HMG-CoA reductase inhibitors prevent bone loss in patients with Type 2 diabetes mellitus.

AIMS: It has been reported that 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors increase bone mineral density (BMD) in vivo. We investigated the effect of HMG-CoA reductase inhibitors on BMD in patients with Type 2 diabetes mellitus. PATIENTS AND METHODS: We selected 122 patients with Type 2 diabetes, who were not taking active vitamin D preparations. Their mean age was 67.3 +/- 9.2 years. They were divided into a control group (n=63) without HMG-CoA reductase inhibitor therapy and an HMG-CoA group (n=59) who were treated with these drugs. The BMD of the distal one-third of the radius was measured by dual-energy X-ray adsorptiometry at baseline and after 2 years. RESULTS: There were no significant differences between the control and HMG-CoA groups at baseline with respect to age, gender, body mass index, duration of diabetes, haemoglobin A1c, fasting plasma glucose, adjusted calcium, serum phosphorus, alkaline phosphatase, albumin excretion rate and radial BMD. However, there was a significantly smaller annual decrease of the radial BMD in the HMG-CoA group. Multiple regression analysis with a forward elimination procedure revealed a positive correlation of the radial BMD Z-score with body mass index, while there was a negative correlation with alkaline phosphatase and albumin excretion rate. In addition, the annual rate of change of the radial BMD showed a positive correlation with HMG-CoA reductase inhibitor therapy. CONCLUSIONS: These findings suggest that HMG-CoA reductase inhibitors may prevent bone loss in patients with Type 2 diabetes.     

Pharmaco-economic impact of HMG-CoA reductase inhibitors in type 2 diabetes.

Dyslipidemia is very common in diabetics and substantially increases the risk of fatal and non-fatal cardiovascular disease. Pharmacological therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') is effective for dyslipidemia, but the cost and efficacy of individual therapies vary. Therefore, the interest in cost-effective pharmacologic interventions for the prevention of cardiovascular disease events in diabetics has increased. In this article, the literature pertaining to the epidemiology, cost and efficacy of statins in preventing cardiovascular disease in patients with type 2 diabetes mellitus, in both the primary and secondary prevention settings, is reviewed. Cost-effectiveness studies of statins in the diabetic population are detailed, along with recommendations for further research.     

The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes.

Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% ( P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.     

Hypolipidemic effects of HMG-CoA reductase inhibitors in patients with hypercholesterolemia

Hypercholesterolemia with increased plasma concentrations of low density lipoproteins (LDL) is a major risk factor for the premature development of coronary atherosclerosis in humans and is best exemplified by patients with familial hypercholesterolemia. The recent development of several specific competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG CoA reductase) has opened up an important new avenue of therapy for patients with hypercholesterolemia who are not responsive to dietary treatment alone. Three drugs, lovastatin (mevinolin), simvastatin (synvinolin) and pravastatin (CS 514), are currently undergoing clinical trials in North America and Europe; the former has recently been approved for general use. Experience with lovastatin and simvastatin in the treatment of patients with primary and secondary causes of hypercholesterolemia is reviewed. The relative potency of simvastatin appears to be greater than that of lovastatin and pravastatin but, with each drug, decreases in the plasma concentrations of LDL cholesterol of 30% to 50% can be achieved. The hypocholesterolemic effects of HMG CoA reductase inhibitors can be potentiated by combination therapy with other approved lipid-lowering medications including the bile acid sequestrants and nicotinic acid. If long-term safety can be satisfactorily established, specific inhibitors of HMG CoA reductase represent a major advance in the therapy of hypercholesterolemia and afford the potential to reduce substantially the high incidence of premature atherosclerosis that occurs in patients with persistent hypercholesterolemia.     

