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Sah DK, Arjunan A, Park SY, Jung YD. Bile acids and microbes in metabolic disease. World J Gastroenterol 2022; 28:6846-6866. [PMID: 36632317 PMCID: PMC9827586 DOI: 10.3748/wjg.v28.i48.6846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/01/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
Bile acids (BAs) serve as physiological detergents that enable the intestinal absorption and transportation of nutrients, lipids and vitamins. BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism, microbiota habitat regulation and cell signaling. BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy, lipid, glucose, and drug metabolism. The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism. Therefore, altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes, such as diabetes mellitus, obesity/hypercholesterolemia, and cardiovascular diseases. BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases. This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases. Moreover, we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders. Finally, we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.
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Affiliation(s)
- Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Archana Arjunan
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Sun Young Park
- Department of Internal Medicine, Chonnam National University, Gwangju 501190, South Korea
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
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Eom YS, Wilson JR, Bernet VJ. Links between Thyroid Disorders and Glucose Homeostasis. Diabetes Metab J 2022; 46:239-256. [PMID: 35385635 PMCID: PMC8987680 DOI: 10.4093/dmj.2022.0013] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/21/2022] [Indexed: 12/13/2022] Open
Abstract
Thyroid disorders and diabetes mellitus often coexist and are closely related. Several studies have shown a higher prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. Thyroid hormone affects glucose homeostasis by impacting pancreatic β-cell development and glucose metabolism through several organs such as the liver, gastrointestinal tract, pancreas, adipose tissue, skeletal muscles, and the central nervous system. The present review discusses the effect of thyroid hormone on glucose homeostasis. We also review the relationship between thyroid disease and diabetes mellitus: type 1, type 2, and gestational diabetes, as well as guidelines for screening thyroid function with each disorder. Finally, we provide an overview of the effects of antidiabetic drugs on thyroid hormone and thyroid disorders.
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Affiliation(s)
- Young Sil Eom
- Division of Endocrinology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Jessica R. Wilson
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Jacksonville, FL, USA
| | - Victor J. Bernet
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Jacksonville, FL, USA
- Corresponding author: Victor J. Bernet https://orcid.org/0000-0002-2477-5631 Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail:
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Jialal I, Singh G. Management of diabetic dyslipidemia: An update. World J Diabetes 2019; 10:280-290. [PMID: 31139315 PMCID: PMC6522756 DOI: 10.4239/wjd.v10.i5.280] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetic dyslipidemia is a cluster of lipoprotein abnormalities characterized by increased triglyceride level, decreased high-density lipoprotein-cholesterol levels and increase in small dense low-density lipoprotein (LDL) particles. It is extremely common in type 2 diabetes (T2DM) affecting around 70 % of patients. Diabetic is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) which is the most common cause of death in the United States and LDL-cholesterol is the number 1 predictor of ASCVD events in T2DM. The purpose of this review is to discuss the pathophysiology and treatment of diabetic dyslipidemia. In this review, we have discussed both non-pharmacological and pharmacological treatment modalities including major treatment trials which have impacted the cardiovascular outcomes in patients with diabetes. Statin therapy is the mainstay of treatment to reduce ASCVD by decreasing LDL-C by 30%-49% or at least 50% depending on risk level. Attractive adjunctive therapies include Ezetimibe which is more cost effective and PCSK9 inhibitors which display potent LDL-cholesterol lowering and ASCVD event reduction. For severe hypertriglyceridemia, to avert the risk of pancreatitis, both fish oil and fenofibrate in concert with diet is the best strategy.
