The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

Population attributable fractions of modifiable risk factors for microvascular complications of type 2 diabetes in China: An analysis using national cross-sectional data.

AIM: To assess the population attributable fractions (PAFs) for modifiable risk factors for microvascular complications of type 2 diabetes (T2D) in China. MATERIALS AND METHODS: Data collected from the China National HbA1c Surveillance System from 2009 to 2013 were used. The PAFs of four predefined risk factors, including an HbA1c of 7% or higher, blood pressure (BP) of 130/80 mmHg or higher, low-density lipoprotein-cholesterol (LDL-C) of 1.8 mmol/L or higher and body mass index (BMI) of 24 kg/m2 or higher, were calculated for diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD) and distal symmetric polyneuropathy (DSPN). PAFs were further adjusted for age, sex and duration of diabetes. RESULTS: In total, there were 998 379 participants with T2D from nationwide mainland China included in this analysis. As for DR, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher conferred PAFs of 16.2%, 15.2%, 5.8% and 2.8%, respectively. In the case of DKD, BP of 130/80 mmHg or higher provided a PAF of 25.2%, followed by an HbA1c of 7% or higher (13.9%), BMI of 24 kg/m2 or higher (8.0%) and LDL-C of 1.8 mmol/L or higher (5.6%). As for DSPN, an HbA1c of 7% or higher, BP of 130/80 mmHg or higher, LDL-C of 1.8 mmol/L or higher and BMI of 24 kg/m2 or higher contributed to PAFs of 14.2%, 11.7%, 5.9% and 5.8%, respectively. PAFs for diabetic microvascular complications were mildly to moderately reduced after adjusting for participants' age, sex and duration of diabetes. CONCLUSIONS: Suboptimal glycaemic and BP control were the main contributors to diabetic microvascular complications, while the PAFs of unmet LDL-C and BMI control targets were quite limited for diabetic microvascular complications. In addition to glycaemic control, BP control should be especially prioritized in the management of diabetic microvascular complications to further reduce the disease burden.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. METHODS: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. RESULTS: A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15-0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05-0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10-0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. CONCLUSIONS: The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

The Biological Disease-Modifying Antirheumatic Drugs and the Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and the risk of cardiovascular events in patients with systemic inflammatory conditions. METHODS: Eligible cohort studies or randomized controlled trials (RCTs) from inception to January 2021 were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for cardiovascular outcomes were calculated in the fixed- and random-effects model accordingly. Associated factors with risks of cardiovascular events were also studied in sensitivity analyses and metaregression analyses. RESULTS: Compared with non-bDMARD users, the risks of myocardial infarction (MI) (OR = 0.74, 95% CI, 0.63 to 0.87), heart failure (OR = 0.84, 95% CI, 0.74 to 0.95), cardiovascular (CV) death (OR = 0.62, 95% CI, 0.40 to 0.95), all-cause mortality (OR = 0.64, 95% CI, 0.58 to 0.70), and 3P-MACE (composite endpoint of MI, stroke, and CV death) (OR = 0.69, 95% CI, 0.53 to 0.89) were significantly reduced in bDMARD users, which were mainly driven by the risk reduction in patients with rheumatoid arthritis (RA). TNF-α inhibitors exhibited consistent benefits in reducing the risks of MI, heart failure, CV death, all-cause mortality, and 3P-MACE. Moreover, the risks of heart failure, CV death, all-cause mortality, and 3P-MACE were significantly reduced in bDMARD users with follow-up over one year. CONCLUSIONS: The use of bDMARDs might be associated with the reduced risks of CV events, especially in patients with RA. The CV events might be less frequent in bDMARD users with TNF-α inhibitors or follow-up over one year. More investigations are needed to validate conclusions.

LAG3 (CD223) and autoimmunity: Emerging evidence.

