of the analysis was to evaluate costs and effects of the use of aPCC and rFVIIa in haemophilia A-inhibitor patients in on-demand treatment, perioperative prophylaxis and long-term prophylaxis. MATERIALS AND METHODS: The cost analysis was performed from the payer's perspective for all treatment schemes. Dosage and duration of treatment were obtained from a systematic review of clinical trials, Summary of Product Characteristics and clinical practice guidelines. Analysis was conducted in accordance with the AHTAPol (Agency for Health Technology Assessment in Poland) guidelines. RESULTS: The use of aPCC in on-demand treatment of children and adults during one day or one episode of bleeding (irrespective of the intensity of bleeding: from mild to severe) reduced the payer's expenditures in comparison to the use of rFVIIa. The use of aPCC in perioperative prophylaxis of children and adults during minor and major surgical interventions and implantations of central venous access devices was associated with savings for the payer in comparison to the use of rFVIIa, irrespectively of dosage of both drugs. Break even point analysis showed that the use of aPCC in long-term prophylaxis may be less expensive than the use of aPCC in on-demand treatment if bleedings last for 2.5 days or more. Sensitivity analysis showed that assumptions concerning body weight of patients significantly influence expenses of the public payer. However, the use of aPCC was associated with lower costs than the use of rFVIIa, irrespectively of the patients' body weight. CONCLUSIONS: In order to demonstrate the actual size of expenditures on treatment of haemophilia A-Inhibitor patients, collection of data concerning real clinical practice in Poland is required.

Review articles, systematic reviews and meta-analyses: which can be trusted?

A large number of scientific articles published every year requires from practicing physicians the ability to choose among them and to use secondary studies, such as guidelines, review articles, meta-analyses and systematic reviews. The aim of this article was to discuss basic differences between meta-analyses and systematic reviews. Meta-analysis is a mathematical method of pooling the results of several or more studies; a meta-analysis may be based on a systematic review, but this is not always the case. A systematic review is a multistage process aimed at the identification of all reliable evidence regarding a specific clinical problem. Systematic reviews make it possible to objectively address particular issues according to the current state of clinical knowledge and therefore constitute a reliable basis for clinical decision-making. An appropriate systematic review should include: 1) a defined clinical question, 2) pre-specified inclusion and exclusion criteria, 3) complex search for medical evidence sources according to a search strategy, 4) critical evaluation of reliability of identified clinical trials, 5) qualitative or quantitative data synthesis and 6) evidence based conclusions. These simple criteria, formulated by Cook et al. more than 10 years ago, allow to differentiate between a reliable systematic review and a "quasi-systematic" one, as well as between a reliable meta-analysis based on a systematic review and a potentially misleading meta-analysis without a systematic review.

The role of surrogate endpoints in the evaluation of efficacy and safety of therapeutic interventions in diabetes mellitus.

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology.