Effects of sodium‐glucose cotransporter 2 inhibitors on risk of venous thromboembolism in patients with type 2 diabetes: A systematic review and meta‐analysis

It has been reported that sodium‐glucose cotransporter 2 (SGLT2) inhibitors could increase blood viscosity, which may further increase risk of venous thromboembolism (VTE). Therefore, we conducted this meta‐analysis to evaluate the association between SGLT2 inhibitors and risk of VTE in patients with type 2 diabetes. We systematically searched electronic databases up to April 2019 to identify randomized trials that reported the events of VTE in SGLT2 inhibitors group and control group (placebo or other active antidiabetic drugs). The primary outcome was VTE, and secondary outcomes included deep venous thrombosis (DVT) and pulmonary embolism (PE). A fixed‐effects meta‐analysis was performed to calculate the risk ratio (RR) with 95% CI. In total, 29 randomized trials involving 56 035 patients with type 2 diabetes were included. Incidence of VTE was not significantly different between SGLT2 inhibitors group and control group (128/32 038 vs 92/23 997), yielding an RR of 0.98 (95% CI, 0.75‐1.28). Similarly, null associations were observed in the subgroup analyses. Our cumulative meta‐analysis demonstrated the stability of our overall result over time. There was no significant association between SGLT2 inhibitors and risk of both DVT (17 trials; 31/17 442 vs 15/10 930; RR, 1.06; 95% CI, 0.60‐1.89) and PE (19 trials; 56/26 118 vs 41/19 517; RR, 0.99; 95% CI, 0.67‐1.46). Low statistical heterogeneity and no evidence of publication bias were observed. Current evidence from randomized trials found no association between SGLT2 inhibitors and risk of VTE among patients with type 2 diabetes.     

Effect of Tight Blood Glucose Control Versus Conventional Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review with Meta‐Analysis of Randomized Controlled Trials

Tight control of blood glucose reduces cardiovascular events and total mortality is conflicting. To summarize clinical effects of tight versus conventional glucose control in patients with type 2 diabetes. We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge with no limits of language and time. Further trials were searched from the reference lists of identified studies. We included randomized controlled comparing different levels of blood glucose control intensity in type 2 diabetic patients. Two independent reviewers extracted data of eligible studies using standard case report forms. We investigated total mortality, cardiovascular and microvascular events, and hypoglycemia in patients with type 2 diabetes. We used random‐effects models to obtain relative risks (RR) with 95% confidence intervals (CI). We included 6 trials involving 27,654 patients. There was no significant effect of tight blood glucose control on all‐cause mortality (RR 1.03; 95% CI 0.90–1.17) or cardiovascular mortality (RR 1.04; 95% CI 0.83–1.29). Tight glucose control reduced the risk for nonfatal MI (RR 0.85; 95% CI 0.76–0.95), although had no effect on the incidence of nonfatal stroke (RR 1.02; 95% CI 0.88–1.17). For microvascular events, tight glucose control reduced the risk progression of retinopathy (RR 0.80; 95% CI 0.71–0.91), incidence of peripheral neuropathy (RR 0.94; 95% CI 0.89–0.99), and progression of nephropathy (RR 0.55; 95% CI 0.37–0.80), but had not significant effect on the incidence of nephropathy (RR 0.69; 95% CI 0.42–1.14). The risk of severe hypoglycemia increased with tight glucose control (RR 2.39; 95% CI 1.79–3.18). Tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all‐cause mortality and cardiovascular mortality. Tight glucose control increases the risk of severe hypoglycemia.     

Meta‐analysis on the efficacy and safety of SGLT2 inhibitors and incretin based agents combination therapy vs. SGLT2i alone or add‐on to metformin in type 2 diabetes

We aimed to determine whether sodium‐glucose cotransporter type 2 inhibitors (SGLT2is) and incretin‐based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl‐Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide‐1 receptor agonists (SGLT2is/GLP‐1RAs) against SGLT2is as monotherapy or add‐on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP‐1RAs exhibited more HbA1c reduction (WMD: ?0.8; 95% CI, ?1.14 to ?0.45%), weight loss (?1.46; 95% CI, ?2.38 to ?0.54 kg), and systolic blood pressure (SBP) reduction (?2.88; 95% CI, ?4.52 to ?1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14‐2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (?0.47; 95% CI, ?0.58 to ?0.37%), a neutral effect on weight (0.19; 95% CI, ?0.11 to 0.48 kg) and SBP (?0.01; 95% CI, ?0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54‐0.97) versus SGLT2is. Meta‐regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin‐based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP‐1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is. We highlight the need for individualized treatment related to the selection of this novel combination therapy.     