Immune checkpoint molecules play pivotal roles in maintaining the immune homeostasis. Targeting these molecules, such as the classical Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell Death Protein 1 (PD1), achieves great success in treating cancers. However, not all the patients respond well. This urges the immunologists to identify novel immune checkpoint molecules. Lymphocyte activation gene-3 (LAG3; CD223) is a newly identified inhibitory receptor. It is expressed on a variety of immune cells, including CD4+ T cells, CD8+ T cells, Tregs, B cells, and NK cells. Its unique intracellular domains, signaling patterns as well as the striking synergy observed in its targeted therapy with anti-PD1 indicate the important role of LAG3 in maintaining immune tolerance. Currently, a variety of agents targeting LAG3 are in clinical trials, revealing great perspectives in the future immunotherapy. In this review, we briefly summarize the studies on LAG3, including its structure, isoforms, ligands, signaling, function, roles in multiple diseases, as well as the latest targeted therapeutic advances, with particular concern on the potential association of LAG3 with autoimmune diseases.

Weight reduction and the risk of gallbladder and biliary disease: A systematic review and meta-analysis of randomized clinical trials.

In this meta-analysis, we aim to evaluate the risk of gallbladder and biliary disease of weight management strategies and investigate the association between weight reduction and risk of gallbladder or biliary disease. Randomized controlled trials (RCTs) with a duration of at least 12 weeks that compare antiobesity medications (AOMs) with placebo or bariatric surgery with less intensive weight management strategy were concluded. Weight management strategy was associated with a significant increased risk of gallbladder or biliary disease (OR 1.361, 95% CI 1.147 to 1.614, P < 0.001, I2 = 3.5%), cholelithiasis, cholecystitis, and cholecystectomy compared with placebo or controls. The increased risk of gallbladder or biliary disease was observed both in pharmacotherapies subgroup and bariatric surgery subgroup. With regards of specific pharmacotherapies, an increased risk of gallbladder or biliary disease was observed in trials with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatments. In addition, trials with indication of obesity and overweight treatment and trials with higher doses showed significant higher risk of gallbladder or biliary disease compared with placebo or controls. In conclusion, weight management strategy was associated with an increased risk of gallbladder or biliary disease when compared with placebo or control groups.

Diminished LAG3+ B cells correlate with exacerbated rheumatoid arthritis.

BACKGROUND: Lymphocyte activation gene-3 (LAG3) positive B cells have been identified as a novel regulatory B cell subset, while the role of LAG3+ B cells in the pathogenesis of rheumatoid arthritis (RA) remains elusive. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) from RA, osteoarthritis (OA) patients and healthy volunteers were collected for flow cytometry staining of LAG3+ B cells. Their correlation with RA patient clinical and immunological features were analyzed. Moreover, the frequencies of LAG3+ B cells in collagen-induced arthritis (CIA) mice and naive mice were also detected. RESULTS: A significant decrease of LAG3+ B cells was observed in RA patients as compared with healthy individuals and OA patients. Notably, the frequencies of LAG3+ B cells were negatively correlated with tender joint count (r = -0.4301, p = .0157) and DAS28-ESR (r = -0.4018, p = .025) in RA patients. In CIA mice, LAG3+ B cell frequencies were also decreased and negatively correlated with the CIA arthritis score. CONCLUSIONS: Impairment of LAG3+ B cells potentially contributes to RA development. Reconstituting LAG3+ B cells might provide novel therapeutic strategies for the persistent disease.Key messagesLAG3+ B cells have been identified as a novel regulatory B cell subset. However, its role in the pathogenesis of RA remains unknown.This study revealed the decreased frequency of LAG3+ B cells in RA patients. Notably, LAG3+ B cells were negatively correlated with RA disease activity including the tender joint count and DAS28-ESR.In CIA mice, LAG3+ B cell frequencies were also decreased and negatively correlated with the CIA arthritis score.Reconstitution of LAG3+ B cells might provide novel therapeutic strategies for disease perpetuation.

Trends in baseline HbA1c and body-mass index in randomised placebo-controlled trials of type 2 diabetes from 1987 to 2022: a systematic review and meta-analysis.

