Randomized clinical trials have shown that treatment with bempedoic acid is associated with improvement in fasting glucose and HbA1c in patients with type 2 diabetes. Additionally, new-onset diabetes mellitus was less frequently observed amongst individuals treated with bempedoic acid. These results are at odds with those observed in patients treated with statins as confirmed by a meta-analysis showing that the overall risk of incident diabetes is increased by 11% in these individuals. Bempedoic acid is converted to ETC-1002-CoA in the liver, which allosterically activates AMPK and inhibits ATP-citrate lyase (ACL), resulting in lower LDL-C and atherosclerosis in mice. The mechanisms by which ETC-1002-CoA directly activates AMPK are currently undefined but appear to involve direct interactions with the beta1 isoform. In the liver, AMPK controls glucose homeostasis mainly through the inhibition of gluconeogenic gene expression and hepatic glucose production. Metformin, the most commonly used drug for type 2 diabetes, also activates AMPK. Glucose production in primary cultured hepatocytes is suppressed by metformin, and in diabetic patients, the glucose lowering effect of metformin is at least partly attributed to its ability to suppress gluconeogenesis. It is still unknown whether bempedoic acid is able to reduce hepatic glucose production by activation of the AMPK signalling pathway thus resulting in improvement in glucose metabolism observed in clinical trials. The principal aims of the present project proposal are: 1) To evaluate if bempedoic acid is able to reduce hepatic glucose production in human hepatoma cells by activation of the AMPK signalling pathway involving phosphorylation of the transcriptional coactivators CBP and TORC2 resulting in the dissociation of the CREB-CBP-TORC2 complex. 2) To evaluate if bempedoic acid is able to reduce hepatic glucose production in hyperglycaemic mouse models by activation of the AMPK signalling pathway.
Cardiovascular disease (CVD) remains the principal cause of death and disability among patients with type 2 diabetes mellitus (T2DM) in whom it typically occurs earlier, with greater severity, and with more diffuse distribution than in individuals without T2DM. About two-thirds of deaths in people with T2DM are attributable to CVD. In addition, prediabetes, the condition of impaired glucose homeostasis that precedes overt T2DM, is linked with increased risk of major manifestations of vascular disease. An estimated 463 million people worldwide have T2DM, and this number is expected to reach 578 million by the year 2030, underscoring the global impact of CVD in diabetes mellitus. Reducing CVD burden in both T2DM and prediabetes is a major clinical imperative that should be prioritized to reduce premature death, improve quality of life, and lessen individual and economic burdens of associated morbidities, decreased work productivity, and high cost of medical care.
T2DM and dyslipidemia commonly occur together, with lipid abnormalities affecting 60% to 70% of diabetic individuals, and hyperglycemia accelerates atheroma formation in the setting of diabetic dyslipidemia. There is strong high level evidence from randomized clinical trials that lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A) reductase inhibitors (statins) reduces CVD event rates in diabetes mellitus, with some benefits potentially attributable to nonlipid-lowering, anti-inflammatory effects of statins. Although there are clear benefits of statins to reduce cardiovascular events and mortality in patients with or at risk for CVD, statins also modestly accelerate the development of diabetes mellitus in individuals with preexisting risk factors. Several meta-analyses have now been performed examining the risk of developing diabetes mellitus in statin treated individuals, and relative risks of diabetes mellitus was 13% higher with no heterogeneity across 5 trials with a total of 57593 patients, mean follow-up of 3.9 years, and 2082 incident cases of diabetes mellitus. Additionally, previous population-based studies have reported a 10¿22% increased risk of diabetes with statins. Because the elevated cardiovascular risk associated with prediabetes may be aggravated by the development of overt diabetes, it is important that multifactorial pharmacological intervention, including lipid lowering therapy aimed at reducing the risk of cardiovascular outcomes, does not worsen glycemic control. Mechanistically, statin therapy was associated with a 24% reduction in insulin sensitivity and 12% reduction in insulin secretion compared with individuals without statin therapy. Understanding the mechanisms, strategies for and challenges with managing CVD risk in prediabetes and diabetes mellitus, as well as the potential cardiovascular risks and benefits of lipid-lowering drugs, is important for managing cardiovascular disease in dysglycemic conditions.
Bempedoic acid is a first-in-class adenosine triphosphate-citrate lyase (ACL) inhibitor. ACL is a cytosolic enzyme integral to the cholesterol synthesis pathway that acts upstream of HMG-CoA reductase. This mechanism of action is distinct from other lipid lowering therapies, including statins and ezetimibe (an inhibitor of intestinal cholesterol absorption). By inhibiting ACL, bempedoic acid suppresses cholesterol synthesis, thereby triggering the upregulation of LDL receptor expression in the liver, resulting in increased clearance of LDL particles and lowering of LDL-cholesterol in the blood. Randomized clinical trials have shown that treatment with bempedoic acid is associated with improvement in fasting glucose and glycosylated hemoglobin in both subjects with impaired fasting glucose and patients with T2DM. Additionally, new-onset diabetes mellitus was less frequently observed amongst individuals treated with bempedoic acid. Bempedoic acid is converted in the liver to ETC-1002-CoA, which allosterically activates AMPK. The latter is a target of metformin, a drug thought to exert its primary antidiabetic action through the suppression of hepatic glucose production mainly involving inhibition of gluconeogenesis due to activation of AMPK. In primary hepatocytes, AMPK activation mediated by metformin has been demonstrated to downregulate key gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), both of which have been shown to contribute to aberrant hepatic glucose production in both pre-diabetes and T2DM. Thus, evaluating if bempedoic acid is able to reduce hepatic glucose production in human hepatic cellular models and in animal model of diabetes may be important to pave the way for future intervention studies to safely treating T2DM patients and preventing T2DM in high risk individual with dyslipidemia.