Efficacy and safety of lomitapide in familial chylomicronaemia syndrome.

BACKGROUND AND AIMS: Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS. METHODS: The open-label, single-arm 'LOCHNES' study of lomitapide in FCS enrolled patients >18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. RESULTS: Eighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452-2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219-801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%-32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment. CONCLUSIONS: Lomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

Lower and higher-potency statins on glycemic control in type 2 diabetes: A retrospective cohort study.

AIMS: Evidences showed a link between statins and new-onset diabetes and large clinical trials in type 2 diabetes (T2DM) suggested a mild glycemic progression in statin treated. Since this effect has not yet elucidated in real world, we investigated the effects of different statins on glycemia in T2DM clinic outpatients. METHODS: In a retrospective cohort study, we recorded at 6 and 12months modifications of fasting glucose (FPG), HbA1c, diabetes intensification therapy and target rate for HbA1c in 421 T2DM non-users and new statin users. Statins were categorized with low or high potency. RESULTS: Compared to statin users, no statin group showed a significant HbA1c reduction from 52.8±14.0mmol/mol to 48.2±8.5 (p=0.003) at 6months and 48.6±8.8 (p=0.007) at 12months. This trend without statins was also observed in FPG starting from 7.1±2.0mmol/l to 6.7±1.6 (p=0.12) at 6months and 6.6±1.5 (p=0.032) at 12months. Statins determined a significant diabetes treatment intensification: 48.7% vs 27.4% (p=0.002) with hazard ratio 2.4 [95% CI 1.14-5.2], p=0.022. HbA1c target was significantly lower in statin users 62.0% vs 75.4%, p=0.042. Only lower-potency statins showed a significant reduction of HbA1c from 52.0±11.1mmol/mol to 50.7±9.0 (p=0.017) and 50.7±9.5 (p=0.038) at 6 and 12months, respectively. The same effect for these statins was registered in FPG from 7.5±2.2mmol/l to 7.0±1.6 (p=0.021) at 6months and 7.2±1.5 (p=0.026) at 12months. CONCLUSIONS: In patients receiving statin therapy a greater intensification diabetes therapy is need. This impact seems to be less pronounced by statins with lower potency.

Variability of triglyceride levels and incidence of microalbuminuria in type 2 diabetes.

BACKGROUND: Experimental and clinical studies have shown a strong association between hypertriglyceridemia and diabetic nephropathy. A variability of triglyceride (TG) levels has been reported in diabetes. OBJECTIVES: To investigate the relationship of TG variability with the incidence of microalbuminuria (albumin excretion rate > 20 µg/min), in patients with type 2 diabetes. METHODS: A longitudinal, retrospective, observational study was performed on a consecutive series of 457 normoalbuminuric outpatients, with measurements of HbA1c, lipids and microalbuminuria thrice per year with 6.8-year follow-up. TG variability, defined as standard deviation of TG (TG-SD) and TG-SD adjusted for the number of visits was calculated. A nested case-control sensitivity analysis was performed to validate the results of the primary cohort study. RESULTS: Incident microalbuminuria (N = 124, 27.1%) was associated with higher median TG-SD (33.6 mg/dL vs 29.0 mg/dL, P < .05) and TG-SD adjusted for the number of visits (31.4 mg/dL vs 26.7 mg/dL, P < .05). At multivariate (Cox) analysis, logTG-SD and adj-logTG-SD were significant predictors of incident microalbuminuria (hazard ratio 2.1 [1.1-4.2], P = .028 and 1.5 [1.1-3.3], P = .042, respectively). In the case-control analysis, time spent with TG > 150 mg/dL during the follow-up was significantly higher in cases vs controls (27.2 ± 19 vs 16.7 ± 12.5 months, P < .05) with hazard ratio 2.0 (1.1-5.1), P < .05, for adj-logTG-SD. CONCLUSIONS: A higher intraindividual TG variability is a predictor of incident microalbuminuria in type 2 diabetes. In addition, time of exposure to elevated TG levels (>150 mg/dL) predicts incident microalbuminuria.

Cardiovascular effects of basal insulins.

Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence.

Correlation between HDL cholesterol levels and beta-cell function in subjects with various degree of glucose tolerance.

