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Aim: Excisional haemorrhoidectomy in patients with ulcerative colitis (UC), especially those undergoing an ileal pouch–anal anastomosis (IPAA), remains controversial. The aim of our study was to determine the safety of excisional haemorrhoidectomy in UC patients with and without an IPAA. Method: A retrospective review of all adult UC patients undergoing excisional haemorrhoidectomy between 1 January 1995 and 1 January 2019 at a tertiary inflammatory bowel disease referral centre was performed. Data collected included patient demographics, clinical characteristics of UC, prior surgical intervention for UC (colectomy, IPAA) and complications after haemorrhoidectomy. Results: Forty‐one adult patients [50% male; median age 52 (range 25–79) years] with UC underwent excisional haemorrhoidectomy between 1 January 1995 and 1 January 2019. The majority (n = 23) had not previously undergone surgery for UC. However, eight had already undergone construction of an IPAA at the time of haemorrhoidectomy, seven had IPAA at the time of haemorrhoidectomy and three had an IPAA constructed subsequent to haemorrhoidectomy. Two (4.9%) patients need to go back to theatre for postoperative bleeding. There were no further 30‐day complications or long‐term nonhealing of the surgical site. There were no pouch complications in those who had haemorrhoidectomy at the time of IPAA construction or in the presence of an IPAA. Conclusion: Our data suggest that excisional haemorrhoidectomy may be performed safely in carefully selected UC patients with symptomatic haemorrhoids with or without IPAA and even at the time of IPAA construction. [ABSTRACT FROM AUTHOR]

Patients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross-sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2α[8-iso-PGF2α] and 11-dehydro-thromboxane-B2 [11-dehydro-TXB2]) in KS patients and healthy controls. Twenty-three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 age- matched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max-A%) was defined as maximal light transmittance reached within 5 min after the addition of 0.2 or 0.4 mM arachidonic acid (AA). A ≥ 50% irreversible light transmittance (LT-50%) following platelet stimulation defined an adequate platelet aggregation and AC-50% was defined as the minimal agonist concentration needed to achieve LT-50%. The AC-50% was 0.26 mM AA for KS and 0.36 mM for controls (p < 0.001). Whereas AA (0.2 mM) induced LT-50% in 69.6% of KS and in 15.2% of controls (p < 0.001), the stimulation with AA (0.4 mM) determined LT-50% in all cases and controls. However, max-A% was higher in KS than in controls both after AA (0.2 mM) (65.61% vs. 46.30%, p = 0.002,) and after AA (0.4 mM) (96.43% vs. 81.04%, p < 0.001). 8-iso-PGF2α and 11-dehydro-TXB2 were higher in KS than in controls (446.54 pg/mg creatinine vs. 230.00 pg/mg creatinine, p < 0.001 and 1278.36 pg/mg creatinine vs. 595.08 pg/mg creatinine, p = 0.001, respectively) and AC-50% inversely correlated with 8-iso-PGF2α (q =0.548, p < 0.001) and with 11-dehydro-TXB2 (q =0.523, p < 0.001). In a linear regression model, KS independently predicted a lower AC-50% (β =0.597, p < 0.001) and higher levels of 8-iso-PGF2α (β = 0.709, p < 0.001) and 11-dehydro-TXB2 (β = 0.605, p < 0.001). In contrast, no correlation has been found between max-A%, testosterone and estradiol levels in KS. We observed increased platelet reactivity in KS. This might, at least in part, explain the increased thrombotic risk associated with this disease. [ABSTRACT FROM AUTHOR]

Understanding the relationships between material surface properties and cellular responses is essential to designing optimal material surfaces for implantation and tissue engineering. In this study, cellulose hydrogels were crosslinked using a non-toxic and natural component namely citric acid. The chemical treatment induces COOH functional groups that improve the hydrophilicity, roughness, and materials rheological properties. The physiochemical, morphological, and mechanical analyses were performed to analyze the material surface before and after crosslinking. This approach would help determine if the effect of chemical treatment on cellulose hydrogel improves the hydrophilicity, roughness, and rheological properties of the scaffold. In this study, it was demonstrated that the biological responses of human mesenchymal stem cell with regard to cell adhesion, proliferation, and differentiation were influenced in vitro by changing the surface chemistry and roughness. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 2045-2056, 2015. [ABSTRACT FROM AUTHOR]