Background: Curbing or reversing high glycated hemoglobin (HbA1c) and body mass index (BMI) are two essential parts in the clinical management of type 2 diabetes (T2D). We delineated the changing patterns of the baseline HbA1c and BMI in patients with T2D from placebo-controlled randomised trials to reflect the unmet clinical needs. Methods: PubMed, Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception to December 19, 2022. Placebo-controlled trials of T2D with reports of baseline HbA1c and BMI were included, of which summary data from published reports were extracted. Pooled effect sizes of baseline HbA1c and BMI of from studies published in the same year were computed in Random-effects model due to the high level of heterogeneity among studies. The main outcome was correlations between the pooled baseline HbA1c, the pooled baseline BMI, and study years. This study was registered in PROSPERO as CRD42022350482. Findings: We identified 6102 studies, of which 427 placebo-controlled trials with 261, 462 participants were finally included in the study. Baseline HbA1c level declined with time (Rs = -0.665, P ï¼œ 0.0001, I2 = 99.4%). Baseline BMI increased over the past 35 years (R = 0.464, P = 0.0074, I2 = 99.4%), rising by around 0.70 kg/m2 per decade. Patients with BMI ≤25.0 kg/m2 dropped substantially from the half in 1996 to none in 2022. Patients with BMI ranging from 25 kg/m2 to 30 kg/m2 stabilized at 30-40% since 2000. Interpretation: A substantial decline in baseline HbA1c levels and a constant increase in baseline BMI levels was found in placebo-controlled trials through the past 35 years, which indicated the improvement in glycemic control and the urgency for the management of obesity in T2D. Funding: National Natural Science Foundation of China (No.81970698), Beijing Natural Science Foundation (No.7202216) and National Natural Science Foundation of China (No.81970708).

Anti-inflammatory therapies were associated with reduced risk of myocardial infarction in patients with established cardiovascular disease or high cardiovascular risks: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: We aimed to evaluate the association between anti-inflammatory therapies and the incidence of cardiovascular events in patients with established cardiovascular disease (CVD) or high cardiovascular risks. METHODS: Literature retrieval was conducted in PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov website from the inception to December 2022. Randomized controlled trials comparing anti-inflammatory therapies with placebo in patients with established CVD or high cardiovascular risks were included. The results of the meta-analysis were computed as the risk ratio (RR) with 95% confidence interval (CI). RESULTS: Compared with placebo, anti-inflammatory therapies were associated with decreased incidence of myocardial infarction (MI) (RR = 0.93, 95% CI, 0.88 to 0.98), which was mainly driven by therapies targeting central IL-6 signaling pathway (RR = 0.83, 95% CI, 0.74 to 0.93). IL-1 inhibitors treatment was associated with reduced risks of heart failure (RR = 0.38, 95% CI, 0.18 to 0.80) while lower incidence of stroke was observed in patients with colchicine treatment (RR = 0.47, 95% CI, 0.28 to 0.77). MI events were less frequent in patients over 65 years of age (RR = 0.90, 95% CI, 0.83 to 0.98) or with follow-up duration over 1 year (RR = 0.90, 95% CI, 0.85 to 0.96) when comparing anti-inflammatory therapies with placebo. CONCLUSIONS: Anti-inflammatory therapies, especially those targeting the central IL-6 signaling pathway, may serve as promising treating strategies to ameliorate the risk of MI. IL-1 inhibitor and colchicine were associated with decreased risks of heart failure and stroke, respectively. MI risk reduction by anti-inflammatory therapies seemed to be more prominent in older patients with long follow-up duration.

Baseline eGFR, albuminuria and renal outcomes in patients with SGLT2 inhibitor treatment: an updated meta-analysis.

AIMS: To elucidate the association between baseline renal characteristics and the disparities in renal outcomes among patients with SGLT2i treatment. METHODS: Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were searched from inception to November 2022. Event-driven randomized controlled trials of SGLT2i with reports of renal outcomes were included. Sensitivity analyses of prespecified eGFR and UACR subgroups were conducted. RESULTS: Generally, compared with placebo, the use of SGLT2i was associated with improved renal prognosis (HR = 0.64, 95%CI 0.59-0.70). The magnitude of risk reductions in composite renal outcomes between SGLT2i versus placebo was comparable among different eGFR stratifications (normal renal function: HR = 0.49, 95%CI 0.31-0.79; mild renal impairment: HR = 0.57, 95%CI 0.48-0.68; moderate renal impairment: HR = 0.70, 95%CI 0.63-0.78; severe renal impairment: HR = 0.72, 95%CI 0.62-0.84; P for subgroup difference = 0.09). However, renal benefits seemd to be more prominent in normal to mildly increased albuminuria stratum (HR = 0.51, 95%CI 0.39-0.66) and severely increased albuminuria stratum (HR = 0.57, 95%CI 0.47-0.68), when compared with moderately increased albuminuria stratum (HR = 0.79, 95%CI 0.65-0.96; P for subgroup difference = 0.01). CONCLUSIONS: Generally, the use of SGLT2i was consistently associated with decreased risk of renal events in all prespecified eGFR and albuminuria spectrums, even in patients with substantial renal impairment. The renal benefits of SGLT2i seemed to be independent of baseline eGFR, while the risk reduction in renal events was more profound among patients with mildly increased albuminuria or severely increased albuminuria.