Effects of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes in women versus men

Sodium-glucose co-transporter-2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA-REG OUTCOME, CANVAS Program, DECLARE TIMI-58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men.     

Effects of SGLT2 inhibitors on cardiovascular and renal outcomes in type 2 diabetes: A meta-analysis with trial sequential analysis

Background:It is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis.Methods:We included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint.Results:Seven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84–0.94), MI (HR 0.91, 95% CI 0.84–0.99), CVD (HR 0.86, 95% CI 0.79–0.93), CVD or HHF (HR 0.77, 95% CI 0.73–0.82), HHF (HR 0.67, 95% CI 0.62–0.74), KFP (HR 0.63, 95% CI 0.56–0.70), and ACD (HR 0.88, 95% CI 0.83–0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88–1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size.Conclusions:Compared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.     

Sodium-glucose linked transporter-2 inhibitor renal outcome modification in type 2 diabetes: Evidence from studies in patients with high or low renal risk

Data from three completed cardiovascular outcome trials (CVOTs), EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium-glucose linked transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes. Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient-relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4401 patients vs. 69 events/34 322 patients, respectively), which shows the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal-specific elements of this primary endpoint (P <0.001). Canagliflozin has therefore become the first US-approved SGLT2 inhibitor to include an indication for RRR, in addition to type 2 diabetes glycaemic control and cardiovascular risk reduction. While confirmatory of the exploratory data from CVOTs, CREDENCE provides the first robust data on the effects of canagliflozin on patient-relevant renal endpoints. Extrapolation to a conclusion of a SGLT2 inhibitor class effect cannot be made until additional renal trials with other SGLT2 inhibitors are reported.     

Comparison between sodium–glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta‐analysis

Aims/Introduction

We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus.

Materials and Methods

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.

Results

A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] ?0.01% [?0.1 mmol/mol], 95% confidence interval [CI] ?0.25 to 0.22% [?2.7 to ?2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD ?0.90 mg/dL, 95% CI: ?15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD ?4.54 kg, 95% CI: ?5.67 to ?3.41 kg; P < 0.001). PIO/INS showed non‐significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD ?2.45 IU/day, 95% CI: ?7.30 to 2.40 IU/day; P = 0.438).

Conclusions

Both PIO and SGLT2i are feasible adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.

     

Burden of Microvascular Disease and Risk of Atrial Fibrillation in Adults with Type 2 Diabetes

BackgroundEpidemiological data on the associations of microvascular disease with atrial fibrillation are scarce. We evaluated the associations of diabetes-related microvascular disease in multiple vascular beds and its burden with incident atrial fibrillation among adults with type 2 diabetes.MethodsA total of 7603 participants with type 2 diabetes and without atrial fibrillation were assessed for diabetic kidney disease, retinopathy, or neuropathy at baseline in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Incident atrial fibrillation events were adjudicated using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) for atrial fibrillation.ResultsOf the 7603 participants (mean age 62.5 years, 38.0% women, 63.4% white), 63.3% (n = 4816) had microvascular disease—defined as the presence of ≥1 of: diabetic kidney disease, retinopathy, or neuropathy at baseline. Over a median of 7 years, there were 137 atrial fibrillation events (1.8%). Participants with microvascular disease had a 1.9-fold higher risk of incident atrial fibrillation compared with those without microvascular disease (RR 1.88; 95% CI, 1.20-2.95). Compared with no microvascular disease, the RRs for atrial fibrillation were 1.62 (95% CI, 1.01-2.61) and 2.47 (95% CI, 1.46-4.16) for those with 1 and ≥2 microvascular territories affected, respectively. The RRs for atrial fibrillation by type of microvascular disease were 1.57 (95% CI, 1.09-2.26), 0.95 (95% CI, 0.53-1.70), and 1.67 (95% CI, 1.15-2.44) for neuropathy, retinopathy, and diabetic kidney disease, respectively.ConclusionsIn a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with higher risk of incident atrial fibrillation.     