HMG-CoA reductase inhibitors suppress the development and progression of carotid artery intimal-medial thickening in hypercholesterolemic type 2 diabetic patients

We reported previously that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (RIs) suppressed in vitro oxidized-low density lipoprotein-induced macrophage growth. To elucidate whether HMG-CoA RIs have anti-atherogenic effects separate from their cholesterol-lowering effect, total plasma levels of cholesterol in patients with type 2 diabetes mellitus (type 2 DM) and hypercholesterolemia were reduced to normal by one-year treatment with HMG-CoA RIs and intimal-medial thickness (IMT) of the common carotid arteries (CCA) was measured. Patients with type 2 DM and hypercholesterolemia received either pravastatin (n = 15) or simvastatin (n = 15), while another group of type 2 DM patients with normocholesterolemia did not receive these agents. IMT of the CCA was measured using Powervision SSA-370A, probe 7.5 Mhz. The mean IMT and the rate of increase of IMT were relatively elevated in the order of the simvastatin-treatment group, pravastatin-treatment group, and control group. Our results suggested that HMG-CoA RIs might have anti-atherogenic effects in addition to their cholesterol-lowering effect.     

HMG-CoA reductase inhibitors and the kidney

HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) have been shown to reduce serum cholesterol and cardiovascular morbidity and mortality. The mechanisms of these beneficial effects are reviewed. Altered inflammatory responses and improved endothelial function mediated by statins are thought to be, in part, responsible for the reduction in cardiovascular events. It has not been well established whether statins confer similar benefits to the kidney. In this review, we critically consider the available data whereby dyslipidemia mediates renal dysfunction by modulating the inflammatory response to diverse cytokines. We also review the emerging database suggesting that statins may modulate renal dysfunction by altering the response of the kidney to dyslipidemia, particularly in patients with end-stage renal disease (ESRD) and post-kidney transplant.     

Pleiotropic effects of HMG-CoA reductase inhibitors

HMG CoA reductase inhibitiors (statins) have been shown to be effective lipid lowering agents and are able to significantly reduce cardiovascular mortality and morbidity in patients at risk for cardiovascular disease. Recent clinical and experimental data suggest that the benefit of statins may extend beyond their hepatic effects on serum cholesterol levels. This review summarizes the current evidence and the molecular mechanisms of the direct effects of statins on plaque stability, inflammation, endothelial function, oxidative stress, thrombosis and stroke. Furthermore, recent data on the effects of statins on bone marrow, bone density and dementia are described. In summary, statins have emerged as a novel and powerful tool to study cardiovascular biology, including protein isoprenylation, small G protein function, leukocyte activity and endothelial progenitor cells. These pleiotropic properties of statins may have important clinical implications in addition to lowering serum cholesterol. Received: 10 October 2001, Accepted: 24 October 2001     

HMG-CoA reductase inhibitors induce apoptosis in pericytes

Pericytes, which surround endothelial cells in precapillary arterioles, capillaries, and postcapillary venules, are important for the development, maturation, and maintenance of the vascular system. Pericytes are also pluripotent cells that can differentiate into a variety of mesenchymal cells including smooth muscle cells and osteoblasts. Possibly because of their vasculature regulating activities and ability to differentiate in situ, pericytes are implicated in several diseases with vascular complications, including diabetic retinopathy, as well as Reynaud's Syndrome, central nervous system dementias, and vascular calcification among others. Statin drugs, which block the conversion of HMG-CoA to mevalonate in the cholesterol synthesis pathway, are known to have apoptotic and growth inhibitory effects on cells in vitro and complex pleiotropic effects on cells and tissues in vivo. Recently, evidence has emerged that statin drug use in human patients results in a significant 20% reduction in cancer incidence. It is not known whether these results are due to direct statin action on normal tissue, growth inhibitory/pro-apoptotic effects on tumor cells, and/or effects on angiogenesis. Because of the role of pericytes in angiogenesis and the effects of statins on cancer incidence, we tested the direct effects of statins on pericytes. Specifically, we demonstrate that 3 statins, simvastatin, lovastatin, and mevastatin induce dose-dependent apoptosis in the TR-PCT1 pericyte cell line, that simvastatin (empirically shown to be the most potent of the 3 statins) induces similar levels of apoptosis in freshly isolated pericytes, and that simvastatin-induced apoptosis in pericytes is cholesterol, caspase-3, and caspase-7 mediated.     

SGLT2抑制剂治疗2型糖尿病的相关研究

钠-葡萄糖协同转运蛋白2( SGLT2)存在于近端肾小管上皮细胞,在肾脏血糖的重吸收中发挥重要作用,因此选择性抑制SGLT2活性,从而特异性抑制肾脏对葡萄糖的重吸收,增加尿糖排泄可以达到降糖目的.目前研发的SGLT2抑制剂包括T-1095、BI-10773、dapagliflozin等.SGLT2抑制剂与体重、低血糖、糖尿病肾病、泌尿系统感染及口渴、多饮、多尿症状的关系未明确,目前已有大量研究证明了其有效性及安全性,这将为糖尿病患者提供一种新的降糖途径.     

