Type 2 Diabetes Mellitus Cardiovascular Risk Research Articles

“COMPARISON OF ATHEROGENIC INDEX OF PLASMA AND CHOLESTEROL/HDL RATIO AMONG TYPE 2 DIABETES MELLITUS PATIENTS IN A TERTIARY CARE HOSPITAL”

Lipid prole though is a well established parameter to predict cardio vascular risk in patients suffering from type 2 diabetes mellitus(T2DM), at present lipid ratios are replacing these age old parameters. Among the lipid ratios Atherogenic index of plasma(AIP) and cholesterol/HDL(Chol/HDL) are found to be of great signicance. This cross-sectional study aimed to compare the predictive value of two lipid ratios, "Atherogenic index of plasma" (AIP) and "Cholesterol/HDL ratio" on basis of insulin resistance (IR) among 55 newly diagnosed cases with Type 2 Diabetes Mellitus (T2DM) and 50 control subjects. HOMA –IR (p value <0.0001), AIP (<0.001) and Cholesterol/HDL ratio (<0.001) were signicantly raised among case group in comparison to controls. Both AIP(r- 0.305, p-0.002) and Chol/HDL ratio(r- 0.23, p value- 0.018) was signicantly correlated with HOMA-IR. ROC curve of AIP and Chol/HDL ratio was plotted for identifying IR. There is no signicant difference between areas under curve (AUC) of AIP (AUC-0.656) and Chol/HDL ratio(AUC-0.630) (p value- 0.49). AIP was found to be correlated better with Insulin resistance than CHOL/HDL ratio. AUC in AIP was found to be slightly higher and overall sensitivity and specicity of AIP was found to be 66% and 69%, of Chol/HDL ratio was 46% and 76% to identify moderate to high-risk group: whereas it is 69%&47% of AIP and 87% and 32% of Chol/HDL ratio to identify low risk group. Both lipid ratios have some signicance in predicting cardio vascular risk in T2DM

SPPARM alpha: the Lazarus effect.

Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.

T cell activation and cardiovascular risk in type 2 diabetes mellitus: a protocol for a systematic review and meta-analysis

IntroductionThe burden of non-communicable diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) has drastically increased in developing countries over the years. Although recent evidence points to chronic immune activation to be a significant aspect in the pathogenesis and development of T2DM and CVDs, the exact role of T cells is not fully understood. Therefore, we aim to investigate T cell function and cardio vascular risk in T2DM. In addition, the therapeutic effect of blood glucose-lowering drugs to reverse hyperglycaemia induced T cell dysfunction and myocardial infarction will be reviewed.MethodsThis will be a systematic review and meta-analysis of published studies assessing T cell activation and cardiovascular risk in adults with T2DM. The search strategy will include medical subject headings (MeSH) words for PubMed/MEDLINE database. The search terms will also be adapted to grey literature, Embase and Cochrane Central Register of Controlled Trials electronic databases. Studies will be independently screened by two reviewers using predefined criteria. Relevant eligible full texts will be screened and data will be extracted. Data extraction will be performed using a pre-piloted structured form. To assess the quality and strengths of evidence across selected studies, the Grading of Recommendations Assessment Development and Evaluation approach will be used. The Cochran’s Q statistic and the I2 statistics will be used to analyse statistical heterogeneity between studies. If included studies show substantial level of statistical heterogeneity, a random-effects meta-analysis will be performed using R statistical software.DiscussionsThis review will not require ethical approval, and the findings will be disseminated through peer-reviewed publication and conferences. Although other previous studies have reported deregulated T cell function in hyperglycaemia, the underlying mechanisms remain controversial. However, evidence suggests that T cells may be a key component in the development of T2DM and CVDs as its complication. Furthermore, they are a potential diagnostic and therapeutic target in the management of the disease.Systematic review registrationPROSPERO CRD42018099745

Evaluation of the role of CDKN2B gene in type 2 diabetes mellitus and hypertension in ethnic Saudi Arabs