Effects of sodium‐glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: A meta‐analysis of randomized controlled trials

Sodium‐glucose cotransporter (SGLT) inhibitors added to insulin therapy have been proposed as treatment strategy for type 1 diabetes (T1D). We thus conducted a meta‐analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of this combination in T1D. We searched the PubMed, EMBASE, and Cochrane Library databases and ClinicalTrials.gov for RCTs. Statistical analyses were performed using STATA 15. Ten eligible placebo‐controlled trials involving 5961 patients were included. Compared with placebo, SGLT inhibitors were associated with a reduction in HbA1c of ?0.39% (95% CI, ?0.43 to ?0.36), an improved mean amplitude of glucose excursion (MAGE) of ?14.81 mg/dL (95% CI, ?19.08 to ?10.54), and a reduction in body weight of ?3.47% (95% CI, ?3.78 to ?3.16), as well as no increased relative risk of hypoglycaemia (1.01; 95% CI, 0.99‐1.02) or severe hypoglycaemia (0.91; 95% CI, 0.77‐1.07). SGLT inhibitors decreased fasting plasma glucose and insulin requirement but increased the risk of genital infection (3.57; 95% CI, 2.97‐4.29) and diabetic ketoacidosis (3.11; 95% CI, 2.11‐4.58). However, the very low dose empagliflozin (2.5 mg) did not increase the risk of diabetic ketoacidosis (risk ratio [RR] 0.67; 95% CI, 0.11‐3.95). SGLT inhibitors had no effect on overall adverse events, urinary tract infection, or bone fracture but slightly increased the risk of serious adverse events (1.35; 95% CI, 1.16‐1.58), severe adverse events (1.84; 95% CI, 1.20‐2.84), adverse events leading to discontinuation (1.50; 95% CI, 1.22‐1.84), drug‐related adverse events (1.78; 95% CI, 1.44‐2.19), and diarrhoea (1.54; 95% CI, 1.15‐2.05). Although adverse events exist, the available data provide evidence that the combination of SGLT inhibitors with basal insulin treatment is beneficial in patients with T1D.     

Sodium-Glucose Co-Transporter 2 Inhibitors and the Risk of Venous Thromboembolism in Patients with Type 2 Diabetes: A Cohort Study

PurposeWe assessed whether sodium-glucose co-transporter type 2 (SGLT2) inhibitors are associated with a higher incidence rate of venous thromboembolism in patients with type 2 diabetes.MethodsWe conducted a population-based cohort study using the InGef database including patients with type 2 diabetes newly treated with noninsulin antidiabetic drugs between 2012 and 2018. Cases of venous thromboembolism identified during follow-up were matched to 40 controls on age, sex, cohort entry date, and duration of follow-up. Using a nested case-control approach, conditional logistic regression estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) of venous thromboembolism adjusted for sociodemographic and clinical variables, comparing current use of SGLT2 inhibitors with current use of dipeptidyl peptidase-4 (DPP-4) inhibitors.ResultsIn a cohort of 219,538 patients, we identified 2152 cases of venous thromboembolism and matched them to 85,104 controls. Compared with DPP-4 inhibitors, current use of SGLT2 inhibitors was associated with a lower rate of venous thromboembolism (RR, 0.75; 95% CI, 0.59-0.94). Effect estimates were similar for dapagliflozin (RR, 0.77; 95% CI, 0.57-1.03) and empagliflozin (RR, 0.71; 95% CI, 0.52-0.98).ConclusionsCompared with DPP-4 inhibitors, SGLT2 inhibitors were not associated with a higher rate of venous thromboembolism, providing reassurance regarding their thromboembolic safety.     

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76

Aims/hypothesis Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes.Methods We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors.Results rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54–0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11–1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27–0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus.Conclusions/interpretation We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.     

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta‐analysis

The effects of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta‐analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75 540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta‐analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.     

Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors

The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections.     

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

Aims/hypothesis

The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of cancer in individuals with type 2 diabetes remains uncertain. This study aimed to evaluate the risk of cancer associated with SGLT2 inhibitor treatment of type 2 diabetes.

Methods

We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to 15 February 2017 to identify eligible randomised controlled trials (RCTs) that report cancer events in individuals with type 2 diabetes treated with SGLT2 inhibitors for at least 24 weeks. We performed pairwise and network meta-analyses as well as a cumulative meta-analysis to calculate ORs and 95% CIs.

