Efficacy and Safety of Stem Cell Therapy for T1DM: An Updated Systematic Review and Meta-Analysis.
ABSTRACT: Background:The long-term insulin therapy for type 1 diabetes mellitus (T1DM) fails to achieve optimal glycemic control and avoid adverse events simultaneously. Stem cells have unique immunomodulatory capacities and have been considered as a promising interventional strategy for T1DM. Stem cell therapy in T1DM has been tried in many studies. However, the results were controversial. We thus performed a meta-analysis to update the efficacy and safety of stem cell therapy in patients with T1DM. Methods:We systematically searched the Medline, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Wan Fang Data, China National Knowledge Infrastructure, VIP database, and the Chinese Biomedical Literature Database (SinoMed) for relevant studies published before March 19, 2019. The outcomes included parameters for glycemic control (i.e., glycosylated hemoglobin (HbA1c) levels and insulin dosages), ? cell function (i.e., fasting C-peptide levels and area-under-curve of C-peptide concentration (AUCC)), and relative risk of adverse events. Statistical analysis was conducted by using RevMan 5.3 and Stata 12.0. Results:Five randomized controlled trials (RCTs) and eight nonrandomized concurrent control trials (NRCCTs) with a total of 396 individuals were finally included into the meta-analysis. Among RCTs, stem cell therapy could significantly reduce HbA1c levels (MD = -1.20, 95% CI -1.91 to -0.49, P = 0.0009) and increase fasting C-peptide levels (MD = 0.25, 95% CI 0.04 to 0.45, P = 0.02) and AUCC (SMD = 0.66, 95% CI 0.13 to 1.18, P = 0.01). Stem cell therapy could also reduce insulin dosages (SMD = -2.65, 95% CI -4.86 to -0.45, P = 0.02) at 6 months after treatment. NRCCTs also had consistent results. Furthermore, RCTs showed stem cell therapy did not increase relative risk of gastrointestinal symptom (RR = 0.69, 95% CI 0.14 to 3.28, P = 0.64) and infection (RR = 0.97, 95% CI 0.40 to 2.34, P = 0.95). However, NRCCTs showed stem cell therapy increased relative risk of gastrointestinal symptom (RR = 44.49, 95% CI 9.20 to 215.18, P < 0.00001). Conclusion:Stem cell therapy for T1DM may improve glycemic control and ? cell function without increasing the risk of serious adverse events. Stem cell therapy may also have a short-term (3-6 months) effect on reducing insulin dosages.
Project description:<h4>Background</h4>Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).<h4>Methods and findings</h4>We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (? = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (? = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (?52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.<h4>Conclusions</h4>In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.
Project description:Diabetes mellitus (DM) is a chronic metabolic disease with high morbidity and mortality. Recently, stem cell-based therapy for DM has shown considerable promise. Here, we undertook a systematic review and meta-analysis of published clinical studies to evaluate the efficacy and safety of stem cell therapy for both type 1 DM (T1DM) and type 2 DM (T2DM). The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and ClinicalTrials.gov databases were searched up to November 2018. We employed a fixed-effect model using 95% confidence intervals (CIs) when no statistically significant heterogeneity existed. Otherwise, a random-effects statistical model was used. Twenty-one studies met our inclusion criteria: ten T1DM studies including 226 patients and eleven T2DM studies including 386 patients. Stem cell therapy improved C-peptide levels (mean difference (MD), 0.41; 95% CI, 0.06 to 0.76) and glycosylated hemoglobin (HbA1c; MD, -3.46; 95% CI, -6.01 to -0.91) for T1DM patients. For T2DM patients, stem cell therapy improved C-peptide levels (MD, 0.33; 95% CI, 0.07 to 0.59), HbA1c (MD, -0.87; 95% CI, -1.37 to -0.37) and insulin requirements (MD, -35.76; 95% CI, -40.47 to -31.04). However, there was no significant change in fasting plasma glucose levels (MD, -0.52; 95% CI, -1.38 to 0.34). Subgroup analyses showed significant HbA1c and C-peptide improvements in patients with T1DM treated with bone marrow hematopoietic stem cells (BM-HSCs), while there was no significant change in the mesenchymal stem cell (MSC) group. In T2DM, HbA1c and insulin requirements decreased significantly after MSC transplantation, and insulin requirements and C-peptide levels were significantly improved after bone marrow mononuclear cell (BM-MNC) treatment. Stem cell therapy is a relatively safe and effective method for selected individuals with DM. The data showed that BM-HSCs are superior to MSCs in the treatment of T1DM. In T2DM, MSC and BM-MNC transplantation showed favorable therapeutic effects.