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Affiliation(s)
- Ishwarlal Jialal
- California North-state University College of Medicine, VA Medical Center, Mather, CA 95757, United States
| | - Gurdeep Singh
- Lady of Lourdes Memorial Hospital, New York, NY 10041, United States
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Abstract
Purpose In addition to lowering hemoglobin A1C, colesevelam has been shown to improve the atherogenic lipoprotein profile of subjects with type 2 diabetes mellitus (T2DM) when used in combination with metformin and/or sulfonylureas. A recent study evaluated the effects of colesevelam as antidiabetes monotherapy in adults with T2DM who had inadequate glycemic control (hemoglobin A1C ≥7.5 to ≤9.5 %) with diet and exercise alone; we report here the effects on lipoprotein particle subclasses. Methods Subjects were randomized to receive oral colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. Changes in lipoprotein particle subclasses were determined by nuclear magnetic resonance spectroscopy. Results At Week 24 with last observation carried forward, colesevelam produced a reduction in total low-density lipoprotein (LDL) particle concentration (baseline: 1,611 nmol/L; least-squares [LS] mean treatment difference: −143 nmol/L, p < 0.0001) versus placebo; reductions were also seen in large, small, and very small LDL particle concentrations (all p < 0.05). There was also a reduction in total very low-density lipoprotein (VLDL) and chylomicron particle concentration (baseline: 88 nmol/L; LS mean treatment difference: −1 nmol/L, p = 0.82) that resulted from a lowering in small VLDL particle concentration (baseline: 45 nmol/L; LS mean treatment difference: −5 nmol/L, p = 0.03). In addition, with colesevelam there was an increase in total high-density lipoprotein (HDL) particle concentration versus placebo (baseline: 31 μmol/L; LS mean treatment difference: +0.6 μmol/L, p = 0.20), due to increases in the large (baseline: 5 μmol/L; LS mean treatment difference: +0.5 μmol/L, p = 0.007) and medium (baseline: 3 μmol/L; LS mean treatment difference: +0.8 μmol/L, p = 0.02) HDL subclasses. Conclusions Colesevelam monotherapy in subjects with T2DM resulted in generally favorable changes in certain lipoprotein subclass profiles compared with placebo.
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Bays HE. Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. Int J Gen Med 2014; 7:355-64. [PMID: 25045281 PMCID: PMC4094576 DOI: 10.2147/ijgm.s65148] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-altering drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy.
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Affiliation(s)
- Harold E Bays
- Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY, USA
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Gavin JR, Jones MR, Ford DM, Truitt KE. Safety and efficacy of colesevelam HCl in the treatment of elderly patients. Drugs Aging 2014; 31:461-70. [PMID: 24777691 PMCID: PMC4033819 DOI: 10.1007/s40266-014-0174-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Colesevelam significantly lowers cholesterol in patients with hypercholesterolemia, and both cholesterol and hemoglobin A1C (A1C) in patients with type 2 diabetes mellitus (T2DM). The purpose of this post hoc analysis was to evaluate the efficacy and safety/tolerability of colesevelam in older (≥65 years) and younger (<65 years) adults. METHODS We conducted post hoc analyses of pooled clinical trial data from seven phase II and III randomized, double-blind, placebo-controlled, primary hyperlipidemia and T2DM clinical trials. The hyperlipidemia safety/tolerability analysis included seven studies (≥65 years, n = 154; <65 years, n = 381); the efficacy analysis utilized one study with sufficient patients in both age groups for meaningful comparison. The T2DM analyses included four studies (safety/tolerability: ≥65 years, n = 249; <65 years, n = 880) or three studies (efficacy). In the hyperlipidemia studies, patients received colesevelam 1.5-4.5 g/day or placebo, alone or with a statin, for 4 weeks to 6 months. In the T2DM studies, colesevelam 3.75 g/day or placebo was added to existing antidiabetes therapies for 16 or 26 weeks. Low-density lipoprotein cholesterol (LDL-C), A1C, and adverse events were assessed. RESULTS In the hyperlipidemia analysis, colesevelam versus placebo produced similar mean reductions from baseline in LDL-C in older (-16.6 vs. +0.5 %) and younger (-13.7 vs. +0.4 %) patients. In the T2DM analysis, older and younger patients had similar reductions from baseline in A1C (treatment difference -0.59 and -0.54 %, respectively; both p < 0.001) and LDL-C (-14.7 and -15.5 %, respectively; both p < 0.001) with colesevelam. In both analyses, adverse event incidence was generally similar between subgroups. In the T2DM analysis, hypoglycemia was slightly more frequent with colesevelam versus placebo in older patients (5.8 vs. 2.3 %); no reports of hypoglycemia were considered serious adverse events. CONCLUSIONS In primary hyperlipidemia and in T2DM, colesevelam appeared to be generally as safe, well tolerated, and efficacious in patients aged ≥65 years as in those aged <65 years.
