-
1.
Dietary calcium intake in relation to type-2 diabetes and hyperglycemia in adults: A systematic review and dose-response meta-analysis of epidemiologic studies.
Hajhashemy, Z, Rouhani, P, Saneei, P
Scientific reports. 2022;(1):1050
Abstract
Several epidemiological studies investigated the relation of Ca intake with type 2 diabetes mellitus (T2DM), but there were inconsistencies in their findings. So, we conducted a systematic review and dose-response meta-analysis to quantify the relation of dietary Ca intake with the risk of T2DM/hyperglycemia in adults. A systematic search was conducted up to May 2021, in MEDLINE (Pubmed), Web of Science (WOS), Scopus electronic databases and Google Scholar, for epidemiological studies that investigated the relation of dietary Ca intake (as the exposure) and T2DM/hyperglycemia (as the outcome) in adults, without restriction in publication date and language. Finally, 8 cohort and 9 cross-sectional studies were included in the analysis. The body of evidence was assessed by the GRADE approach. Combining effect sizes from prospective cohort studies included 255,744 general adult population illustrated that highest level of dietary Ca intake, compared to lowest category, was related to an 18% reduced risk of T2DM (RR: 0.82; 95% CI 0.74-0.92). Based on linear dose-response analysis (including 255,744 healthy individuals and 13,531 patients with T2DM), each 300, 600 and 1000 mg/day increment in dietary Ca intake was respectively associated to 7, 14 and 23% reduced risk of T2DM. There was a steeper reduction in risk of T2DM when dietary Ca intake increased from low levels to 750 mg/day. Nevertheless, meta-analysis of cross-sectional studies revealed an inverse significant association between dietary Ca intake and T2DM/hyperglycemia only in the female population (OR: 0.66; 95% CI 0.50-0.88). This meta-analysis illustrated an inverse association between dietary Ca intake and risk of T2DM in general adult populations in prospective cohort studies, in a dose-response manner. It seems that increasing dietary Ca intake from low levels to around 750 mg/day was inversely related to risk of T2DM. In cross-sectional studies, an inverse relation between dietary Ca intake and T2DM/hyperglycemia was found only in females.
-
2.
Recessive Genome-Wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes.
O'Connor, MJ, Schroeder, P, Huerta-Chagoya, A, Cortés-Sánchez, P, Bonàs-Guarch, S, Guindo-Martínez, M, Cole, JB, Kaur, V, Torrents, D, Veerapen, K, et al
Diabetes. 2022;(3):554-565
-
-
Free full text
-
Abstract
Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 case subjects and 279,507 control subjects from 7 European-ancestry cohorts, including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five variants had minor allele frequency of <5% and were each associated with more than a doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19; P = 1 × 10-16) and a stronger effect in men than in women (for interaction, P = 7 × 10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL cholesterol and a 20% increase in triglycerides; colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared with GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.
-
3.
Anthropometric and adiposity indicators and risk of type 2 diabetes: systematic review and dose-response meta-analysis of cohort studies.
Jayedi, A, Soltani, S, Motlagh, SZ, Emadi, A, Shahinfar, H, Moosavi, H, Shab-Bidar, S
BMJ (Clinical research ed.). 2022;:e067516
Abstract
OBJECTIVE To present a comprehensive review of the association between measures of body weight, waist, and fat, and different ratios of these measures, and the risk of type 2 diabetes. DESIGN Systematic review and dose-response meta-analysis of cohort studies. DATA SOURCES PubMed, Scopus, and Web of Science up to 1 May 2021. REVIEW METHODS Cohort studies looking at the association between general or central adiposity and body fat content and the risk of type 2 diabetes in the general adult population were included. Two of the authors extracted the data in duplicate. Random effects dose-response meta-analyses were performed to estimate the degree of the associations. Curvilinear associations were modelled with a one stage weighted mixed effects meta-analysis. RESULTS 216 cohort studies with 2.3 million individuals with type 2 diabetes among 26 million participants were identified. Relative risks were 1.72 (95% confidence interval 1.65 to 1.81; n=182 studies) for an increase in body mass index of 5 units, 1.61 (1.52 to 1.70; n=78) for a 10 cm larger waist circumference, 1.63 (1.50 to 1.78; n=34) for an increase in waist-to-hip ratio of 0.1 units, 1.73 (1.51 to 1.98; n=25) for an increase in waist-to-height ratio of 0.1 units, 1.42 (1.27 to 1.58; n=9) for an increase in visceral adiposity index of 1 unit, 2.05 (1.41 to 2.98; n=6) for a 10% higher percentage body fat, 1.09 (1.05 to 1.13, n=5) for an increase in body shape index of 0.005 units, 2.55 (1.59 to 4.10, n=4) for a 10% higher body adiposity index, and 1.11 (0.98 to 1.27; n=14) for a 10 cm larger hip circumference. A strong positive linear association was found between body mass index and the risk of type 2 diabetes. Positive linear or monotonic associations were also found in all regions and ethnicities, without marked deviation from linearity at a specific cut-off value. Indices of central fatness, independent of overall adiposity, also had positive linear or monotonic associations with the risk of type 2 diabetes. Positive linear or monotonic associations were also found for total and visceral fat mass, although the number of studies was small. CONCLUSIONS A higher body mass index was associated with a greater risk of developing type 2 diabetes. A larger waist circumference, independent of overall adiposity, was strongly and linearly associated with the risk of type 2 diabetes. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021255338.