BackgroundCoronary heart disease (CAD) is a multiple with several contributory risk traits, including type 2 diabetes and hypertension, which may share common genetic risk variants with the disease. Genome-wide association studies (GWASs) have yielded a wealth of information suggesting that CAD, the extent of contributory variants may differ according to genetic locus. The present study aimed at verifying whether the cyclin-dependent kinase 4 inhibitor B (CDKN2B) genomic region strongly associated with coronary artery disease (CAD)/myocardial infarction (MI) may also constitute risk for its risk factors type 2 diabetes mellitus (T2DM) and hypertension (HTN) in ethnic Saudi Arabs. MethodologyWe genotyped eight CDKN2B SNPs for cardiovascular risk in a total of 4650 Saudi Arabs, (3049 male and 1601 female) by Taqman assay. Of these individuals, 3732 had primary hypertension and 2576 had type 2 diabetes mellitus. ResultsOut of the eight studied SNPs, two, rs10757274_A [0.915 (0.840–1.00); p = 0.042], rs1333045_T [0.92(0.84–1.00); p = 0.048] were initially associated with type 2 diabetes but lost the association after multivariate adjustments for CAD, hypertension and MI, while rs10757274_A showed borderline association with hypertension. ConclusionsOur finding does not support the notion of a critical role for the CDKN2B gene locus as a HTN or T2DM cardiovascular risk in ethnic Arabs. The study also demonstrates the importance of replication studies in ascertaining the role of a genomic sequence in disease.

Elevated triglycerides and low high-density lipoprotein cholesterol level as marker of very high risk in type 2 diabetes.

The aim of this review is to describe in diabetic patients the determinants underlying atherogenic dyslipidemia, a complex dyslipidemia defined as the coexistence of fasting hypertriglyceridemia and low high-density lipoprotein cholesterol level. Atherogenic dyslipidemia is often comorbid with hyperglycemia in patients with the common form of type 2 diabetes mellitus (T2DM), namely that associated with obesity, insulin resistance, hyperinsulinemia and the metabolic syndrome phenotype. The role of triglyceride-rich lipoproteins, both fasting and nonfasting, is increasingly considered as a direct driver of atherosclerosis in diabetic patients, even in those receiving best standards of care, including low-density lipoprotein cholesterol level adequately controlled by statins and/or ezetimibe. The residual cardiovascular risk related to atherogenic dyslipidemia in T2DM patients can be inferred from subgroup analysis of diabetic patients within landmark lipid-lowering trials, or from T2DM-only trials, such as Fenofibrate Intervention and Event Lowering in Diabetes study or Action to Control Cardiovascular Risk in Diabetes-Lipid trial. The presence of atherogenic dyslipidemia markedly increases cardiovascular risk, and there is evidence that part of the residual cardiovascular risk in T2DM can be safely and effectively reduced by fibrates. Ongoing trials will determine whether new classes of drugs or dietary intervention targeting hypertriglyceridemia (such as n-3 fatty acids or SPPARMα) will reduce macro and microvascular residual risk in T2DM patients with atherogenic dyslipidemia at inclusion.

Effects of canagliflozin on cardiovascular risk factors in patients with type 2 diabetes mellitus.

SummaryBackground and aimsCardiovascular disease is the most common cause of morbidity and mortality among people with type 2 diabetes mellitus (T2DM). The main contributors to cardiovascular risk in T2DM are chronic hyperglycaemia, reduced insulin sensitivity, hypertension and dyslipidaemia. Other cardiovascular risk factors include obesity and visceral adiposity, increased arterial stiffness and renal dysfunction. Results from clinical trials, including a long‐term cardiovascular outcome study, have shown that sodium glucose co‐transporter 2 (SGLT2) inhibitors can provide multiple cardiometabolic benefits beyond glycaemic control including inducing mild osmotic diuresis, natriuresis and weight loss. This review article describes the effects of canagliflozin on cardiovascular risk factors based on results from its clinical development programme.MethodsThis review is based on structured searches to identify literature related to the effects of canagliflozin on cardiovascular risk factors in patients with T2DM.Discussion and conclusionsCanagliflozin treatment has been shown to provide glycaemic improvements as well as reductions in blood pressure and body weight across a broad range of patients with T2DM, including those with elevated cardiovascular risk. Other observed effects of canagliflozin that may contribute to improved cardiometabolic outcomes include reduction in uric acid levels, decreased albuminuria and increases in serum magnesium. Results of ongoing long‐term cardiovascular outcomes studies of canagliflozin are expected to provide additional evidence on the cardiometabolic effects of canagliflozin treatment.