The correlations between steady-state concentration, duration of action and molecular weight of GLP-1RAs and their efficacy and gastrointestinal side effects in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: To assess the influence of steady-state concentration, duration of action and molecular weight of glucagon-like peptide-1 receptor (GLP-1RA) on efficacy and gastrointestinal (GI) side effects in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to April 2022. Randomized controlled trials (RCTs) comparing GLP-1RA versus non-GLP-1RA agents in patients with T2DM were included. Sensitivity analyses on steady-state concentration, duration of action and molecular weight of GLP-1RA were conducted. RESULTS: 113 RCTs were included. Greater HbA1c reduction between GLP-1RA users versus non-GLP-1RA users was observed in the high-steady-state-concentration stratum and long-acting stratum compared with the low-steady-state-concentration stratum (Psubgroup difference = 0.0004) and short-acting stratum (Psubgroup difference<0.0001). The risk of GI adverse events in GLP-1RA users versus non-GLP-1RA users was decreased in the high-steady-state-concentration stratum, long-acting stratum and heavy-molecular-weight stratum compared with low-steady-state-concentration stratum (Psubgroup difference<0.0001), short-acting stratum (Psubgroup difference = 0.002) and light-molecular-weight stratum (Psubgroup difference = 0.0008). CONCLUSION: GLP-1RA with high steady-state concentration and long duration of action showed better hypoglycemic effect. GLP-1RA with high steady-state concentration, long duration of action and heavy molecular weight was associated with lower risk of GI adverse events.

Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes?

IMPORTANCE: Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. OBJECTIVE: To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). DATA SOURCES: PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. STUDY SELECTION: Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. DATA EXTRACTION AND SYNTHESIS: Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. MAIN OUTCOMES AND MEASURES: Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. RESULTS: In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. CONCLUSIONS AND RELEVANCE: GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.

Indirect comparison of efficacy and safety of chiglitazar and thiazolidinedione in patients with type 2 diabetes: A meta-analysis.

BACKGROUND: Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors (PPAR)-α, δ and γ, and has therapeutic potential for type 2 diabetes (T2D). However, to date, no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γ agonist thiazolidinediones (TZDs). A meta-analysis concerning this topic is therefore required. AIM: To compare the efficacy and safety of chiglitazar and TZD in patients with T2D. METHODS: PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022. Randomized controlled trials (RCTs) of chiglitazar or TZD vs placebo in patients with T2D were included. Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest. RESULTS: We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo. For efficacy endpoints, the augmented dose of chig-litazar resulted in greater reductions in hemoglobin (Hb)A1c [weighted mean difference (WMD) = -0.15%, 95% confidence interval (CI): -0.27 to -0.04%], triglycerides (WMD = -0.17 mmol/L, 95%CI: -0.24 to -0.11 mmol/L) and alanine aminotransferase (WMD = -5.25 U/L, 95%CI: -8.50 to -1.99 U/L), and a greater increase in homeostasis model assessment-ß (HOMA-ß) (WMD = 17.75, 95%CI: 10.73-24.77) when compared with TZD treatment. For safety endpoints, the risks of hypoglycemia, edema, bone fractures, upper respiratory tract infection, urinary tract infection, and weight gain were all comparable between the augmented dose of chiglitazar and TZD. In patients with baseline HbA1c ≥ 8.5%, body mass index ≥ 30 kg/m2 or diabetes duration < 10 years, the HbA1c reduction and HOMA-ß increase were more conspicuous for the augmented dose of chiglitazar compared with TZD. CONCLUSION: Augmented dose of chiglitazar, a pan-activator of PPARs, may serve as an antidiabetic agent with preferable glycemic and lipid control, better ß-cell function preserving capacity, and does not increase the risk of safety concerns when compared with TZD.