-
4.
Regional variation of effects of new antidiabetic medications in cardiovascular outcome trials.
Cotter, G, Davison, BA, Edwards, C, Senger, S, Teerlink, JR, Zannad, F, Nielsen, OW, Metra, M, Mebazaa, A, Chioncel, O, et al
American heart journal. 2021;:73-80
Abstract
BACKGROUND In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. METHODS We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. RESULTS The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). CONCLUSION The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.
-
5.
Tolerability and Efficacy of Ipragliflozin in The Management of Inadequately Controlled Type 2 Diabetes mellitus: A Systematic Review and Meta-analysis.
Elgebaly, A, Abdelazeim, N, Abdelazeim, B, El Ashal, G, Mattar, O, Namous, L, Nasreldin, N
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2021;(1):56-72
Abstract
AIM: Ipragliflozin is a new antidiabetic agent that works through enhancing renal glucose excretion. We aim to synthesize evidence from published randomized controlled trials (RCTs) on the safety and efficacy of ipragliflozin in the management of type 2 diabetes mellitus (T2DM). METHODS We searched PubMed, Scopus, Web of Science, and Cochrane Central register of clinical trials using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup and sensitivity analyses were conducted. RESULTS We included 13 RCTs (N=2535 patients) in the final analysis. The overall effect estimates favoured ipragliflozin 50mg monotherapy group over placebo in terms of: HbA1c (Standardized mean difference (SMD)=-1.20%, 95% Confidence interval (95% CI)=[-1.47, -0.93]; p<0.001), fasting plasma glucose (SMD=-1.30 mg/dL, 95% CI [-1.93, -0.67]; p<0.001), fasting serum insulin (SMD=-1.64 μU/mL, 95% CI [-2.70, -0.59]; p=0.002), and body weight (SMD=-0.85 kg, 95% CI [-1.19, -0.51]; p<0.001). Similarly, better glycemic control and significant body weight reduction compared to placebo were attained in ipragliflozin 50 mg combination with metformin, insulin with/without dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone. Ipragliflozin, either alone or in combination, exhibits acceptable safety profile. CONCLUSION The presented meta-analysis provides class one evidence that ipragliflozin is safe and effective in the management of T2DM either as monotherapy or an add-on.
-
6.
Adding Sodium-Glucose Co-Transporter 2 Inhibitors to Sulfonylureas and Risk of Hypoglycemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Jiang, M, Liu, Q, Jiang, T, Nizigiyimana, P, Lei, M
Frontiers in endocrinology. 2021;:713192
Abstract
BACKGROUND Hypoglycemia is an important event that could be related to increased mortality in patients with diabetes. The risk of hypoglycemia is not clearly illustrated to increase when Sodiumglucose co-transporter 2 (SGLT-2) inhibitors are used concomitantly with sulfonylureas. The present study will assess the risk of hypoglycemia associated with the concomitant use of SGLT-2 inhibitors and sulfonylureas compared with placebo and sulfonylureas. METHOD We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov and identified the randomized trials comparing SGLT-2 inhibitors with placebo for type 2 diabetes treated with sulfonylureas. The risk of bias in each trial was assessed using the Cochrane tool. The risk ratio of hypoglycemia was measured using the Mantel Haenszel method. We also performed subgroup analysis to examine the dosage effects. The number needed to harm (NNH) was measured according to the duration of intervention. RESULTS A total of 12 studies, including 3761 participants, were enrolled in our systematic review and meta-analysis. The risk ratio of hypoglycemia was 1.67 (95% CI 1.42 to 1.97). The NNH was 13 (95% CI 9 to 21) for a treatment duration of 24 weeks or less, 11 (8 to 18) for 25 to 48 weeks, and 7 (5 to 10) for more than 48 weeks. Subgroup analysis showed that no difference was found between higher and lower doses of SGLT-2 inhibitors. The risk ratio related to lower dose SGLT-2 inhibitors was 1.56 (95% CI 1.30 to 1.88), and the risk ratio related to higher dose SGLT-2 inhibitors was 1.70 (95% CI 1.42 to 2.04). CONCLUSIONS The risk of hypoglycemia was significantly increased in subjects treated with SGLT-2 inhibitors compared with placebo. Addition of SGLT-2 inhibitors to sulfonylureas would lead to one more case of hypoglycemia in every 13 patients with a treatment duration less than 24 weeks. This suggests that a decrease in sulfonylureas dose may be an important recommendation when adding SGLT-2 inhibitors to sulfonylureas.