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Affiliation(s)
- James R Gavin
- Healing Our Village, Inc., 145 Bayberry Run, Fayetteville, GA, 30214, USA,
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Lew KN, Kent DJ, Muñoz AA, Melkus GD. Therapeutic options for lowering LDL-C in type 2 diabetes: a nurse practitioner's perspective. J Am Assoc Nurse Pract 2013; 25:488-94. [PMID: 24170653 DOI: 10.1002/2327-6924.12053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
PURPOSE The majority of patients with type 2 diabetes mellitus (T2DM) have multiple risk factors for cardiovascular disease (CVD). Low-density lipoprotein cholesterol (LDL-C) is a key therapeutic target to reduce CVD risk. This article reviews therapeutic strategies that nurse practitioners (NPs) may use in the management of patients with T2DM requiring lipid management. DATA SOURCES The evidence used in developing this review included evidence-based reviews, clinical trials, guidelines, and consensus statements. Relevant publications were identified through a search of the literature using PubMed and other search engines. CONCLUSIONS Lowering LDL-C levels may reduce CVD risk, but achieving goals can be challenging. Lifestyle modifications (including diet, exercise, and smoking cessation) are key components of lipid management and reduction of CVD risk. Statins can be effective to reduce lipids. However, patients may not achieve lipid goals with monotherapy or may experience intolerable adverse effects. Alternative statins or statins along with other lipid-lowering agents remain good options. IMPLICATIONS FOR PRACTICE Achieving LDL-C goals requires a comprehensive treatment plan that incorporates lifestyle and pharmacologic interventions. Patient commitment in setting goals and self-management is essential. NPs can play an important role in educating patients as well as prescribing appropriate treatments.
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Abstract
Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug-drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.
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Hamilton SJ, Watts GF. Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment. Rev Diabet Stud 2013; 10:133-56. [PMID: 24380089 DOI: 10.1900/rds.2013.10.133] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.
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Affiliation(s)
- Sandra J Hamilton
- Combined Universities Centre for Rural Health, University of Western Australia, Geraldton, Australia
| | - Gerald F Watts
- School of Medicine and Pharmacology, Royal Perth Hospital Unit, University of Western Australia, Perth, Australia
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Abstract
The inexorable increase in the prevalence of obesity is a global health concern, which will result in a concomitant escalation in health-care costs. Obesity-related metabolic syndrome affects approximately 25% of adults and is associated with cardiovascular and renal disease. The heart and kidneys are physiologically interdependent, and the pathological effects of obesity can lead to cardiorenal syndrome and, ultimately, kidney and heart failure. Weight loss can prevent or ameliorate obesity-related cardiorenal syndrome, but long-term maintenance of a healthy weight has been difficult to achieve through lifestyle changes or pharmacotherapy. Bariatric surgery offers both sustained weight loss and favourable metabolic changes, including dramatic improvements in glycaemic control and symptoms of type 2 diabetes mellitus. Procedures such as Roux-en-Y gastric bypass offer immediate multisystemic benefits, including bile flow alteration, reduced gastric size, anatomical gut rearrangement and altered flow of nutrients, vagal manipulation and enteric hormone modulation. In patients with cardiorenal syndrome, bariatric surgery also offers renoprotection and cardioprotection, and attenuates both kidney and heart failure by improving organ perfusion and reversing metabolic dysfunction. However, further research is required to understand how bariatric surgery acts on the cardiorenal axis, and its pioneering role in novel treatments and interventions for cardiorenal disease.