Disparities in efficacy and safety of sodium-glucose cotransporter 2 inhibitor among patients with different extents of renal dysfunction: A systematic review and meta-analysis of randomized controlled trials.

Background: The pleiotropic efficacy of SGLT2is in patients with different eGFR levels has not been well-understood. This systematic review and meta-analysis assessed the disparities in the efficacy and safety of SGLT2i treatment across stratified renal function. Methods: We searched four databases from inception to December 2021. We included randomized controlled trials (RCTs) with reported baseline eGFR levels and absolute changes from baseline in at least one of the following outcomes: HbA1c, body weight, blood pressure, and eGFR. Continuous outcomes were evaluated as the weighted mean differences (WMDs) and 95% confidence intervals (CIs). Categorical outcomes were evaluated as odds ratios (ORs) and accompanying 95% CIs. Results: In total, 86 eligible RCTs were included. SGLT2is produces a substantial benefit in glycemic control, weight control, and blood pressure control even in patients with impaired renal function. HbA1c and weight reductions observed in SGLT2i users were generally parallel with the renal function levels, although there was an augmented weight reduction in severe renal dysfunction stratum [HbA1c: -0.49% (-0.58 to -0.39%) for normal renal function, -0.58% (-0.66 to -0.50%) for mild renal function impairment, -0.22% (-0.35 to -0.09%) for moderate renal function impairment, and -0.13% (-0.67 to 0.42%) for severe renal function impairment (p < 0.001 for subgroup differences); weight: -2.12 kg (-2.66 to -1.59 kg) for normal renal function, -2.06 kg (-2.31 to -1.82 kg) for mild renal function impairment; -1.23 kg (-1.59 to -0.86 kg) for moderate renal function impairment; -1.88 kg (-3.04 to -0.72 kg) for severe renal function impairment (p = 0.002 for subgroup differences)]. However, the blood pressure reduction observed in SGLT2i users was independent of renal function. When compared with the placebo, the occurrence of hypoglycemia was more frequent in patients with favorable renal function rather than in those with substantial renal dysfunction. Conclusion: The HbA1c and body weight reductions observed in SGLT2i users were generally parallel with their baseline eGFR levels, while blood pressure reductions in SGLT2i users were independent of their baseline eGFR levels. Consistently, when compared with the placebo, hypoglycemia was more frequent in patients with favorable renal function, where the HbA1c reduction was profound.

The association between the use of sodium glucose cotransporter 2 inhibitor and the risk of diabetic retinopathy and other eye disorders: a systematic review and meta-analysis.

OBJECTIVE: To assess the association between the use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and the incidence of diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS: PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov were searched from inception to October 2021. Randomized controlled trials (RCTs) with reports of incidence of DR and other eye disorders between SGLT2i and non-SGLT2i users with type 2 diabetes mellitus were included. RESULTS: In general, the incidences of DR were comparable between SGLT2i and non-SGLT2i users (OR = 0.80, 95%CI 0.61 to 1.06, P = 0.12). However, compared with non-SGLT2i users, the incidence of DR was significantly reduced in SGLT2i users with diabetes duration less than 10 years (OR = 0.32, 95%CI 0.13 to 0.76, P = 0.01). Weight reduction in SGLT2i users was associated with a decreased risk of retinal detachment. Moreover, longer study duration was associated with lower incidence of cataract and retinal vasculopathy in SGLT2i users. CONCLUSIONS: In general, the use of SGLT2i was not associated with the incidence of DR. However, a reduced risk of DR was observed in SGLT2i users with diabetes duration less than 10 years. An early initiation of SGLT2i might be more likely to provide with ocular benefits.

Dipeptidyl peptidase 4-inhibitor treatment was associated with a reduced incidence of neoplasm in patients with type 2 diabetes: a meta-analysis of 115 randomized controlled trials with 121961 participants.