Effects of sodium-glucose cotransporter-2 inhibitors on appetite markers in patients with type 2 diabetes mellitus

Background and aimsGlycosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to weight loss and improved diabetes control, but a significant disparity exists between observed and expected weight loss with these medications, hindering clinical effects. This study investigated whether this discrepancy could be explained by compensatory increases in appetite and associated alterations in appetite-regulating hormones.Methods and resultsThis was a prospective single-center observational pilot study. Adults 18–70 years old newly prescribed an SGLT2 inhibitor through usual care were invited to participate. Fasting and postprandial appetite was assessed immediately before, 1 week after, and 12 weeks after SGLT2 inhibitor initiation. Serum samples were collected at corresponding time points to measure ghrelin, leptin, and peptide tyrosine–tyrosine (PYY). Seven patients were included. At 1 and 12 weeks after SGLT2 inhibitor initiation, self-reported appetite did not change significantly and trended toward a decrease in appetite. There were no significant differences in fasting or postprandial ghrelin, leptin, or PYY.ConclusionResults suggest the discrepancy between expected and observed weight loss with SGLT2 inhibitors cannot be explained by increases in appetite or changes in appetite-regulating hormones. Further studies are needed to investigate alternative metabolic compensatory mechanisms to optimize weight loss with SGLT2 inhibitor use.     

HMG-CoA reductase inhibitors and coenzyme Q10

The most concerning adverse reaction with HMG-CoA reductase inhibitors (statins) is myotoxicity. Statins inhibit the production of mevalonate, a precursor of both cholesterol and coenzyme Q10, a compound believed to be crucial for mitochondrial function and the provision of energy for cellular processes. There is speculation that a reduction in coenzyme Q10 concentrations may promote the myopathies that have been associated with statin treatment as a result of mitochondrial damage. Although studies have repeatedly demonstrated a reduction in circulating coenzyme Q10 concentrations with statin therapy, it is unclear as to whether tissue levels of coenzyme Q10 are significantly affected. Coenzyme Q10 supplementation has been shown to reverse statin-induced decreases in circulating coenzyme Q10 concentrations, although the effect of supplementation on tissue coenzyme Q10 concentrations and any resulting clinical benefit has not been adequately assessed. Although there is not much of a safety concern with coenzyme Q10 supplementation, there is also not enough evidence to support its routine use for preventing the adverse effects of statin therapy, and it is therefore not recommended for this purpose at this time.     

Direct vascular effects of HMG-CoA reductase inhibitors

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, or statins, are potent inhibitors of cholesterol synthesis and large clinical trials have demonstrated that these agents reduce cholesterol and the incidence of cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Because statins also inhibit the synthesis of isoprenoid intermediates in the cholesterol biosynthetic pathway, they may have pleiotropic effects on vascular wall cells. In particular, the small GTP-binding protein, Rho, whose membrane localization and activity are affected by post-translational isoprenylation, may play an important role in mediating the direct vascular effects of statins.     

Inhibition of HMG-CoA reductase with cerivastatin lowers dense low density lipoproteins in patients with elevated fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus.

OBJECTIVE: While 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors effectively decrease LDL cholesterol, it remains controversial whether these agents also lower dense LDL, which are considered particularly atherogenic. METHODS: We examined the effects of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin on lipids, lipoproteins, and apolipoproteins in 69 patients with elevated fasting glucose, impaired glucose tolerance, or type 2 diabetes, combined hyperlipoproteinemia and increased concentrations of dense LDL (apo B in LDL-5 plus LDL-6 > 25 mg/dl). The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n = 34) and placebo (n = 35). RESULTS: Cerivastatin significantly reduced cholesterol (- 20 %, p < 0.001), IDL cholesterol - 37 %, p < 0.001), LDL cholesterol (- 26 %, p < 0.001), apolipoprotein B (- 25 %, p < 0.001), triglycerides (- 12 %, p < 0.05), and raised HDL cholesterol (+ 7.5 %, p < 0.05) and apolipoprotein AI (+ 7.2 %, p < 0.05). Cerivastatin signficantly lowered apolipoprotein B in all LDL subfractions (- 21 to - 28 %, p < 0.05). Absolute changes were greatest in dense LDL and the change in dense LDL made the largest contribution to the change of total LDL. The change of dense LDL was highly correlated with baseline values. There was no consistent relationship between the effect of cerivastatin on triglycerides and the decrease of dense LDL. CONCLUSIONS: The HMG CoA reductase inhibitor cerivastatin lowers total and LDL cholesterol and the concentration of dense LDL in patients with elevated fasting glucose, impaired glucose tolerance or type 2 diabetes.     