Results

In total, 580 incidences of cancer among 34,569 individuals were identified from 46 independent RCTs with a mean trial duration of 61 weeks. When compared with comparators (placebo or other active glucose-lowering treatments), SGLT2 inhibitors were not significantly associated with an increased risk of overall cancer (OR 1.14 [95% CI 0.96, 1.36]). For pre-specified cancer types, the risk of bladder cancer might be increased with SGLT2 inhibitors (OR 3.87 [95% CI 1.48, 10.08]), especially empagliflozin (OR 4.49 [95% CI 1.21, 16.73]). Interestingly, canagliflozin might be protective against gastrointestinal cancers (OR 0.15 [95% CI 0.04, 0.60]).

Conclusions/interpretation

Current evidence from short-term RCTs did not indicate a significantly increased risk of overall cancer among individuals with type 2 diabetes using SGLT2 inhibitors. Given the short-term trial durations and uncertainty of evidence, future long-term prospective studies and post-marketing surveillance studies are warranted.

     

Sodium‐glucose co‐transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta‐analysis of randomized controlled trials

Given inconsistent trial results of sodium‐glucose cotransporter 2 (SGLT2) inhibitors in addition to insulin therapy for treating type 2 diabetes mellitus (T2DM), a meta‐analysis was performed to evaluate the efficacy and safety of this combination for T2DM by searching available randomized trials from PubMed, Embase, CENTRAL and ClinicalTrials.gov . Our meta‐analysis included seven eligible placebo‐controlled trials involving 4235 patients. Compared with placebo, SGLT2 inhibitor treatment was significantly associated with a mean reduction in HbA1c of ?0.56%, fasting plasma glucose of ?0.95 mmol/L, body weight of ?2.63 kg and insulin dose of ?8.79 IU, but an increased risk of drug‐related adverse events by 36%, urinary tract infections by 29% and genital infections by 357%. No significant increase was observed in risk of overall adverse events [risk ratio (RR), 1.00], serious adverse events (RR, 0.90), adverse events leading to discontinuation (RR, 1.16), hypoglycaemia events (RR, 1.07) and severe hypoglycaemia events (RR, 1.24). No diabetic ketoacidosis events were reported. Further studies are needed to establish optimal combination type and dose.     

Birth weight and risk of type 2 diabetes: A dose‐response meta‐analysis of cohort studies

The association between birth weight and type 2 diabetes mellitus has been debated for several decades. The objective of this systematic review and meta‐analysis was to quantitatively clarify the association between birth weight and risk of type 2 diabetes mellitus based on cohort studies. We searched PubMed, Web of Science, and Embase databases for cohort study articles on the association between birth weight and risk of type 2 diabetes mellitus published up to 1 March 2018. Random effects of generalized least square regression models were used to estimate relative risk (RR). Restricted cubic splines were conducted to model the dose‐response relationship. We included 21 studies (19 articles) involving 1 041 879 individuals and 35 699 cases of type 2 diabetes mellitus, with follow‐up ranged from 6 to 47 years. We identified significant decreasing trend for the highest versus lowest category of birth weight for the association with type 2 diabetes mellitus risk: The risk was reduced by 35% (RR, 0.65; 95% confidence interval [CI], 0.53‐0.81) and by 12% (RR 0.88; 95% CI, 0.85‐0.91) per 500‐g increment in birth weight. Our results showed a dose‐response relationship between birth weight and diabetes risk, which was nonlinear (P_nonlinearity < 0.001) and L‐shaped. With increasing birth weight (<5000 g), the risk of type 2 diabetes mellitus decreased substantially. The association between birth weight and type 2 diabetes mellitus was curvilinear and L‐shaped.     

Uric acid and the cardio-renal effects of SGLT2 inhibitors

Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio-renal risk. Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the “metabolic syndrome” of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes.     

Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A protocol for systematic review and meta-analysis

Background:Many studies have shown the effects of SGLT2 inhibitors on type 2 diabetes, but the effects in patients with type 2 diabetes with chronic kidney disease remains unclear. This study aims to evaluate the effects of SGLT2 inhibitors on renal outcomes in patients with type 2 diabetes mellitus with chronic kidney disease.Methods:We conducted systematic searches of PubMed, Embase, and Cochrane Central Register of Controlled Trials up to April 30, 2020 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) reporting estimated glomerular filtration rate (eGFR) and/or urine albumin/creatinine ratio (UACR) changes and/or acute kidney injury or failure (AKI). Random effects models were adopted to measure the pooled outcomes.Results:Nine studies with 8826 participants were included. SGLT2 inhibitors were not associated with a significant change in eGFR (mean difference (MD), −0.75 ml/minutes per 1.73 m², 95% CI −1.61 to 0.10, P = .09) in type 2 diabetic patients with CKD. UACR reduction after SGLT2 inhibitors was significant in type 2 diabetic patients with CKD (MD −24.27 mg/g, 95% CI −44.46 to −4.09, P = .02). SGLT2 inhibitors associated with AKI in the patients were significant (OR 0.80, 95% CI [0.66 to 0.98], P = .03).Conclusion:SGLT2 inhibitors had no significant effect on kidney function (eGFR measured) in the pooled analysis. And SGLT2 inhibitors effectively reduced UACR in T2DM with CKD. Besides, SGLT2 inhibitors could reduce the incidence of AKI.     