Aim: We assessed the efficacy of eight classes of diabetes medications used in current clinical practice [metformin, sulphonylureas, α-glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) analogues and insulin analogues] to reach the HbA1c target <7% in type 2 diabetes. Methods: MEDLINE, EMBASE and the Cochrane CENTRAL were searched from inception through April 2011 for randomized controlled trials (RCTs) involving antidiabetic drugs. RCTs had to report the effect of any diabetes medication on the HbA1c levels, to include at least 30 subjects in every arm of the study, and to report the effect of therapy after a minimum of 12 weeks. Data were summarized across studies using random-effects meta-regression. Results: A total of 218 RCTs (339 arms and 77 950 patients) met the inclusion criteria. The proportion of patients who achieved the HbA1c goal ranged from 25.9% (95% CI 18.5-34.9) with α-glucosidase inhibitors to 63.2% (54.1-71.5) with the long-acting GLP-1 analogue. There was a progressive decrease of the proportion of patients at target for each 0.5% increase in baseline HbA1c, ranging from 57.8% for HbA1c ≤7.5% to 20.8% for HbA1c ≥10% (p for trend <0.0001), with some difference between insulin and non-insulin drugs: for insulin, the proportion of patients at goal reached a plateau for basal HbA1c value >9.0% with no further decrease, whereas for non-insulin drugs the relationship was continuous without any evidence of plateau. Conclusions: There is a considerable variability with regard to attainment of HbA1c goal of <7% among the different classes of diabetes medications; baseline HbA1c is an important determinant of observed efficacy. [ABSTRACT FROM AUTHOR]

Aims: To compare the efficacy and safety of insulin lispro protamine suspension (ILPS) versus insulin glargine once daily in a basal-bolus regimen in type 2 diabetes mellitus (T2DM) patients. Methods: Three hundred eighty-three insulin-treated patients were randomized to either ILPS plus lispro or glargine plus lispro in this open-label 24-week European study. Insulin doses were titrated to predefined blood glucose (BG) targets. Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of the 95% confidence interval (CI) for the change of HbA1c from baseline to week 24 (adjusted for country and baseline HbA1c) with the non-inferiority margin of 0.4%. Secondary endpoints included HbA1c categories, BG profiles, insulin doses, hypoglycaemic episodes, adverse events and vital signs. Results: Non-inferiority of ILPS versus glargine in the change of HbA1c from baseline was shown: least-square mean between-treatment difference (95% CI) was 0.1% (−0.11; 0.31). Mean changes at week 24 were −1.05% (ILPS) and −1.20% (glargine). HbA1c <7.0% was achieved by 21.7 versus 29.4% of patients. Mean basal/mealtime insulin doses at week 24 were 29.6/36.2 IU/day (ILPS) versus 32.8/42.2 IU/day (glargine); the difference was not statistically significant for total dose (p = 0.7). In both groups, 56.1/25.7% versus 63.6/19.3% of patients experienced any/nocturnal hypoglycaemia (p = 0.2 for both). No relevant differences were noted in any other variables. Conclusions: A basal-bolus regimen with ILPS once daily resulted in non-inferior glycaemic control compared to a similar regimen with glargine, without statistically significant or clinically relevant differences in hypoglycaemia. ILPS-based regimens can be considered an alternative to basal-bolus regimens with glargine for T2DM patients. [ABSTRACT FROM AUTHOR]

