The concurrent management of type 2 diabetes mellitus (T2DM) and chronic congestive heart failure presents several therapeutic challenges. Of concern is that insulin and insulin-sensitizing medications detrimentally "flood" the heart with energy-providing substrates, including fats and glucose. In this population, treatment of T2DM should focus on the reduction of increased substrate supply. Sodium glucose cotransporter-2 (SGLT-2) inhibitors, a new class of antidiabetic medication, operate via this principle by blocking the reabsorption of glucose in the kidney and subsequently releasing glucose through the urine. In this review, we begin with an examination of the mechanisms of glucotoxicity and lipotoxicity in the heart. Then we analyze the potential role of SGLT-2 inhibitor therapy in patients with concurrent T2DM and chronic heart failure. Based on the available evidence, SGLT-2 inhibitors are safe and can be recommended to treat T2DM in patients with chronic heart failure and intact renal function. Further studies are in progress to assess long-term survival benefits.
High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this salutary property is impaired in the setting of inflammation. GlycA, a novel integrated glycosylation marker of five acute phase reactants, is linked to cardiovascular (CV) events. We assessed the hypothesis that GlycA is associated with measures of impaired HDL function and that dysfunctional HDL may contribute to the association between GlycA and incident CV events. Baseline measurements of HDL cholesterol (HDL-C), HDL particle concentration (HDL-P), apoliprotein A1 (Apo A1), cholesterol efflux capacity, GlycA and high-sensitivity C-reactive protein (hs-CRP) were obtained from the Dallas Heart Study, a multi-ethnic cohort of 2643 adults (median 43 years old; 56% women, 50% black) without cardiovascular disease (CVD). GlycA was derived from nuclear magnetic resonance imaging. Participants were followed for first nonfatal MI, nonfatal stroke, coronary revascularization, or CV death over a median of 12.4 years (n = 197). The correlation between GlycA and hs-CRP was 0.58 (p < 0.0001). In multivariate models with HDL-C, GlycA was directly associated with HDL-P and Apo A1 and inversely associated with cholesterol efflux (standardized beta estimates: 0.08, 0.29, -0.06, respectively; all p ≤ 0.0004) GlycA was directly associated with incident CV events (adjusted hazard ratio (HR) for Q4 vs. Q1: 3.33, 95% confidence interval (CI) 1.99, 5.57). Adjustment for cholesterol efflux mildly attenuated this association (HR for Q4 vs. Q1: 3.00, 95% CI 1.75 to 5.13). In a multi-ethnic cohort, worsening inflammation, as reflected by higher GlycA levels, is associated with higher HDL-P and lower cholesterol efflux. Impaired cholesterol efflux likely explains some of the association between GlycA and incident CV events. Further studies are warranted to investigate the impact of inflammation on HDL function and CV disease.
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