Some reports showed direct effects of high density lipoprotein cholesterol (HDL-C) on beta-cells survival and insulin secretion, suggesting an its role on glucose metabolism. We queried, whether subjects screened for type 2 diabetes (DM2) could display some impairment of beta-cell performance related to their HDL-C levels. A total of 1,087 clinical outpatients at risk of DM2 with no history of diabetes were studied. All participants were assessed for anthropometry, fasting lipid profile, and 2hOGTT with blood samples for plasma glucose and insulin determinations. Matsuda index of insulin sensitivity, early (insulinogenic index × Matsuda) and total (insulin secretion-sensitivity index-2 [ISSI-2]) indices of beta-cell function OGTT derived were applied. Linear regression analyzed the association between HDL-C levels and indices of beta-cell activity in subjects with normal glucose tolerance (NGT), impaired fasting glycemia (IFG), and impaired glucose tolerance (IGT). After adjustment for triglyceride levels, waist circumference, blood pressure and age, in total NGT subjects the HDL-C levels were not significantly associated with IGI × Matsuda (ß = 0.039, P = 0.10) and ISSI-2 index (ß = 0.069, P = 0.18), while in NGT with low HDL-C and IFG subjects the IGI × Matsuda (ß = 0.052, P = 0.019) and ISSI-2 indices (ß = 0.061, P = 0.023) were significantly associated with HDL-C levels. This significant linear correlation has been also observed in IGT patients for both indices (ß = 0.264, P = 0.0001 and ß = 0.191, P = 0.002, respectively). In conclusion, in subjects with impaired glucose regulation, HDL-C levels are associated with indices of beta-cell dysfunction; thus, more attention, it should be deserve to HDL-C concentrations in IFG/IGT patients due their potential conversion to DM2.

Lipid accumulation product and 25-OH-vitamin D deficiency in type 2 diabetes.

BACKGROUND: Emerging data suggest a link between vitamin D (25(OH)D) deficiency, type 2 diabetes (T2D), and visceral adiposity. The lipid accumulation product (LAP), strictly correlated with abdominal fat depots, is proposed as marker of dysfunctional adiposity. AIM: To verify the association between 25(OH)D levels and LAP in T2D. METHODS: Body mass index (BMI), waist circumference (WC), glucose, HbA1c, lipids, and 25(OH)D were assessed in 420 T2D outpatients and in 150 non-diabetic obese with similar anthropometric characteristics. LAP was computed as the product of sex-specific enlarged WC and triglycerides (TG). RESULTS: In T2D patients, 63.0% showed 25(OH)D deficiency (<20 ng/ml) vs. 71.3% in the obese control group. Overweight males showed a higher prevalence of 25(OH)D deficiency (60.3%) than women (48.8%, p < 0.001), while in obese patients this prevalence was not significant. In both genders, 25(OH)D was not significantly associated with HbA1c and fasting glucose. Age-adjusted 25(OH)D levels were inversely correlated with BMI (p < 0.001), WC (p < 0.001), and LAP (p < 0.001) in both genders. Metabolic syndrome presented an odds ratio (OR) for 25(OH)D deficiency of 1.6 (1.1-2.5, p = 0.048) in females and 1.7 (1.2-2.7, p = 0.016) in males, while the highest quartile of LAP showed an OR of 2.1 (1.2-3.6, p = 0.019) in females and 3.2 (1.6-6.5, p = 0.02) in males. A similar trend was observed in the obese control group. CONCLUSIONS: In the presence of excess weight, subjects with and without T2D frequently feature low 25(OH)D levels. Subjects with higher LAP exhibit a high risk of 25(OH)D deficiency, suggesting that dysfunctional adiposity is a worsening factor for vitamin D hypovitaminosis.

Lipids seasonal variability in type 2 diabetes.

OBJECTIVE: The objective was to evaluate the seasonal lipid variations in type 2 diabetic (DM2) outpatients. MATERIALS/METHODS: 302 (183 women and 119 men) DM2 subjects with or without statins therapy were screened. Body weight, HbA1c, total cholesterol (TC), high density lipoprotein (HDL-C), triglycerides (Trg) and low density lipoprotein cholesterol (LDL-C) were measured and patients' data of diet and physical activity were recorded during fall/winter (F/W) and spring/summer (S/S) seasons. RESULTS: HbA1c levels showed seasonal variability without statistical significance. During the colder seasons we observed an increase (P<.05) of weight associated with higher calorie intake and reduced physical activity. We showed a peak of TC, LDL-C and Trg levels during F/W while HDL-C levels were reduced. Median TC levels in F/W with respect to S/S were 197 vs 185 mg/dL (P<.001) without statins therapy and 172 vs 161 mg/dL (P<.001) in patients under statins therapy. Median LDL-C levels, without or with statin therapy, were 122 vs 114 mg/dL (P<.001) and 97.5 vs 88.5 mg/dL (P<.001), respectively. This seasonal lipids changes from F/W to S/S, modulated the percent of patients at LDL-C target <100 mg/dL, both without or under statins treatment: from 22% to 29.5% (P<.05) with odds ratio 0.73 (95% CI 0.62-0.87) and from 47% to 55% (P<.001) with odds ratio 0.68 (95% CI 0.58-0.76), respectively. CONCLUSIONS: DM2 patients showed a peak of TC and LDL-C during colder months associated with changes of diet and lifestyle habits. This seasonal lipid trend modified the percentage of patients at LDL-C therapeutical target.