Insulin therapy may increase blood pressure levels in type 2 diabetes mellitus

OBJECTIVE: To assess the effects of insulin therapy on blood pressure levels in type 2 diabetes mellitus (T2 DM). MATERIAL AND METHODS: This is a retrospective analysis of clinical records of 313 T2DM patients (125 men and 188 women), excluding those with proteinuria or hypertensive diseases and those taking drugs that may influence blood pressure levels except antihypertensive therapy. Mean age was 56.3 +/- 11.7 years and mean duration of diabetes was 7.1 +/- 5.5 years. After one week of observation under diet and maximal doses of oral antidiabetic drugs, patients who did not improve their glucose control were changed towards insulin therapy (n=129) and formed the insulin treated group (ITG), those who improved their glucose levels were maintained under oral therapy (n=184) and formed the orally treated group (OTG). Blood pressure levels were compared between the two groups at baseline and after a mean follow-up period of 12.1 +/- 6.1 months. Hypertension was considered if patients were known and treated or if SBP >=140 mmHg and/or DBP >=90 mmHg. RESULTS: At baseline, patients in ITG were moderately older (58.4 +/- 11 vs 54.9 +/- 12.1 years, p<0.05), had a longer duration of diabetes (9.2 +/- 6.2 vs 5.7 +/- 5 years, p<0.01), a lower BMI (24.6 +/- 4.6 vs 28.8 +/- 6.6 kg/m(2), p<0.01) and a higher frequency of retinopathy (44% vs 31.1%, p<0.05). There was no significant difference regarding sex ratio, WHR, family history of hypertension, plasma levels of creatinine and lipid parameters. SBP, DBP and frequency of hypertension were similar in both groups at baseline. After follow up, insulin treated group exhibited higher levels of SBP (150 +/- 25.7 vs 138.6 +/- 27.1 mmHg, p<0.001) and DBP (84.1 +/- 13 vs 75.8 +/- 14.9 mmHg, p<0.001) than orally treated group. Progression rate of hypertension frequency was mildly but not significantly higher in ITG than in OTG (+21% vs +12%, p=0.08) and was associated with weight gain in ITG only. SBP increase was mildly correlated with weight gain (p=0.06). In ITG, higher values of BMI (> 27 kg/m(2)) at baseline were associated with the highest increases of blood pressure levels under insulin therapy. No significant relationship was found with insulin doses. CONCLUSION: Insulin therapy may contribute to the development of hypertension in T2DM obese patients. Additional prospective randomised studies are required for a better appreciation of such influence.     

SGLT2抑制剂对2型糖尿病患者血尿酸水平的影响

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一种新型降糖药,可控制血糖、降低心血管事件、改善肾功能等。越来越多的数据表明,SGLT2抑制剂也可降低血尿酸水平。可能的机制是近端肾小管腔内葡萄糖的排泄增强,通过顶端膜上葡萄糖转运蛋白(GLUT)9亚型2促进细胞内尿酸盐的交换,导致尿酸分泌增加,且SGLT2抑制剂抑制肾小管重吸收葡萄糖,导致尿中葡萄糖增加,这可能会抑制集合管中GLUT9亚型2介导的尿酸重吸收。另一种可能的机制是SGLT2抑制剂通过降低血清胰岛素浓度,减少尿酸盐重吸收转运蛋白1(URAT1)对尿酸的重吸收。     

Use of sodium–glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus

Aim

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long‐term use of SGLT2 inhibitors in older patients with diabetes.

Methods

A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016.

Results

The mean age of the patients was 73.7 ± 10.0 years. During the follow‐up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow‐up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment.

Conclusions

In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108–114 .