We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. We conducted an electronic search for randomized controlled trials (RCTs) involving DPP-4 inhibitors through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more and reported the proportion of patients reaching the HbA1c target of <7%. A total of 43 RCTs reporting 52 comparisons met the selection criteria, which included 19 101 study participants evaluated for the primary endpoint, 10 467 treated with a DPP-4 inhibitor and 8634 treated with placebo or a comparator drug. DPP-4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40% of participants achieved the HbA1c goal of <7%: this was associated with weight neutrality and no greater hypoglycaemia. The reduction of the HbA1c level and the rate of HbA1c goal attainment was not different from comparator drugs, with similar hypoglycaemia, and different effect on weight owing to the nature of comparator (metformin, sulfonylurea or glitazones). Baseline HbA1c was the best predictor for achievement of A1C target (overall weighted r value = 0.410, p < 0.001). A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with DPP-4 inhibitors compared to placebo, with no weight gain, and no hypoglycaemic risk when used alone; DPP-4 inhibitors were not different from comparator drugs. [ABSTRACT FROM AUTHOR]

The article discusses the relationship between obesity, sexual dysfunction and metabolic syndrome in men. It states that increased prevalence of visceral adiposity and related risk factors are linked with a proinflammatory state which causes decline in nitric oxide (NO) availability. Reduced NO availability results in endothelial injury and erectile dysfunction (ED). It further states that reduction in testosterone levels due to obesity and metabolic syndrome also contribute to ED.

Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are markers of endothelial injury and repair. We compared the effects of pioglitazone versus metformin on the circulating numbers of EMPs and EPCs in patients with newly diagnosed type 2 diabetes. This was a randomized, double-blind, comparator-controlled, 24-week single-centre trial conducted in a Teaching Hospital in Naples, Italy. One hundred and ten people with newly diagnosed type 2 diabetes who were never treated with antihyperglycaemic drugs and had haemoglobin A1c (HbA1c) levels between 7 and 10% were given pioglitazone hydrochloride (15-45 mg/day) (n = 55) or metformin (1000-2000 mg/day) (n = 55) as an active comparator. Absolute change from baseline to final visit in circulating EMPs and EPCs and their ratio were the main outcomes. Baseline characteristics did not differ between the study groups. The decrease in circulating EMPs CD31+ [intergroup difference, −32 counts/µl (95% CI −51 to −9)] and the increase in EPCs CD34+/KDR+ [intergroup difference, 33 cells/10 events (95% CI 13 to 55)] were greater with pioglitazone versus metformin. EMPs/EPCs ratio was reduced with pioglitazone and unchanged with metformin [difference, −1.5 (95% CI −2.6 to −0.5), p < 0.001]. Participants assigned to pioglitazone gained more weight and experienced greater improvements in some coronary risk measures [high-density lipoprotein (HDL)-cholesterol, triglycerides, adiponectin and C-reactive protein (CRP)] than did those assigned to metformin. Compared with metformin, pioglitazone treatment improved the imbalance between endothelial damage and repair capacity and led to more favourable changes in coronary risk factors in patients with newly diagnosed type 2 diabetes. [ABSTRACT FROM AUTHOR]