Lipid levels in obese and nonobese subjects as predictors of fasting and postload glucose metabolism.

BACKGROUND: Dyslipidemia in the overweight/obese patient often is associated with impaired glucose metabolism. The authors of large clinical trials in different ethnic groups highlighted the correlation between glycemia and lipid profile, although the effect of abdominal adiposity was not explored. OBJECTIVE: To evaluate the relationship of visceral adiposity and lipid profile with fasting (FPG) and postload glucose (2hPG) in subjects without known diabetes (DM2). METHODS: A total of 3030 subjects were divided in three groups: obese subjects (OB; n = 490), nonobese subjects with an increased waist circumference (NOB/W+; n = 500), and nonobese subjects without an increased waist circumference (NOB/W-; n = 2040). We performed a linear regression analysis among lipid fractions and fasting and 2hPG in the three groups, with or without diagnosis of DM2 after 2hPG. RESULTS: Our data confirmed the significant association (P < .01) of high triglycerides and low high-density lipoprotein cholesterol (HDL-C) with fasting and 2hPG in all three groups such as for non-HDL cholesterol, whereas total cholesterol (TC) showed a significant correlation only with fasting glucose in OB and NOB/W+ subjects (P < .01). The analysis with or without DM2 demonstrated no difference in the statistical significance, although a better correlation in subjects without DM2 was observed. In addition, for each quartile of TC a significant trend (P < .01) in prevalence of fasting hyperglycemia in obese and in NOB/W+ patients was observed. CONCLUSION: This study suggests that triglycerides and HDL-C, together with non-HDL cholesterol, are associated with impaired fasting and 2hPG and that high total cholesterol levels are associated with abnormalities of fasting glucose metabolism only in patients with elevated waist circumference.

Dyslipidemia and diabetes: reciprocal impact of impaired lipid metabolism and Beta-cell dysfunction on micro- and macrovascular complications.

Patients with diabetes frequently exhibit the combined occurrence of hyperglycemia and dyslipidemia. Published data on their coexistence are often controversial. Some studies provide evidence for suboptimal lifestyle and exogenous hyperinsulinism at "mild insulin resistance" in adult diabetic patients as main pathogenic factors. In contrast, other studies confirm that visceral adiposity and insulin resistance are the basic features of dyslipidemia in type 2 diabetes (T2D). The consequence is an excess of free fatty acids, which causes hepatic gluconeogenesis to increase, metabolism in muscles to shift from glucose to lipid, beta-cell lipotoxicity, and an appearance of the classical "lipid triad", without real hypercholesterolemia. Recently, it has been proposed that cholesterol homeostasis is important for an adequate insulin secretory performance of beta-cells. The accumulation of cholesterol in beta-cells, caused by defective high-density lipoprotein (HDL) cholesterol with reduced cholesterol efflux, induces hyperglycemia, impaired insulin secretion, and beta-cell apoptosis. Data from animal models and humans, including humans with Tangier disease, who are characterized by very low HDL cholesterol levels, are frequently associated with hyperglycemia and T2D. Thus, there is a reciprocal influence of dyslipidemia on beta-cell function and inversely of beta-cell dysfunction on lipid metabolism and micro- and macrovascular complications. It remains to be clarified how these different but mutually influencing adverse effects act in together to define measures for a more effective prevention and treatment of micro- and macrovascular complications in diabetes patients. While the control of circulating low-density lipoprotein (LDL) cholesterol and the level of HDL cholesterol are determinant targets for the reduction of cardiovascular risk, based on recent data, these targets should also be considered for the prevention of beta-cell dysfunction and the development of type 2 diabetes. In this review, we analyze consolidated data and recent advances on the relationship between lipid metabolism and diabetes mellitus, with particular attention to the reciprocal effects of the two features of the disease and the development of vascular complications.

Metformin and cancer occurrence in insulin-treated type 2 diabetic patients.

OBJECTIVE: Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. RESEARCH DESIGN AND METHODS: A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort. RESULTS: During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25-0.85], P = 0.014 and 0.75 [0.39-1.45], P = 0.40, respectively). CONCLUSIONS: The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.

Vascular endothelial growth factor receptor-2 and low affinity VEGF binding sites on human glomerular endothelial cells: Biological effects and advanced glycosilation end products modulation.