-
7.
Water intake and risk of type 2 diabetes: A systematic review and meta-analysis of observational studies.
Janbozorgi, N, Allipour, R, Djafarian, K, Shab-Bidar, S, Badeli, M, Safabakhsh, M
Diabetes & metabolic syndrome. 2021;(4):102156
Abstract
BACKGROUND AND AIMS The association of water intake with type 2 diabetes mellitus (T2DM) is still unclear. Therefore, the aim of this systematic review and meta-analysis was to synthesize the knowledge about the relationship between water intake and the risk of T2DM. METHODS We conducted a systematic search in PubMed and Scopus up to June 2018 for observational studies. Risk ratios (RR)s and 95% confidence intervals (95% CI)s were calculated and fixed effects models were used. RESULTS Overall, 6 studies were included in the meta-analyses. There was an inverse relationship between water intake and risk of T2DM (RR: 0.94; 95% CI: 0.91-0.97, P < 0.001) with low heterogeneity (I2 = 24%, P = 0.24). CONCLUSION Our findings indicated that the intake of water was correlated with reduced risk of type 2 diabetes in women and men. These results support the current recommendations of water intake as an inseparable part of a diet with the lowest risk of diabetes mellitus.
-
8.
Clinical Adverse Events Associated with Sodium-Glucose Cotransporter 2 Inhibitors: A Meta-Analysis Involving 10 Randomized Clinical Trials and 71 553 Individuals.
Lin, DS, Lee, JK, Chen, WJ
The Journal of clinical endocrinology and metabolism. 2021;(7):2133-2145
Abstract
CONTEXT SGLT2is are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined adverse events (AEs) associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. OBJECTIVE This meta-analysis aimed to investigate the occurrence of various AEs associated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) and to examine the level of risk of AEs in patients with different underlying diseases. METHODS We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library on January 31, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose vs low dose). RESULTS Our analysis included 10 eligible studies with a total of 71 553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% CI 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72-0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs 0.96, P = .066). CONCLUSION The use of SGLT2is is generally safe. SGLT2is may be associated with increased risks of genital infection but are protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2is lies in the identification of high-risk populations and close surveillance of patients after treatment.
-
9.
Sodium-glucose cotransporter inhibitors as add-on therapy in addition to insulin for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials.
Zou, H, Liu, L, Guo, J, Wang, H, Liu, S, Xing, Y, Deng, C, Xiao, Y, Zhou, Z
Journal of diabetes investigation. 2021;(4):546-556
Abstract
AIMS/INTRODUCTION Several clinical trials reported the effects of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes patients. This meta-analysis aimed to assess the efficacy and safety of SGLT inhibitors in type 1 diabetes patients. MATERIALS AND METHODS Relevant studies were identified in the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure and Wan Fang databases through 1 April 2020. Differences were expressed as the 95% confidence interval (CI) or weighted mean difference (WMD) for continuous outcomes, and risk ratio (RR) for discontinuous outcomes. RESULTS A total of 13 RCTs with 7,962 cases were included. SGLT inhibitors reduced the fasting plasma glucose level (WMD -1.320 mmol/L, 95% CI -1.609 to -1.031, P < 0.001), glycated hemoglobin level (WMD -0.386%, 95% CI -0.431 to -0.342, P < 0.001) and daily total insulin dose (WMD -5.403, 95% CI -7.218 to -3.859, P < 0.001). However, higher risks of diabetic ketoacidosis (RR 5.042, 95% CI 3.160-8.046, P < 0.001), urinary tract infections (RR 1.259, 95% CI 1.034-1.533,P = 0.022) and genital infections (RR 2.995, 95% CI 1.953-4.594, P < 0.001) were associated with SGLT inhibitors, but SGLT inhibitors did not increase the hypoglycemia risk (RR 0.980, 95% CI 0.840-1.144,P = 0.799). In subgroup analysis, with a significant reduction of fasting plasma glucose, glycated hemoglobin and daily insulin doses, SGLT1/2 inhibitor did not increase genitourinary tract infections compared with a placebo. CONCLUSIONS SGLT2 and SGLT1/2 inhibitors can improve glycemic control in patients with type 1 diabetes.
-
10.
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.