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Abstract: Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5–6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47,296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7–14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85–0.96; P =0.0009), cardiovascular mortality (0.87, 0.81–0.93; P <0.0001) and major coronary events (0.79, 0.72–0.86; P <0.00001) was observed in favour of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74–0.93; P =0.001), cardiovascular mortality (0.81, 0.69–0.95; P =0.01) and major coronary events (0.77, 0.63–0.95; P =0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95–1.04; P =0.79), deaths from cancers (1.00, 0.93–1.07; P =0.98) and non-cardiovascular mortality (0.95, 0.90–1.00; P =0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms. [Copyright &y& Elsevier]

Abstract: Backgroud: Angiotensin converting enzyme inhibitors (ACEIs) have been linked to reduced risk of new-onset diabetes, but the evidence was insufficient. Objective and methods: The aim of this study was to evaluate the effect of ACEIs on the development of new-onset type 2 diabetes. Randomized controlled trials (RCTs) about ACEIs and new-onset diabetes were identified by electronic and manual searches. Results: Nine RCTs with 92,404 patients (72,128 non-diabetic patients at baseline) were included in this study. Compared with control group, incidence of new-onset diabetes was significantly reduced in the ACEIs group [OR 0.80, (0.71, 0.91)], irrespective of achieved blood pressure levels at the follow-up. ACEIs therapy was associated with significant reduction in the risk of new-onset diabetes compared with beta-blockers/diuretics [OR 0.78, (0.65, 0.93)], placebo [OR 0.79, (0.64, 0.96)], or calcium channel blockers [OR 0.85, (0.73, 0.99)]. ACEIs treatment was associated with significant reduction in the risk of new-onset diabetes in patients with hypertension [OR 0.80, (0.68, 0.93)], coronary artery disease (CAD) or cardiovascular disease [OR 0.83, (0.68, 1.00)], or heart failure [OR 0.22, (0.10, 0.47)]. Among patients with impaired glucose tolerance or impaired fasting glucose, ramipril did not significantly reduce the incidence of diabetes [OR 0.91, (0.79, 1.05)], but significantly increased regression to normoglycemia. Conclusion: ACEIs have beneficial effects in preventing new-onset diabetes. ACEIs provide additional benefits of lowering the risk of new-onset diabetes in patients with hypertension, CAD or other cardiovascular disease. [Copyright &y& Elsevier]

Abstract: Background: Angiotensin receptor blockers (ARBs) have been linked to reduced risk of new-onset diabetes, but the evidence was insufficient. Objective and methods: The aim of this study was to evaluate the effect of ARBs on the development of new-onset type 2 diabetes. Randomized controlled trials (RCTs) about ARBs and new-onset diabetes were identified by electronic and manual searches. Results: Eleven RCTs with 79,773 patients (59,862 non-diabetic patients at baseline) were included in this study. Compared with control group, incidence of new-onset diabetes was significantly reduced in ARBs group [OR 0.79, (0.74, 0.84)] and various categories of ARBs subgroup. ARBs were associated with significant reduction in the risk of new-onset diabetes compared with placebo [OR 0.83, (0.78, 0.89)], beta-blocker [OR 0.73, (0.62, 0.87)], calcium channel blocker [OR 0.76, (0.68, 0.85)] and non-ARB [OR 0.57, (0.36, 0.91)]. ARBs were associated with significant reduction in the risk of new-onset diabetes in patients with hypertension [OR 0.74, (0.68, 0.81)], heart failure [OR 0.70, (0.50, 0.96)], impaired glucose tolerance [OR 0.85, (0.78, 0.92)] or cardiocerebrovascular diseases [OR 0.84, (0.72, 0.97)]. Compared with control group, incidence of new-onset diabetes was significantly reduced in ARBs group, irrespective of achieved blood pressure level. ARBs were associated with a lower incidence of new-onset diabetes in Western population [OR 0.81, (0.76, 0.85)] and Japanese population [OR 0.61, (0.48, 0.79)]. Conclusion: There is sufficient evidence that ARBs have beneficial effect in preventing new-onset type 2 diabetes. ARBs should be considered in patients with high risk of developing diabetes. [Copyright &y& Elsevier]

Abstract: Background: It remains unclear whether lowering postprandial glucose by alpha-glucosidase inhibitors (alpha-GIs) can prevent the progression of carotid intima-media thickness (IMT). Methods and results: We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to evaluate the effect of alpha-GIs on the progression of carotid IMT. Five RCTs with 411 patients were included in this study. Alpha-GIs therapy was associated with a significant reduction in the annual progression of carotid IMT (WMD, −0.06mm/year, 95% CI −0.11, −0.01; P =0.02) and the progression in carotid IMT at the end of follow-up (WMD, −0.07mm, 95% CI −0.12, −0.02; P =0.003). In subgroup analysis, alpha-GIs therapy was associated with a significant reduction in the annual progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM) (WMD, −0.08mm/year, 95% CI −0.10, −0.06; P <0.00001), and in the progression of carotid IMT in patients with impaired glucose tolerance (IGT) at the end of follow-up (WMD, −0.03mm, 95% CI −0.05, −0.01; P =0.01). Alpha-GIs treatment was associated with significant increase in HDL-C (WMD 1.56mg/dl, 95% CI 0.09, 3.03; P =0.04) and decrease in basal immunoreactive insulin as well as had favorable trends towards reducing HbA1c, triglyceride and diastolic blood pressure. Conclusion: It suggests that alpha-GIs therapy may be an effective strategy in preventing the progression of carotid IMT in patients with IGT or T2DM. It partially contributes to the improvement in atherogenic metabolic parameters induced by alpha-GIs. More studies, especially large multi-centre RCTs, are still warranted to further clarify the anti-atherosclerotic effect of alpha-GIs. [Copyright &y& Elsevier]