We performed a meta-analysis of randomised controlled trials (RCTs) with insulin analogues in type 2 diabetes utilising a least-squared regression model in order to assess the relationship between baseline HbA1c, the magnitude of HbA1c decrease and attainment of HbA1c target of < 7%. Randomised controlled trials involving insulin regimens (basal, prandial, biphasic and basal-bolus) were identified through electronic searches (MEDLINE, EMBASE, CINAHL and The Cochrane Library) through September 2010. We included any study arm of RCTs if they were at least 12 weeks in duration; the number of patients in any arm was more than 30 and reported the baseline HbA1c and change from baseline HbA1c. We found 87 studies, with a total of 135 arms, and 38,803 patients. The weighted R values for the overall analysis assessing the association between baseline HbA1c and absolute change in HbA1c or the proportion of patients at target were 0.485 (p < 0.001) and 0.146 (p < 0.001), respectively. Subanalyses of insulin regimens for the association between basal HbA1c and absolute decrease of HbA1c produced weighted R, which were significant for all insulin regimens with the highest association for basal-bolus (R=0.719, p < 0.001). The strong positive relationship between baseline HbA1c and the magnitude of HbA1c change we found in RCTs using insulin analogues in type 2 diabetes should be considered when assessing the clinical efficacy of insulin therapies. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 911–917 (2010) Objective To investigate the possibility of reversing endothelial dysfunction and inflammation by glucose normalization, antioxidants and insulin per se, in different subgroups of Type 1 diabetic patients. Methods Three subgroups of Type 1 diabetic patients were studied: patients within 1 month of diagnosis (subgroup 1); patients with approximately 5 years’ disease duration and with glycated haemoglobin (HbA1c) ≤ 7.0% (subgroup 2) or > 7.0% since diagnosis (subgroup 3). Participants underwent four procedures: 2-h hyperglycaemic clamp followed by: (A) 12 h near-normalization of blood glucose, with the addition of vitamin C during the last 6 h; (B) 12-h vitamin C and near-normalization of blood glucose for the last 6 h; (C) both vitamin C and near-normalization of blood glucose for 12 h; (D) hyperglycaemic–hyperinsulinaemic clamp for 12 h, with the addition of vitamin C during the last 6 h. Results After 2 h of hyperglycaemia, markers of endothelial dysfunction, nitrotyrosine, 8-iso prostaglandin F2α, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, interleukin (IL)-6 and IL-18 were increased in all the subgroups. Levels were normalized, at all time points, by treatments A, B and C in the subgroups 1 and 2. In the third subgroup, levels were normalized only by the simultaneous normalization of blood glucose and vitamin C treatment. During treatment D, the levels were improved at 6 h in all the subgroups, but normalized at 12 h only after vitamin C in subgroups 1 and 2, but not in subgroup 3. Conclusions This study suggests that different subgroups of Type 1 diabetic patients react identically to acute hyperglycaemia and insulin, but differently to glucose normalization. [ABSTRACT FROM AUTHOR]

Aims Mediterranean-type diets reduce the risk of Type 2 diabetes. Whether a Mediterranean-type diet improves glycaemic control in diabetes remains unknown. Methods We conducted a cross-sectional analysis in 901 outpatients with Type 2 diabetes attending diabetes clinics located in Campania County, South Italy. We explored the relation between glycated haemoglobin (HbA1c), measured centrally, self-measured pre- and postprandial glucose levels and consumption of a Mediterranean-type diet. Adherence to a Mediterranean-type diet was assessed by a 9-point scale that incorporated the salient characteristics of this diet (range of scores, 0–9, with higher scores indicating greater adherence). The study was conducted from 2001 to 2007. Results Diabetic patients with the highest scores (6–9) had lower body mass index and waist circumferences, a lower prevalence of the metabolic syndrome and lower HbA1c and post-meal glucose levels than diabetic patients with the lowest scores (0–3). In multivariate analysis, mean HbA1c and 2-h post-meal glucose concentrations were significantly lower in diabetic patients with high adherence to a Mediterranean-type diet than those with low adherence [difference: HbA1c 0.9%, 95% confidence intervals (CI) 0.5–1.2%, P < 0.001; 2-h glucose 2.2 mmol/l, 95% CI 0.8–2.9 mmol/l, P < 0.001]. Conclusions In Type 2 diabetes, greater adherence to a Mediterranean-type diet is associated with lower HbA1c and postprandial glucose levels. [ABSTRACT FROM AUTHOR]

