Update on Management of Type 2 Diabetes for Cardiologists.

The management of type 2 diabetes mellitus has evolved over the last several years as new antidiabetic agents continue to arrive and change the goals of diabetes care. In 2008, the U.S. Food and Drug Administration mandated that all new antidiabetic agents must demonstrate cardiovascular (CV) safety, which has led to a series of CV outcome trials. In this article, we review the key findings from these CV outcome trials and their impact on diabetes care guidelines.

Analysis of VEGFA Variants and Changes in VEGF Levels Underscores the Contribution of VEGF to Polycystic Ovary Syndrome.

BACKGROUND: Vascular endothelial growth factor (VEGF) contributes to the pathogenesis of polycystic ovary syndrome (PCOS), and genetic variations in VEGFA gene were suggested to contribute to VEGF secretion and PCOS. AIM: To evaluate the association of altered VEGF levels, stemming from the presence of specific VEGFA variants, with altered risk of PCOS. SUBJECTS AND METHODS: Retrospective case-control study, performed between 2012-2015. Study subjects comprised 382 women with PCOS, and 393 control subjects. ELISA measured VEGF levels; genotyping of VEGFA variants was done by allelic exclusion. RESULTS: Among the 12 tested VEGFA SNPs, minor allele frequency of only rs3025020 was significantly higher in PCOS cases than control women. Increased and reduced PCOS risk was seen with rs3025020 and rs2010963 genotypes, respectively. Increases and reduction in VEGF levels were associated with rs3025020 and rs2010963, respectively. Increased fasting insulin and HOMA-IR, and bioactive testosterone were linked with rs3025020, while carriage of rs2010963 was linked with reduction in fasting insulin, and free and bioactive testosterone. Of the 12 VEGFA variants, 9 were in LD, thus allowing construction of 9-locus haplotypes. Increased frequency of CAACAGCGA haplotype was seen in PCOS cases, after controlling for BMI, free and bioactive testosterone, SHBG, free insulin and HOMA-IR. CONCLUSION: This study confirms the contribution of altered VEGF secretion, resulting from genetic variation in VEGFA gene into the pathogenesis of PCOS. This supports a role for VEGF as PCOS candidate locus.

Common Variants in the Sex Hormone-Binding Globulin (SHBG) Gene Influence SHBG Levels in Women with Polycystic Ovary Syndrome.

BACKGROUND: Decreased sex hormone-binding globulin (SHBG) levels were associated with polycystic ovary syndrome (PCOS). SHBG polymorphisms associated with reduced SHBG production were tested for their association with PCOS, but with inconclusive results. We tested whether altered SHBG levels and SHBG variants were associated with PCOS. METHODS: The study subjects included 242 women with PCOS and 238 control women. SHBG genotyping was done by real-time PCR. RESULTS: Higher minor allele frequency of rs13894, rs858521 and rs727428 was seen in PCOS cases, and significant differences in rs858521 and rs727428 genotypes distribution were seen between PCOS cases and controls. Multivariate regression analysis confirmed the association of only rs727428 with PCOS. Though it was not statistically significant, serum SHBG levels were reduced according to rs727428 genotypes in PCOS cases than in controls. Carriage of rs727428 minor allele was associated with significant increases in free/bioactive testosterone in PCOS cases. Seven-locus (rs9898876-rs13894-rs858521-rs1799941-rs6257-rs6259-rs727428) haploview analysis showed increased frequency of GCCGTGA, GTCGTGA and GTCATGG, and reduced frequency of GTCGTGG haplotypes in PCOS cases than in controls, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. CONCLUSION: Specific SHBG variants affecting serum SHBG levels and SHBG haplotypes are associated with PCOS, suggesting the role for SHBG as PCOS candidate gene.