Project description:Introduction:Strict glucose control using multiple doses of insulin is the standard treatment for type 1 diabetes mellitus (T1DM), but increased risk of hypoglycemia is a frequent drawback. Regular insulin in multiple doses is important for achieving strict glycemic control for T1DM, but short-acting insulin analogues may be better in reducing hypoglycemia and postprandial glucose levels. Objective:We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose in patients with T1DM. Methods:Searches were run on the electronic databases MEDLINE, Cochrane-CENTRAL, EMBASE, ClinicalTrials.gov, LILACS, and DARE for RCTs published until August 2017. To be included in the study, the RCTs had to cover a minimum period of 4 weeks and had to assess the effects of short-acting insulin analogues vs regular human insulin on hypoglycemia and postprandial glucose levels in patients with T1DM. Two independent reviewers extracted the data and assessed the quality of the selected studies. The primary outcomes analyzed were hypoglycemia (total episodes, nocturnal hypoglycemia, and severe hypoglycemia) and postprandial glucose (at all times, after breakfast, after lunch, and after dinner). Glycated hemoglobin (HbA1c) levels and quality of life were considered secondary outcomes. The risk of bias of each RCT was assessed using the Cochrane Collaboration Risk of Bias table, while the quality of evidence for each outcome was assessed using the GRADEpro software. The pooled mean difference in the number of hypoglycemic episodes and postprandial glucose between short-acting insulin analogues vs. regular human insulin was calculated using the random-effects model. Results:Of the 2897 articles retrieved, 22 (6235 patients) were included. Short-acting insulin analogues were associated with a decrease in total hypoglycemic episodes (risk rate 0.93, 95% CI 0.87-0.99; 6235 patients; I2?=?81%), nocturnal hypoglycemia (risk rate 0.55, 95% CI 0.40-0.76, 1995 patients, I2?=?84%), and severe hypoglycemia (risk rate 0.68, 95% CI 0.60-0.77; 5945 patients, I2?=?0%); and with lower postprandial glucose levels (mean difference/MD -?19.44 mg/dL; 95% CI -?21.49 to -?17.39; 5031 patients, I2?=?69%) and lower HbA1c (MD -?0,13%; IC 95% -?0.16 to -?0.10; 5204 patients; I2?=?73%) levels. Conclusions:Short-acting insulin analogues are superior to regular human insulin in T1DM patients for the following outcomes: total hypoglycemic episodes, nocturnal hypoglycemia, severe hypoglycemia, postprandial glucose, and HbA1c.
Project description:Purpose: We aimed to examine the possible association role of vitamin D and vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) in type 1 diabetes mellitus (T1DM) development, glycemic control and complications among a cohort of Egyptian children. Subjects and methods: A prospective case-control study has been conducted on 50 Egyptian children with T1DM who were comparable with 50 controls. Vitamin D and HbA1c were measured. VDR-SNPs [ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410)] detection was done by polymerase chain reaction through restriction fragment length polymorphism (PCR-RFLP) technique. Vitamin D supplements were given to the included T1DM children with low vitamin D and reassessments of both HbA1c% and 25(OH)D serum levels were performed in those children three months later. Results: Eighty percent of the included diabetic patients have poor glycemic control. Vitamin D was deficient in 68% and insufficient in 16% of diabetic patients. Significant improvements in both vitamin D and glycemic status among T1DM children, who have low vitamin D and received vitamin D supplementations. There were significantly negative correlations between serum levels of vitamin D with both HbA1c % (r= -0.358, P?0.05) and daily insulin dose (r=-0.473, P?0.05). Compared with controls, T1DM children presented more commonly with ApaI a allele (OR: 2.87; 95%CI: 1.39-5.91, P?0.05) and BsmI b allele (OR: 4.38; 95%CI: 2.30-8.33, P?0.05). TaqI t allele wasn't significantly differing among patients and controls (P?0.05). Aa+aa and Bb+bb genotypes were significantly higher among T1DM vs the controls (OR: 3.08;, 95%CI: 1.33-7.15, P?0.05 and OR: 9.33; 95%CI: 3.61-24.17, P?0.05respectively). Conclusion: ApaI and BsmI were associated with risk of T1DM development among Egyptian children. Low vitamin D status was frequently occurring among T1DM with significant improvement in the glycemic control of such children when adding vitamin D supplements to the standard insulin therapy.