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Mathers MC, Zarbock SD, Sutton EE. New and Future Medications for the Treatment of Type 2 Diabetes Mellitus. Am J Lifestyle Med 2013. [DOI: 10.1177/1559827613498694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
With almost 30 million individuals predicted to be diagnosed by the year 2025, type 2 diabetes mellitus (T2DM) has become one of the most prevalent diseases in the United States. Because of the progressive dysfunction of the pancreatic β-cells and increasing insulin resistance over time, the need for treatments with different mechanisms or addition of medications to a regimen is becoming commonplace. Because of this, developing new medications to treat T2DM has been the focus of a lot of recent research and drug development. Molecular substrates such as glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), and the sodium glucose transporter-2 (SGLT2) have all become new therapeutic targets. GLP-1 agonists and DPP-4 inhibitors are 2 of the newest classes of Food and Drug Administration–approved medications for diabetes. By increasing GLP-1 to supraphysiologic levels (GLP-1 agonists) and delaying endogenous GLP-1 degradation (DPP-4 inhibitors), these drugs increase insulin secretion and decrease glucagon production. SGLT2 inhibitors, the newest antihyperglycemic class, promote glycosuria by inhibiting sodium and glucose reabsorption in the proximal tubule of the renal nephron. Other novel agents for the treatment of diabetes include the use of the dopamine agonist bromocriptine, the cholesterol medication colesevelam, and a new form of inhaled insulin.
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Affiliation(s)
- Michael C. Mathers
- Albany College of Pharmacy and Health Sciences–Vermont Campus, Colchester, Vermont
| | - Sommer D. Zarbock
- Albany College of Pharmacy and Health Sciences–Vermont Campus, Colchester, Vermont
| | - Emily E. Sutton
- Albany College of Pharmacy and Health Sciences–Vermont Campus, Colchester, Vermont
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12
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Abstract
The role of lipid lowering in reducing the risk of mortality and morbidity from cardiovascular disease (CVD) is well established. Treatment particularly aimed at decreasing low-density lipoprotein cholesterol (LDL-C) is effective in reducing the risk of death from coronary heart disease and stroke. Statins form the cornerstone of treatment. However, in some individuals with a high risk of CVD who are unable to achieve their target LDL-C due to either intolerance or lack of efficacy, there is the need for alternative therapies. This review provides an overview of the different classes of currently available lipid-lowering medications including statins, fibrates, bile acid sequestrants (resins), and omega-3 fatty acids. Data are presented on their indications, pharmacology, and the relevant end point clinical trial data with these drugs. It also discusses the human trial data on some novel therapeutic agents that are being developed including those for homozygous familial hypercholesterolemia--the antisense oligonucleotide mipomersen and the microsomal transfer protein inhibitor lomitapide. Data are presented on phase II and III trials on agents with potentially wider applications, cholesterol ester transfer protein inhibitors and proprotein convertase subtilisin kexin 9 inhibitors. The data on a licensed gene therapy for lipoprotein lipase deficiency are also presented.
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Affiliation(s)
- Mfon Ewang-Emukowhate
- Department of Chemical Pathology, Guy's & St Thomas Hospitals, St Thomas' Hospital Campus, London, England.
