A continuous publication, open access, peer-reviewed journal ACCESS ONLINE REVIEW Impact of lipid-lowering therapy on glycemic control and the risk for new-onset diabetes mellitus Constantine E Kosmas MD, PhD1, Delia Silverio MD2, Andreas Sourlas3, Frank Garcia MD2, Peter D Montan MD2, Eliscer Guzman MD1 1 Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA;2 Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USA; 3School of Medicine, University of Crete, Heraklion, Greece Abstract would outweigh the risk of side effects. This review aims to Lipid-lowering therapy is used very commonly nowadays not present and discuss the clinical and scientific data pertaining to only for the optimization of the lipid profile but also to reduce the impact of lipid-lowering therapy on glycemic control and cardiovascular risk. However, some studies have linked the the risk for new-onset diabetes mellitus. use of certain lipid-lowering agents with an increased risk for Keywords: cardiovascular risk, diabetes mellitus, glycemic impaired glycemic control and new-onset diabetes mellitus, control, lipid-lowering. a condition well established as an important risk factor for cardiovascular disease. On the other hand, some other lipid- Citation lowering agents have been shown to have a beneficial effect on Kosmas CE, Silverio D, Sourlas A, Garcia F, Montan PD, Guzman E. glucose metabolism. Profound knowledge of these differences Impact of lipid-lowering therapy on glycemic control and would enable the clinician to choose the right lipid-lowering the risk for new-onset diabetes mellitus. Drugs in Context medication for each individual patient, so that the benefits 2018; 7: 212562. DOI: 10.7573/dic.212562 Introduction Bile acid sequestrants Lipid-lowering therapy is used very commonly nowadays not Bile acids are endogenous molecules synthesized in the only for the optimization of the lipid profile but also to reduce liver from cholesterol and constitute the major pathway for cardiovascular risk.1–3 However, some studies have linked fecal excretion of cholesterol. These molecules facilitate the use of certain lipid-lowering agents with an increased glucose metabolism, lipid homeostasis, lipid-soluble vitamin risk for impaired glycemic control and new-onset diabetes absorption, and energy metabolism through the activation of mellitus, a condition well established as an important risk bile acid receptors in the gut, peripheral tissues, and liver. The factor for cardiovascular disease.4,5 On the other hand, certain two main bile acid receptors associated with the regulation of other lipid-lowering agents may actually improve glucose metabolism are the nuclear farnesoid X receptor (FXR) and the metabolism. membrane-bound Takeda G protein coupled receptor 5 (TGR5). Both receptors play an important role in the development of This review aims to present and discuss the clinical and metabolic disorders, such as diabetes and obesity.6,7 scientific data pertaining to the impact of lipid-lowering therapy on glycemic control and the risk for new-onset Bile acid sequestrants (BAS), such as colesevelam, cholestyramine, diabetes mellitus. Thus, we conducted a PubMed search until and colestipol, constitute a class of drugs that bind negatively September 2018 through the English literature using the charged bile acids in the intestinal lumen, leading to the search terms referring to the different classes of the lipid- formation of a nonabsorbable complex, which disrupts the lowering agents (‘Bile acid sequestrants’, ‘Fibrates’, ‘Niacin’, enterohepatic circulation of bile acids, resulting in increased fecal ‘Ezetimibe’, ‘statins’, ‘PCSK9 inhibitors’) in combination with excretion. The increased fecal excretion of bile acids promotes an the search term ‘Diabetes’. We also included references increase in bile acid synthesis, resulting in the upregulation of low- from the articles identified and publications available in the density lipoprotein (LDL) receptors in the liver and, subsequently, authors’ libraries. decreased circulating levels of LDL cholesterol (LDL-C).8,9 Kosmas CE, Silverio D, Sourlas A, Garcia F, Montan PD, Guzman E. Drugs in Context 2018; 7: 212562. DOI: 10.7573/dic.212562 1 of 7 ISSN: 1740-4398 REVIEW – Impact of lipid-lowering therapy on glycemic control and risk for new-onset diabetes mellitus drugsincontext.com BAS were initially developed with the purpose of treating also on normoglycemic individuals.22,23 This effect is more hypercholesterolemia; however, current studies have shown prominent when niacin therapy is initiated or the dose is improved glycemic control when used in diabetic patients.10 increased. Therefore, glucose control should be monitored Colesevelam, added to the antidiabetic