Project description:Background:Type 1 diabetes mellitus (T1DM) causes the irreversible destruction of pancreatic beta cells. The Bacillus Calmette-Guerin (BCG) vaccine can modulate the immune response and decelerate disease progression. The aim of this study is to investigate the efficacy of the BCG vaccine for the treatment of T1DM. Objective:Six databases were systematically searched from inception to the end of August 2019. The randomized controlled trials (RCTs) that evaluated glycemic control in response to the BCG vaccine for T1DM were enrolled. The primary outcome was glycated hemoglobin (HbA1c) level, and secondary outcomes included fasting and stimulated C-peptide level, daily insulin dosage, and clinical remission. The revised Cochrane risk of bias tool was used for quality assessment, and meta-analyses were conducted to evaluate the efficacy of the BCG vaccine. Results:Four studies with a total of 198 subjects were included. The results of HbA1c and fasting C-peptide levels were extracted for further quantitative assessment. The pooled meta-analysis demonstrated no significant difference in HbA1c levels (mean difference [MD], -0.12; 95% confidence interval [CI], -0.53 to 0.30; I 2 = 56%) or fasting C-peptide levels (MD, -0.15; 95% CI, -0.35 to 0.06; I 2 = 0%) in the BCG intervention group as compared with that in the placebo group. Conclusions:There is no robust evidence to support the use of the BCG vaccine for the treatment of T1DM although the HbA1c levels tended to improve. Additional RCTs to assess the long-term effects of the BCG vaccine on glycemic control are warranted.
Project description:OBJECTIVE:Combined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain, and gastrointestinal side effects in T1DM patients. METHODS:We searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects. RESULTS:Nine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels [weighted mean difference (WMD) -0.17%, 95% confidence interval (CI) -0.24 to -0.11, P<0.001)], total daily insulin dose (WMD -5.53 IU/day, 95% CI -8.89 to -2.17, P=0.001) and body weight (WMD -3.24 kg, 95% CI -4.43 to -2.04, P<0.001). Incretins did not increase the risk of severe hypoglycaemia [odds ratio (OR) 0.83, 95% CI 0.60 to 1.16, P=0.287] but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20 to 5.45 P<0.001). CONCLUSIONS:In T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.
Project description:INTRODUCTION: Hyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury. RESULTS: Sixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I2 = 75%). Mortality was non-significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44). CONCLUSIONS: Intensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate.
Project description:Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) has already been proven an efficient treatment option for type 2 diabetes. This combination can effectively improve glycated hemoglobin levels, cause weight loss and reduce the dosage of insulin. In addition, it can also reduce the risk of hypoglycemia. Several randomized controlled trials have confirmed that this treatment may be just as effective for type 1 diabetes mellitus (T1DM) patients. The objective of this meta-analysis was to assess the effects and efficacy of the treatment on glycemic changes, weight loss and insulin dosage in type 1 diabetes mellitus patients.We searched Embase, PubMed and Cochrane for randomized controlled trials (no time restrictions) that investigated combined insulin and GLP-1 treatment. The main endpoints were measurements of glycated hemoglobin and changes in the weight and the dosage of insulin.In total, 1093 were studies identified, and 7 studies were included in our meta-analysis. GLP-1 agonist and insulin combination therapy led to greater reductions in HbA1c levels [P = 0.03; mean difference -0.21; 95% confidence intervals (CI) (-0.40, 0.02)] and weight [P < 0.05; -3.53 (-4.86, 2.19)] compared to control treatments. The combination therapy did not significantly influence the daily weight-adjusted total insulin dose [P = 0.05; -0.11 (-0.23, 0)], but it did reduce the daily weight-adjusted bolus insulin dose [P = 0.001; -0.06 (-0.1, 0.02)].Our meta-analysis supports the use of a combined therapeutic regimen of insulin and GLP-1RAs for treating patients with T1DM. Combination therapy with GLP-1 and insulin could achieve an ideal treatment effect on glycemic control, weight loss and bolus insulin dose in patients with T1DM.