Transcription Factor-7-Like 2 Gene Variants Affect the Metabolic Phenotypes of Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy, which shares genetic features with type 2 diabetes mellitus (T2DM). Insofar as transcription factor 7-like 2 (TCF7L2) is consistently replicated T2DM susceptibility locus, this study evaluates whether common TCF7L2 variants are associated with PCOS and related metabolic features. METHODS: The association between TCF7L2 rs4506565, rs7903146, rs12243326, and rs12255372 SNPs and PCOS was tested in 242 women with PCOS and in 236 control women. RESULTS: The allelic distribution of rs4506565, rs7903146, rs12243326, and rs12255372 TCF7L2 variants was not significantly different between women with PCOS and control women. The genotype distribution of the 4 TCF7L2 loci was comparable between PCOS cases and controls, irrespective of the genetic analysis model used (additive, dominant, recessive). Carriage of rs4506565 minor allele correlated with free insulin and homeostasis model assessment of insulin resistance, while the presence of rs12243326 and rs12255372 minor allele correlated with waist changes. Four-locus (rs4506565-rs7903146, rs12243326, and rs12255372) haplotype analysis identified PCOS-susceptible (ACTG) and -protective (TTTG) haplotypes, which remained significant after controlling for multiple comparisons and for key covariates. CONCLUSIONS: Although individual TCF7L2 variants were not associated with the presence of PCOS in Bahraini women, specific TCF7L2 haplotypes were identified, which were both positively and negatively associated with PCOS.

DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome.

Recent genome-wide association studies and replication analyses reported an association between variants of DENND1A gene and polycystic ovary syndrome (PCOS), mostly in Asians. We therefore examined whether the common DENND1A SNPs rs10818854, rs2479106, and rs10986105 are associated with PCOS in Bahraini Arab population. This case-control study involved 191 women with PCOS diagnosed according to the Rotterdam criteria, and 202 control women. SNP genotyping was performed by the allelic discrimination in real-time PCR. The outcome was that the minor allele frequencies of SNPs rs10818854, rs2479106, and rs10986105 were similar between women with PCOS and control women (P>0.05), even before correcting for multiple testing, and none of the tested DENND1A SNPs were associated with PCOS under co-dominant, dominant, or recessive genetic models. None of the tested DENND1A variants were associated with PCOS features (hirsutism, insulin sensitivity, menses pattern, free testosterone, and free androgen index). Taking common GTA haplotype as reference (OR=1.00), [rs10818854/rs2479106/rs10986105] 3-locus haplotype analysis demonstrated lack of association of any of the DENND1A haplotypes with PCOS, even before correcting for multiple testing. To conclude we demonstrated lack of association of DENND1A SNPs rs10818854, rs2479106, and rs10986105, previously associated with PCOS in Asians, with PCOS in Bahraini Arab women.

Is the "3+3" dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design.

PURPOSE: Phase I clinical trials are generally conducted to identify the maximum tolerated dose (MTD) or the biologically active dose (BAD) using a traditional dose-escalation design. This design may not be applied to cancer vaccines, given their unique mechanism of action. The FDA recently published "Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines." However, many questions about the design of cancer vaccine studies remain unanswered. EXPERIMENTAL DESIGN: We analyzed the toxicity profile in 239 phase I therapeutic cancer vaccine trials. We addressed the ability of dose escalation to determine the MTD or the BAD in trials that used a dose-escalation design. RESULTS: The rate of grade 3/4 vaccine-related systemic toxicities was 1.25 adverse events per 100 patients and 2 per 1,000 vaccines. Only two of the 127 dose-escalation trials reported vaccine-related dose limiting toxicities, both of which used bacterial vector vaccines. Out of the 116 trials analyzed for the dose-immune response relationship, we found a statistically significant dose-immune response correlation only when the immune response was measured by antibodies (P < 0.001) or delayed type hypersensitivity (P < 0.05). However, the increase in cellular immune response did not appear further sustainable with the continued increase in dose. CONCLUSIONS: Our analysis suggests that the risks of serious toxicities with therapeutic cancer vaccines are extremely low and that toxicities do not correlate with dose levels. Accordingly, the conventional dose-escalation design is not suitable for cancer vaccines with few exceptions. Here, we propose an alternative design for therapeutic cancer vaccine development.