regimen of patients very closely on initiating or increasing the dosage of niacin, with diabetes mellitus, demonstrated statistically significant especially in patients with diabetes.24 reductions in glycosylated hemoglobin (HbA1c) by 0.5% and However, despite initial favorable results in patients with fasting plasma glucose (FPG) by an average of 15 mg/dL. coronary artery disease (CAD),25 in more recent trials, niacin, Furthermore, colesevelam treatment was associated with coadministered with statins, not only failed to reduce reductions in the circulating levels of postprandial glucose and cardiovascular risk but was also associated with an increased fructosamine.11,12 risk of adverse events.26,27 This led to a significant decrease in Even though the exact mechanism by which BAS improve the use of niacin in current clinical practice. glycemic control is not well understood, these lipid-lowering medications have been shown to increase circulating incretin hormones and to improve tissue glucose metabolism.13 Ezetimibe Ezetimibe selectively reduces dietary and biliary cholesterol absorption by targeting the Niemann–Pick C1-like 1 (NPC1L1) Fibrates protein at the hepatocytes and at the brush-border membrane These fenofibric acid derivatives exert their hypolipidemic of enterocytes. NPC1L1 mediates intestinal cholesterol effects primarily via the activation of peroxisome proliferator- absorption and hepatic biliary cholesterol secretion.28,29 activated receptor alpha (PPAR-α), a ligand-activated Ezetimibe decreases LDL-C by approximately 18% and may transcription factor that belongs to the steroid hormone also provide a modest reduction of TGs and a modest increase receptors, which plays a central role in lipid and lipoprotein in HDL-C levels. It can be used as a monotherapy for the metabolism, resulting in a reduction of plasma triglyceride (TG) management of hypercholesterolemia but is more frequently levels and an increase in high-density lipoprotein cholesterol used as an adjunct to statin therapy in high-risk patients who do 14,15 (HDL-C) levels. not achieve the desired LDL-C goal with statin monotherapy.30 In addition to their hypolipidemic effects, fibrates may When added to statin therapy, ezetimibe resulted in contribute to the reduction of atherosclerosis progression and incremental lowering of LDL-C levels and improved cardiovascular events and appear to have beneficial effects on cardiovascular outcomes.31 diabetes-related microvascular diseases.16 Ezetimibe does not increase fasting glucose levels,32 and its use Fibrates have not been associated with an increased risk of has been associated with an improved glucose metabolism in new onset diabetes mellitus. On the contrary, even though patients with insulin resistance.33 the mechanism is not well understood, fibrate therapy has been linked to a better glycemic control and improved insulin sensitivity.16,17 Statins Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an essential enzyme in the cholesterol Niacin synthesis. Statins are the standard of care in the management Nicotinic acid (Niacin, Vitamin B3) is a water-soluble vitamin. of hypercholesterolemia in current clinical practice. Their It serves as a precursor for two essential coenzymes, effectiveness in LDL-C-lowering and in the reduction of nicotinamide adenine dinucleotide (NAD), and nicotinamide cardiovascular risk in both primary and secondary prevention adenine dinucleotide phosphate (NADP), which participate is indisputable.34–39 in oxidation–reduction reactions and are essential in several Besides their LDL-C-lowering properties, statins are now widely metabolic processes.18 accepted to have anti-inflammatory effects, which significantly With regard to its use in the management of dyslipidemia, contribute to the reduction of cardiovascular risk.40,41 However, niacin decreases apo-B containing lipoproteins (LDL and the use of statins has been linked to an increased incidence of very low-density lipoprotein [VLDL]) and increases apo A-1 new-onset diabetes mellitus. containing lipoproteins (HDL). Studies also have shown In a randomized, double-blind, placebo-controlled, multicenter that niacin directly inhibits hepatocyte diacylglycerol trial (JUPITER trial), treatment with rosuvastatin was associated acyltransferase-2, an essential enzyme for the synthesis with a 25% increase in the incidence of physician-reported of TGs, and also has antioxidative, anti-inflammatory, and newly diagnosed diabetes.41 In a meta-analysis, which included antiatherogenic properties.19–21 57,593 patients with a mean follow-up of 3.9 years, statin use Unfortunately, niacin use has been associated with a rise in led to a 13% increase in the risk of diabetes.42 In another large