OBJECTIVE: To evaluate the association between dipeptidyl peptidase 4 inhibitor (DPP-4i) and the incidence of neoplasm in patients with type 2 diabetes (T2D). METHODS: Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov website were searched from May 2002 to December 2021. Randomized controlled trials with reports of neoplasm events which compared DPP-4i versus non-DPP-4i users. RESULTS: Generally, DPP-4i was associated with a decreased incidence of overall neoplasm events in patients with T2D when compared with non-DPP-4i agents (OR = 0.91, 95%CI, 0.8 to 0.97). Moreover, the incidence of rectal neoplasm, especially rectal malignant neoplasm, and the incidence of skin neoplasm were significantly decreased in DPP-4i users. The overall neoplasm events were less frequent in DPP-4i users who were elderly, or male, or obese, or Caucasian, or with over 10 years of diabetes, or with follow-up duration over 52 weeks. CONCLUSIONS: DPP-4i was associated with decreased risks of overall neoplasm, rectal neoplasm, rectal malignant neoplasm and skin neoplasm in patients with T2D. The overall neoplasm events were less frequent in patient with DPP-4i treatment who were elderly, male, obese, Caucasian, with long diabetes durations and with long follow-up durations. Further investigations are still required. META-ANALYSIS REGISTRATION: CRD42021273627.

The Urinary Glucose Excretion by Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis.

Objective: Previous evidence suggested that sodium-glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta-analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function. Methods: We conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes. Results: In total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences]. Conclusions: SGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.

SGLT2i increased the plasma fasting glucagon level in patients with diabetes: A meta-analysis.

Increased glucagon level was hypothesized to participate in the ketoacidosis associated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) treatment. However, the effect of SGLT2i on glucagon remains controversial. Hence, we conducted this meta-analysis to assess the overall effect of SGLT2i treatment on plasma fasting glucagon level in patients with diabetes. PubMed/MEDLINE, Embase, and Cochrane databases were searched for studies published before August 2020. Clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of glucagon changes before and after SGLT2i intervention were included. Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly. In total, ten trials were included in this meta-analysis. Compared with the non-SGLT2i treatment group, SGLT2i treatment resulted in increased plasma fasting glucagon levels with significance (WMD, 8.35 pg/ml; 95% CI, 2.17-14.54 pg/ml, P＜0.01) in patients with diabetes mellitus. Besides, when compared with non-SGLT2i control group, the insulin level decreased (WMD, -2.78 µU/ml; 95% CI, -5.11 to -0.46 µU/ml, P = 0.02) and ketone body level increased (WMD, 0.17 mmol/l; 95% CI, 0.09-0.25 mmol/l, P＜0.01) in patients with type 2 diabetes. In conclusion, our result indicated SGLT2i intervention would increase the plasma fasting glucagon level in patients with diabetes mellitus. The increase in plasma fasting glucagon level may be associated with reduced insulin level. The increased glucagon-insulin ratio after the use of SGLT2i may make diabetic patients susceptible to ketosis.

The Effect of Physical Activity on Glycemic Variability in Patients With Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Purpose: The effect of physical activity on glycemic variability remains controversial. This meta-analysis aimed to assess the overall effect of physical activity treatment on glycemic variability in patients with diabetes. Methods: PubMed/MEDLINE, Embase, and Cochrane databases were searched for clinical trials that conducted in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with reports of the mean amplitude of glycemic excursion (MAGE), time in range (TIR), time above range (TAR), or time below range (TBR). Eligible trials were analyzed by fixed-effect model, random effect model, and meta-regression analysis accordingly. Results: In total, thirteen trials were included. Compared with the control group, physical activity intervention was significantly associated with increased TIR (WMDs, 4.17%; 95% CI, 1.11 to 7.23%, P<0.01), decreased MAGE (WMDs, -0.68 mmol/L; 95% CI, -1.01 to -0.36 mmol/L, P<0.01) and decreased TAR (WMDs, -3.54%; 95% CI, -5.21 to -1.88%, P<0.01) in patients with diabetes, but showed insignificant effects on TBR. Patients with higher baseline BMI levels was associated with a greater decrease in MAGE (ß=-0.392, 95% CI: -0.710, -0.074), and patients with lower baseline HbA1c levels was associated with a greater increase in TBR during physical activities (ß=-0.903, 95% CI: -1.550, -0.255). Conclusion: Physical activity was associated with significantly decreased glycemic variability in patients with diabetes. Patients with higher BMI might benefit more from physical activity therapy in terms of a lower MAGE. Hypoglycemia associated with physical activity treatment still warranted caution, especially in patients with intensive glycemic control. Systematic Review Registration: PROSPERO [CRD42021259807].