Coppola A, Astarita C, Liguori E, Fontana D, Oliviero M, Esposito K, Coppola L, Giugliano D (Second University of Naples, Naples; and S. Maria della Misericordia Hospital, Sorrento, Italy) Impairment of coronary circulation by acute hyperhomocysteinaemia and reversal by antioxidant vitamins.J Intern Med2004;256:398–405.To evaluate the effect of acute hyperhomocysteinaemia with and without antioxidant vitamins pretreatment on coronary circulation and circulating chemokine levels.Observer-blinded, randomized crossover study.This study was conducted at a university hospital and at a general hospital in Italy.Sixteen healthy hospital staff volunteers (nine men, seven women), aged 26–40 years.Subjects were given each three loads in random order at 1-week intervals: oral methionine, 100 mg kg−1 in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo).Coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography, blood pressure, heart rate, lipid and glucose, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) parameters evaluated at baseline and 4 h following ingestion of the loads.The oral methionine load increased plasma homocysteine from 12.8 ± 1.8 to 33.3 ± 3.4 μmol L−1 at 4 h (P < 0.001). A similar increase was observed with same load plus vitamins (P < 0.001) but not with placebo (P = 0.14). Circulating MCP-1 and IL-8 levels rose after the methionine load (P < 0.001), but not after placebo or methionine plus vitamins. The methionine load significantly reduced CFVR (decrease, 26 ± 8.2%;P < 0.001). The methionine load with ingestion of vitamins partially prevented the impairment of CFVR (decrease, 11 ± 4%;P < 0.001).Our data suggest that acute hyperhomocysteinaemia reduces CFVR and increases plasma MCP-1 and IL-8 levels in healthy subjects. Pretreatment with antioxidant vitamin E and ascorbic acid prevents the effects of hyperhomocysteinaemia, suggesting an oxidative mechanism. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: A meta-analysis of randomized clinical trials," by R. A. DeFronzo and colleagues that was published in the previous issue.

Aim: To assess and compare the metabolic and vascular effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in the clinical practice of patients with type 2 diabetes in Italy., Materials and Methods: GIOIA is a 2-year prospective, multicentre, quasi-experimental study that enrolled patients with type 2 diabetes initiating SGLT-2i or DPP-4i for inadequate glycaemic control [glycated haemoglobin (HbA1c) >7%] between March 2018 and March 2021. The primary endpoints were changes in markers of organ damage [carotid intima-media thickness (CIMT), albuminuria, myocardial function] and HbA1c from baseline to year 2., Results: In total, 1150 patients were enrolled in the study (SGLT-2i n = 580, DPP-4i n = 570). Patients initiated on SGLT-2i were younger (about 6 years) and heavier (about 11 kg), had higher HbA1c level (1% more), more albuminuria and cardiovascular events (16% more) than patients initiated on DPP-4i. CIMT and echocardiographic parameters were not significantly different. Propensity score matching yielded two groups, each consisting of 155 patients with diabetes with similar baseline characteristics. Despite a significant similar reduction in HbA1c levels in both groups (-0.8%), more patients on SGLT-2i had regression of CIMT and albuminuria (22% and 10%, respectively, p < .001 vs. DPP-4i); more patients on DPP-4i had progression of CIMT and albuminuria (23% and 28%, respectively, p < .001 vs. SGLT-2i). Left ventricular ejection fraction improved slightly (3%, p = .043) on SGLT-2i only., Conclusions: In a real-world setting, both SGLT-2i and DPP-4i improve glycaemic control persisting after 2 years of treatment, with a robust effect on both CIMT and albuminuria regression for SGLT-2i as compared with DPP-4i in the propensity score matching., (© 2024 John Wiley & Sons Ltd.)

A meta-analysis of cardiorenal outcomes of sodium-glucose co-transporter-2 inhibitors (SGLT-2is) available in Europe or the United States in patients with type 2 diabetes (T2D) is presented. An electronic search up to 6 January 2021 was conducted to determine eligible trials. A total of eight cardiorenal outcomes trials of SGLT-2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) were identified, with 65,587 patients. Data were analysed using a random effects model. Overall, SGLT-2is were associated with a 12% reduced risk of major adverse cardiovascular events (MACE; HR = 0.88; 95% CI, 0.83-0.93; Q statistic, p = .19), with no significant heterogeneity (p for interaction = .465) between subgroups of patients with or without cardiovascular disease (CVD). The risk of the composite renal outcome was significantly reduced by treatment with SGLT-2is (HR = 0.61, 95% CI, 0.54-0.70), with no significant heterogeneity of associations with outcome (I 2 = 37%, p = .11), and no difference in the risk between patients with or without CVD (p for interaction = .665). SGLT-2is have moderate benefits on MACE and major benefits on the progression of diabetic kidney disease., (© 2021 John Wiley & Sons Ltd.)