Vascular Endothelial Growth Factor (VEGF), binding to its receptor in endothelial cells, seems to modulate the increased blood flow in the early phase of diabetic renal disease. The aim of the study was to evaluate, in a diabetic milieu, the expression, biological function and modulation of VEGF binding sites in human glomerular endothelial cells (GENC). We demonstrated the presence of VEGF binding sites with high (VEGFR-2) and low (heparan sulfate proteoglycans, HSPG) affinity. VEGF165 and VEGF121 working through VEGFR-2 stimulated nitric oxide (NO) production at low doses (0.1-1 nM), whereas only VEGF165 at high doses (10-100 nM) increased thymidine incorporation. 1 nM VEGF165 and VEGF121 induced in GENC a significant peak of inducible NO synthase (iNOS) production and, at a lower level, of endothelial NOS (eNOS). The copresence of VEGF165 with aminoguanidine (iNOS inhibitor) determined an increase of eNOS and a significant increase in thymidine incorporation. Advanced glycation end products (AGEs) working through specific receptors (RAGE) up-regulated the expression of VEGFR-2, decreased the expression of HSPG sites and reduced GENC growth. These results identify in GENC VEGFR-2 as a mediator of iNOS and eNOS release under control of VEGF, whereas HSPG binding sites seem to mediate the weak growth effect. The presence of AGEs, up-regulating the VEGFR-2 and decreasing HSPG sites might participate to the block of glomerular angiogenesis addressing the VEGF effects on glomerular permeability.

AT1 and AT2 receptors in human glomerular endothelial cells at different passages.

In human adult kidney angiotensin II (AngII) effects are mediated by the AT1 receptor, while the functions of AT2 receptors are mostly unknown. Since AngII regulates endothelial cell growth by AT1 and AT2 receptors, we analysed their functional aspects at different passages in human glomerular endothelial cells (GENC). Semiquantitative reverse transcription-polymerase chain reaction revealed the presence of AT1 and AT2 receptors between 2p and 15p cell passages with different levels of expression. In fact, binding studies of different families of displacement curves using AngII, DUP753 (AT1 antagonist), and PD123177 (AT2 antagonist) showed the presence of AT1a and AT2 receptors at 4p-9p while in GENC 2p only the presence of AT2. In terms of mitogenic activity, AngII was unable to stimulate GENC 2p growth. On the contrary, in GENC 4p-9p and 15p a significant thymidine incorporation was observed. This stimulatory effect seemed to be induced also by the concomitant release of PDGF-BB AT1a mediated. In conclusion, AT1a and AT2 receptors are represented in GENC with a different ratio depending upon the cell passage. AngII regulates the mitogenic effect through AT1a receptors (in later cell passages 4p-15p) involving the release of PDGF-BB, while AT2 (in early cell passage 2p) showed a predominant negative growth control.

An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.

The chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC regulate lymphocyte chemotaxis, mediate vascular pericyte proliferation, and act as angiostatic agents, thus inhibiting tumor growth. These multiple activities are apparently mediated by a unique G protein-coupled receptor, termed CXCR3. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including a powerful angiostatic effect, but its specific receptor is still unknown. Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4. Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. Overexpression of CXCR3-A induced an increase of survival, whereas overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways. Remarkably, primary cultures of human microvascular endothelial cells, whose growth is inhibited by CXCL9, CXCL10, CXCL11, and CXCL4, expressed CXCR3-B, but not CXCR3-A. Finally, monoclonal antibodies raised to selectively recognize CXCR3-B reacted with endothelial cells from neoplastic tissues, providing evidence that CXCR3-B is also expressed in vivo and may account for the angiostatic effects of CXC chemokines.

The role of insulin-like growth factor-II in cancer growth and progression evidenced by the use of ribozymes and prostate cancer progression models.

Towards understanding the IGF system during cancer growth and progression, progressive prostate cancer models, such as SV40 large T antigen immortalized human prostate epithelial cells (P69, M2182, M2205, and M12) and LNCaP sublines (C4, C4-2, and C4-2B4), were used. IGF-II mRNA levels progressively increase as prostate cancer cells become more tumorigenic and metastatic, suggesting that IGF-II contributes in part to prostate cancer progression. The role of IGF-II in cancer cell growth was evaluated in LNCaP, PC3, and M12 prostate cancer cell lines and MCF-7 breast cancer cell line by ribozyme/antisense strategies which were previously shown to suppress endogenous IGF-II expression and cell growth in PC-3 cells [Xu et al., Endocrinol 140 (1999) 2134]. Retroviral mediated transient expression of IGF-II-specific ribozyme (RZ) caused extensive cell death. In stably cloned cell lines, both RZ and mutant ribozyme (MRZ) inhibited cancer cell growth, suggesting that antisense effects of MRZ may be sufficient for cell growth inhibition. These results confirm an important role of IGF-II in cancer cell growth and progression, and support further development of gene therapy targeting IGF-II.