Sodium‐glucose co‐transporter‐2 inhibitors as add‐on therapy to insulin for type 1 diabetes mellitus: Systematic review and meta‐analysis of randomized controlled trials

New treatments for type 1 diabetes are an unmet need. We investigated the efficacy and safety of adding sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors to insulin for type 1 diabetes by conducting a meta‐analysis of prospective randomized, placebo‐controlled trials. A search of electronic databases up to October 2017 identified 1361 studies, of which 14 were investigated (N = 4591). Meta‐analysis showed that SGLT2 inhibitor therapy significantly reduced glycated haemoglobin (HbA1c) concentration by 0.4% (95% confidence interval [CI] 0.35, 0.46; P < .001, I² = 0%), fasting plasma glucose by 1.14 mmol/L (95% CI 0.8,1.47), body weight by 2.68 kg (95% CI 2.0, 3.36), and systolic blood pressure by 3.37 mmHg (95% CI 1.46, 5.28). In addition, bolus insulin decreased by 3.6 units/day (95% CI 2.0, 5.3), and basal insulin decreased by 4.2 units/day (95% CI 2.2, 6.3). Continuous glucose monitoring showed a decrease in glucose excursions compared with placebo, with reduced variation of mean blood glucose, glucose standard deviation, and mean amplitude of glucose excursion. There was no significant increase in the rate of hypoglycaemia or severe hypoglycaemia; however, SGLT2 inhibitor therapy increased diabetic ketoacidosis (odds ratio [OR] 3.38) and genital tract infection (OR 3.44). Add‐on SGLT2 inhibitor therapy might be advantageous for type 1 diabetes, but its use should be considered carefully.     

Fiber and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis

BACKGROUND: Prospective studies on fiber and magnesium intake and risk of type 2 diabetes mellitus were inconsistent. We examined associations between fiber and magnesium intake and risk of type 2 diabetes and summarized existing prospective studies by meta-analysis. METHODS: We conducted a prospective cohort study of 9702 men and 15 365 women aged 35 to 65 years who were observed for incident diabetes from 1994 to 2005. Dietary intake of fiber and magnesium were measured with a validated food-frequency questionnaire. We estimated the relative risk (RR) by means of Cox proportional hazards analysis. We searched PubMed through May 2006 for prospective cohort studies of fiber and magnesium intake and risk of type 2 diabetes. We identified 9 cohort studies of fiber and 8 studies of magnesium intake and calculated summary RRs by means of a random-effects model. RESULTS: During 176 117 person-years of follow-up, we observed 844 incident cases of type 2 diabetes in the European Prospective Investigation Into Cancer and Nutrition-Potsdam. Higher cereal fiber intake was inversely associated with diabetes risk (RR for extreme quintiles, 0.72 [95% confidence interval [CI], 0.56-0.93]), while fruit fiber (0.89 [95% CI, 0.70-1.13]) and vegetable fiber (0.93 [95% CI, 0.74-1.17]) were not significantly associated. Meta-analyses showed a reduced diabetes risk with higher cereal fiber intake (RR for extreme categories, 0.67 [95% CI, 0.62-0.72]), but no significant associations for fruit (0.96 [95% CI, 0.88-1.04]) and vegetable fiber (1.04 [95% CI, 0.94-1.15]). Magnesium intake was not related to diabetes risk in the European Prospective Investigation Into Cancer and Nutrition-Potsdam (RR for extreme quintiles, 0.99 [95% CI, 0.78-1.26]); however, meta-analysis showed a significant inverse association (RR for extreme categories, 0.77 [95% CI, 0.72-0.84]). CONCLUSION: Higher cereal fiber and magnesium intakes may decrease diabetes risk.