Aim: In order to disclose relations between reduction of haemoglobin A1c (HbA1c) levels and risk of major cardiovascular events (MACE), we performed a meta-analysis with metaregression of all cardiovascular outcome trials (CVOTs) so far published in patients with type 2 diabetes (T2D)., Materials and Methods: An electronic search up to February 10, 2020 was conducted to determine eligible trials. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression., Results: The 15 CVOTs included evaluated 138,250 patients. In the pooled analysis, the risk of MACE was significantly reduced by 9% (hazard ratio, HR = 0.91, 0.87-0.95, P <0.001) as compared with placebo, with significant heterogeneity between trials (I 2 = 44%, P = 0.060) There was a robust relation between the reduction in achieved HbA1c at the end of the trial and the HR reduction for MACE (beta = -0.3169, P = 0.029), explaining most (78%) of the between-study variance; this relation was totally driven by the risk reduction of non-fatal stroke only, which explained 100% of between-study variance, and apparently restricted to the class of glucagon-like peptide 1 receptor agonists (GLP-1RAs). There was no relation between the reduction in achieved HbA1c and the HR for heart failure (variance explained = 0%) or all-cause mortality (variance explained = 6%)., Conclusion: The blood glucose reduction observed in CVOTs may play some role in reducing the risk of non-fatal stroke, at least during treatment with GLP-1RAs, without affecting the other two components of MACE., (© 2020 John Wiley & Sons Ltd.)

We are observing a resurgence of major diabetic vascular complications after a period of dramatic decrease during the period 1990 to 2010. The classical division of cardiovascular prevention into primary (with an event) and secondary (without an event) is largely used to describe cardiovascular risk in type 2 diabetes (T2D); however, there is evidence that the cardiovascular risk in diabetes may range from highest in patients who experienced a previous cardiovascular event to mild in patients with the main risk factors at target. Herein, we present details of the 14 cardiovascular outcome trials (CVOTs) published to date, including the total population investigated, and their separation into primary (T2D + multiple risk factors) and secondary prevention (T2D + established cardiovascular disease [CVD]) populations as detailed within the trials. We also summarize evidence for the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium glucose co-transporter-2 inhibitors (SGLT-2i) versus placebo on the risk of major cardiovascular events (MACE), heart failure (HF) and diabetic kidney disease (DKD). In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results., (© 2019 John Wiley & Sons Ltd.)

A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80-0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68-0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease., (© 2019 John Wiley & Sons Ltd.)

Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end-stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl-peptidase inhibitors (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CARMELINA with linagliptin) and with glucagon-like peptide-1 receptor agonists (GLP-1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long-term estimated glomerular filtration rate, suggesting that SGLT-2is are more effective at mitigating loss of kidney function than incretin-based therapies; moreover, SGLT-2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT-2is, and to a lesser extent some GLP-1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk. There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD., (© 2019 John Wiley & Sons Ltd.)