SGLT2 inhibitors - an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin.

Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These “concomitant effects” are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program described in this review article.

Glycemia Lowering and Risk for Heart Failure: Recent Evidence from Studies of Dipeptidyl Peptidase Inhibition.

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics.

Triglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM. Plasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r=0.36), triglycerides (r=0.59), low-density lipoprotein cholesterol (r=0.16), fasting glucose (r=0.16), and glycosylated hemoglobin (r=0.12; P<0.0001 for all). In age, sex, and race-adjusted analysis, ApoC-III levels were positively associated with coronary artery calcification (Tobit regression ratio, 1.78; 95% confidence interval, 1.27-2.50 per SD increase in ApoC-III; P<0.001). As expected for an intermediate mediator, these findings were attenuated when adjusted for both triglycerides (Tobit regression ratio, 1.43; 95% confidence interval, 0.94-2.18; P=0.086) and separately for very low-density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75-1.71; P=0.53). In persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM.

Prevalence of metabolic syndrome in type 2 diabetic patients: A comparative study using WHO, NCEP ATP III, IDF and Harmonized definitions

To determine the prevalence of metabolic syndrome (MetS) in Malaysian type 2 diabetic patients using WHO, NCEP ATP III, IDF and the new Harmonized definitions, and the concordance between these definitions. This study involved 313 patients diagnosed with type 2 diabetes mellitus (T2DM) at two Malaysian tertiary hospitals. Socio-demographic data were assessed using a pre-tested interviewer-administered structured questionnaire. Anthropometric measurements were carried out according to standard protocols. Clinical and laboratory characteristics were examined. Kappa (k) statistics were used for the agreement between the four MetS definitions. The overall prevalence rates of MetS (95% CI) were 95.8% (93.6-98.1), 96.1% (94.0-98.3), 84.8% (80.8-88.9) and 97.7% (96.1-99.4) according to the WHO, NCEP ATP III, IDF and the Harmonized definitions, respectively. The Kappa statistics demonstrated a slight to substantial agreement between the definitions (k = 0.179-0.875, p k = 0.875, p hest specificity (100%) in identifying MetS. In conclusion, the new Harmonized criteria established the highest prevalence of MetS among the four definitions applied. There was a very good concordance between the WHO and NCEP ATP III criteria. The extremely high prevalence of MetS observed in type 2 diabetic patients indicates an impending pandemic of CVD risk in Malaysia. Aggressive treatment of MetS components is required to reduce cardiovascular risk in T2DM.

Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data.

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular (CV) disease; however, conclusive evidence that glycemic control leads to improved cardiovascular outcomes is lacking. Saxagliptin is a potent, selective dipeptidyl peptidase-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Saxagliptin was evaluated in a series of phase III trials as monotherapy; add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione; and as initial therapy in combination with metformin. Saxagliptin consistently improved glycemic control (as reflected by significant decreases in glycated hemoglobin, fasting plasma glucose, and postprandial glucose compared with controls) and was generally well tolerated. In these analyses, saxagliptin had clinically neutral effects on body weight, blood pressure, lipid levels, and other markers of CV risk compared with controls. A retrospective meta-analysis of 8 phase II and phase III trials found no evidence that saxagliptin increases CV risk in patients with T2DM (Cox proportional hazard ratio, 0.43; 95% CI, 0.23-0.80 for major adverse cardiovascular events retrospectively adjudicated). Instead, it raised the hypothesis that saxagliptin may reduce the risk of major adverse CV events. A long-term CV outcome trial, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-THrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) is currently ongoing to determine whether saxagliptin reduces CV risk in T2DM.