Abstract: Aims: To evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) on diabetic peripheral neuropathy (DPN). Methods: Randomized controlled trials (RCTs) comparing TENS with routine care, pharmacological interventions or placebo devices on patients with symptomatic DPN, were identified by electronic and manual searches. Studies were selected and available data were extracted independently by two investigators. Meta-analysis was performed by RevMan 4.2.8 software. Results: Three RCTs involving 78 patients were included in this study. The reductions in mean pain score were significantly greater in TENS group than in placebo TENS group in 4 weeks and 6 weeks follow-up [4 weeks, SMD-5.37, 95% CI (−6.97, −3.77); 6 weeks, SMD-1.01, 95% CI (−2.01, −0.01)], but not in 12 weeks follow-up [SMD-1.65, 95% CI (−4.02, 0.73)]. TENS therapy was associated with significantly subjective improvement in overall neuropathic symptoms in 12 weeks follow-up [WMD-0.18, 95% CI (−0.32, −0.051)]. No TENS-related adverse events were registered in TENS group. Conclusions: TENS therapy may be an effective and safe strategy in treatment of symptomatic DPN. Due to small sample and short-term treatment duration, large multi-centre RCTs are needed to further evaluate the long-term effect of TENS on DPN. [Copyright &y& Elsevier]

Abstract: Background: Recent experimental studies have demonstrated that thiazolidinediones (TZDs) therapy inhibits proliferation and migration of vascular smooth muscle cells, accelerates endothelium reparation and attenuates neointimal hyperplasia. It implies that TZDs therapy may have beneficial effects on in-stent restenosis (ISR). Several small-sample clinical trials have evaluated the effect of TZDs therapy on ISR, however, the results were inconsistent across trials. Methods and results: We performed a meta-analysis of all relevant randomized controlled trials to evaluate the effect of TZDs therapy on in-stent restenosis in patients undergoing coronary stenting. Eight trials involving 366 patients were included in this study. TZDs therapy was associated with a significant reduction in the risk of ISR in both diabetic (RR 0.37, 95% CI 0.23–0.59; P <0.0001) and non-diabetic patients (RR 0.16, 95% CI 0.05–0.45; P =0.0006). TZDs therapy was associated with a significant reduction in late lumen loss (WMD −0.54mm, 95% CI −0.87mm, −0.22mm; P =0.001), percent diameter stenosis (WMD −15.7%, 95% CI −19.4%, −12.0%; P <0.00001), neointimal area/volume (SMD −0.76, 95% CI −1.13, −0.39; P <0.0001) and target lesion revascularization (RR 0.32, 95% CI 0.18–0.57; P =0.0001). Conclusions: Our study suggests that TZDs therapy is an effective strategy in preventing ISR in both diabetic and non-diabetic patients undergoing coronary stenting. More studies, especially large multi-centre RCTs, are still warranted to further clarify the anti-restenotic effect of TZDs therapy. [Copyright &y& Elsevier]

Abstract: Background: It has been well established that cilostazol has anti-proliferative effect against in-stent restenosis. However, it remains unclear whether cilostazol can prevent the progression of carotid atherosclerosis. Methods and results: We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to evaluate the effect of cilostazol on the progression of carotid intima-media thickness (IMT). Five RCTs with 698 patients [597 subjects with type 2 diabetes mellitus (T2DM)] were included in this study. Cilostazol was associated with a significant reduction in the progression of carotid IMT (WMD, −0.08mm, 95% CI −0.13, −0.04; P =0.00003). Subgroup analysis shows that cilostazol monotherapy or addition to dual antiplatelet therapy (aspirin and clopidogrel) was superior to placebo (WMD, −0.04mm, 95% CI −0.05, −0.03; P <0.00001), no antiplatelet medication (WMD, −0.12mm, 95% CI −0.21, −0.03; P =0.008), aspirin monotherapy (WMD, −0.06mm, 95% CI −0.12, 0.00; P =0.04) or dual antiplatelet therapy (WMD, −0.16mm, 95% CI −0.30, −0.02; P =0.03) in preventing the progression of carotid IMT. Cilostazol resulted in a significant decrease in total cholesterol (WMD −8.47mg/dl, 95% CI −14.18, −2.75; P =0.004) and LDL-C (WMD −8.25mg/dl, 95% CI −14.15, −2.36; P =0.006) and favorable trends in reducing triglyceride (WMD −15.83mg/dl, 95% CI −32.14, 0.48; P =0.06). Conclusion: It suggests that cilostazol may have beneficial effects in preventing the progression of carotid atherosclerosis and improving pro-atherogenic lipid profile, especially in patients with T2DM. Whether the anti-atherosclerotic effect of cilostazol is independent of improving pro-atherogenic dyslipidemia is worth further investigation. [Copyright &y& Elsevier]