Background The value of glycemic control and preexisting cardiovascular disease in determining the risk of major cardiovascular events (MACE) in type 2 diabetes mellitus is uncertain. Intensive glucose control trials suggest that the 9% lower risk of MACE associated with intensive glycemic control, as compared with conventional glycemic control, is only driven by patients with type 2 diabetes mellitus without cardiovascular disease at baseline. Methods and Results We did a meta-analysis of cardiovascular outcome trials dividing patients with or without preexisting cardiovascular disease; we found that the lower risk of MACE is confined to patients with cardiovascular disease at baseline. Compared with placebo, the use of both glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors was associated with a significant 14% lower MACE risk in patients with preexisting cardiovascular disease and with a nonsignificant 2% higher MACE risk in those without preexisting cardiovascular disease ( P for interaction=0.021). The meta-regression analysis of all 12 trials demonstrated a significant ( P=0.002) association between reductions of glycated hemoglobin in glycated hemoglobin A 1C . Accordingly, the reduction of MACE expected if all cardiovascular outcome trials had achieved a 0.9% glycated hemoglobin reduction would have been 33%. Routine clinical care data complement the results of cardiovascular outcome trials but with some differences: the lower risk of MACE with sodium-glucose cotransporter-2 inhibitor use is evident in patients with type 2 diabetes mellitus with or without preexisting cardiovascular disease. Conclusions Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists should be included in the therapeutic plan of patients with type 2 diabetes mellitus and overt cardiovascular disease, with due attention paid to improvement of glycemic control, which may amplify their benefit on MACE.

An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) (EMPA-REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti-hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT-2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP-1RAs and SGLT-2i must be interpreted within the frame of the single trial., (© 2019 John Wiley & Sons Ltd.)

A meta-analysis is presented of randomized controlled trials (RCTs) comparing free or fixed combinations of a glucagon-like peptide-1 receptor agonist plus basal insulin versus insulin intensification on metabolic control in patients with type 2 diabetes. Electronic databases were searched for RCTs assessing changes in HbA1c, proportion of patients at HbA1c target of <7% (53 mmol/mol), hypoglycaemia and body weight. A random-effect model was used to calculate the weighted mean difference (WMD) or relative risk (RR) with 95% CI. Eleven RCTs were identified, lasting 24-30 weeks and involving 6176 patients. In the overall analysis, the combination therapy led to a mean HbA1c decrease significantly greater than insulin up-titration (WMD -0.53%, 95% CI, -0.66, -0.40%, P < 0.001), more patients at HbA1c target (RR 1.69, 95% CI, 1.42, 2.00, P < 0.001), similar hypoglycaemic events (RR 0.97, 95% CI, 0.84, 1.12, P = 0.114), and reduction in body weight (WMD -1.9, 95% CI -2.3, -1.4, P < 0.001), with heterogeneity (I 2 > 71%, P < 0.001). Results did not differ in either the free or fixed combination subgroups. Combination strategies, either free or fixed, represent a good option for intensifying basal insulin therapy in patients with type 2 diabetes who need amelioration of glycaemic control., (© 2018 John Wiley & Sons Ltd.)

Consumption of selected dietary components is favourably associated with prevention of type 2 diabetes, but discordant results for some foods or single nutrients continue to appear. The study of complete dietary patterns represents the most adequate approach to assess the role of diet on the risk of diabetes. The term 'Mediterranean diet' essentially refers to a primarily plant-based dietary pattern whose greater consumption has been associated with higher survival for lower all-cause mortality. At least five large prospective studies report a substantially lower risk of type 2 diabetes in healthy people or at risk patients with the highest adherence to a Mediterranean diet. Five randomized controlled trials have evaluated the effects of a Mediterranean diet, as compared with other commonly used diets, on glycaemic control in subjects with type 2 diabetes. Improvement of HbA1c levels was greater with a Mediterranean diet and ranged from 0.1% to 0.6% for HbA1c . No trial reported worsening of glycaemic control with a Mediterranean diet. Although no controlled trial specifically assessed the role of a Mediterranean diet in reducing cardiovascular events in type 2 diabetes, there is evidence that post-infarct or high-risk patients, including diabetic patients, may have cardiovascular benefits from a Mediterranean diet. The evidence so far accumulated suggests that adopting a Mediterranean diet may help prevent type 2 diabetes; moreover, a lower carbohydrate, Mediterranean-style diet seems good for HbA1c reduction in persons with established diabetes., (Copyright © 2013 John Wiley & Sons, Ltd.)