Project description:INTRODUCTION:To evaluate in an Italian real-world setting the safety and effectiveness of insulin degludec 100 units/mL, given once daily in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) after switching from other basal insulins. METHODS:ReFLeCT was a multicenter, prospective, observational study conducted across seven European countries which involved adult patients whose physician planned to switch their medication from basal insulin to insulin degludec. The primary outcome was the change in the number of hypoglycemic episodes before and after the switch to insulin degludec. Results are expressed as 12-month follow-up/baseline incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). RESULTS:The Italian cohort of the ReFLect study comprised 148 patients with T1DM and 311 patients with T2DM. In patients with T1DM, the switch to insulin degludec was associated with significantly lower rates of overall (IRR?0.69, 95% CI 0.57-0.82), non-severe (IRR?0.72, 95% CI 0.60-0.85), and nocturnal hypoglycemia (IRR?0.46, 95% CI 0.31-0.69). Following the switch, hemoglobin A1c (HbA1c) levels decreased significantly by 0.35% (95% CI -?0.50 to ?-?0.20), with no significant changes in fasting plasma glucose (FPG) and basal insulin dose. Body weight increased by 0.83 kg (95% CI 0.16-1.50). In patients with T2DM, significant reductions in the rates of overall (IRR?0.40, 95% CI 0.29-0.55), non-severe (IRR?0.47, 95% CI 0.34-0.63), and nocturnal hypoglycemia (IRR?0.27, 95% CI 0.09-0.86) were documented. HbA1c and FPG decreased significantly by 0.45% (95% CI -?0.58 to?-?0.31) and 0.90 mmol/L (95% CI -?1.21 to?-?0.59], respectively, with no significant changes in basal insulin dose or body weight. Treatment satisfaction significantly improved in both diabetes types. CONCLUSION:In Italian routine clinical practice, switching from other basal insulins to insulin degludec reduced the total episodes of hypoglycemia and improved glycemic control and treatment satisfaction in patients with T1DM and T2DM. TRIAL REGISTRATION:ClinicalTrials.gov NCT02392117.
Project description:Potential benefits of carbohydrate counting for glycemic control in patients with type 1 diabetes mellitus (T1DM) remain inconclusive. Our aim is to systematically assess the efficacy of carbohydrate counting in patients with T1DM. We searched PubMed, Embase, Web of Science, Cochrane Library and the Chinese Biology Medicine (CBM) up to December 2015. Randomized controlled trials (RCTs) with at least 3 months follow-up that evaluated carbohydrate counting compared with usual or other diabetes dietary education in patients with T1DM were included. Overall meta-analysis identified a significant decrease in HbA1c concentration with carbohydrate counting versus other diabetes diet method or usual diabetes dietary education (SMD: -0.35, 95%CI: -0.65 to -0.05, P?=?0.023). Subgroup analysis restricted to trials which compared carbohydrate counting with usual diabetes dietary found a significant decrease in HbA1c in carbohydrate counting group (SMD: -0.68, 95%CI: -0.98 to -0.38, P?=?0.000), and a similar result has emerged from six studies in adults (SMD: -0.40, 95%CI: -0.78 to -0.02, P?=?0.037). Carbohydrate counting may confer positive impact on glucose control. Larger clinical trials are warranted to validate this positive impact.