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Handelsman Y, Fonseca V, Rosenstock J. Is combination therapy an effective way of reaching lipid goals in type 2 diabetes mellitus? Expert Rev Clin Pharmacol 2012; 5:43-54. [PMID: 22142158 DOI: 10.1586/ecp.11.73] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus is associated with a specific pattern of plasma lipid and lipoprotein abnormalities. Lipid goals are often not attained with statins alone, and combination lipid-lowering strategies may need to be considered in an attempt to further reduce the residual cardiovascular risk. Combination therapy utilizes various classes of lipid-lowering medications with different mechanisms of action and different effects on lipid levels. Clinical trial data support the efficacy of combining statins with fibrates, niacin, ezetimibe (cholesterol absorption inhibitor) and colesevelam (bile acid sequestrant) with the caveat that there are insufficient clinical trial data to show a further robust benefit on cardiovascular outcomes. Of the different combination therapy options to potentiate low-density lipoprotein cholesterol lowering in combination with a statin, colesevelam provides additional beneficial effects by further reducing hemoglobin A1c levels in Type 2 diabetes mellitus.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark Street, Suite #212, Tarzana, CA 91356, USA.
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Marrs JC. Glucose and low-density lipoprotein cholesterol lowering in elderly patients with type 2 diabetes: focus on combination therapy with colesevelam HCl. Drugs Aging 2012; 29:e1-e12. [PMID: 22530704 PMCID: PMC3586066 DOI: 10.2165/11599290-000000000-00000] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The prevalence of type 2 diabetes mellitus is high among the elderly population. Treatment of elderly patients with type 2 diabetes presents challenges because of co-morbidities and the potential increase in the risk of adverse effects. Hyperlipidaemia is also common in the elderly population. Glucose-and lipid-lowering treatment in elderly patients should be individualized on the basis of the patient’s life expectancy, health status and cardiovascular risk factors, and evidence-based guideline recommendations. Because elderly patients often have impaired renal and hepatic function, careful considerations must be made when selecting appropriate glucose- and lipid-lowering therapy. There are a number of potential safety issues associated with various glucose- and lipid-lowering therapies that are relevant to elderly patients, including increased risk of heart failure exacerbations, weight loss, increased risk of hypoglycaemia, increased risk of myopathy, and contraindications of some agents in patients with hepatic or renal impairment. The bile acid sequestrant colesevelam HCl is unique compared with other glucose- and lipid-lowering therapies because it is the only product approved by the US Food and Drug Administration, as an adjunct to diet and exercise, to lower both glucose and low-density lipoprotein cholesterol (LDL-C) in adults with type 2 diabetes and primary hyperlipidaemia, respectively. Furthermore, colesevelam has been shown to have similar glucose- and lipid-lowering efficacy in patients aged <65 years and those aged ≥65 years. Colesevelam was not associated with weight gain, was associated with a low incidence of hypoglycaemia, and can be safely combined with a broad range of glucose-lowering agents (metformin, sulfonylureas and insulin) and lipid-lowering statins. Currently, colesevelam is available in tablet form and as a powder for oral suspension formulation; the latter may be of benefit to elderly patients with swallowing difficulties. As colesevelam has both glucose- and lipid-lowering effects, its use may reduce the drug burden in elderly patients receiving multiple agents for glucose and lipid lowering. Colesevelam may be a valuable treatment option as an add-on to existing glucose- and/or lipid-lowering therapy to help improve haemoglobin A1c and to lower LDL-C levels in elderly patients with type 2 diabetes and primary hyperlipidaemia.
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Affiliation(s)
- Joel C Marrs
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
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15
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Jialal I, Smith G. Managing the Dyslipidemia of Metabolic Syndrome: Beyond Statin Therapy. Metab Syndr Relat Disord 2012; 10:159-60. [DOI: 10.1089/met.2012.1500] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Ishwarlal Jialal
- Laboratory of Atherosclerosis and Metabolic Disorders, University of California Davis Medical Center, Sacramento, California
| | - Gerred Smith
- Laboratory of Atherosclerosis and Metabolic Disorders, University of California Davis Medical Center, Sacramento, California
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Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol 2012; 8:515-25. [DOI: 10.1517/17425255.2012.672973] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Neda T, Inukai K, Kurihara S, Ono H, Hosaka T, Nakamoto H, Katayama S, Awata T. Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity. Endocr J 2012; 59:239-46. [PMID: 22230809 DOI: 10.1507/endocrj.ej11-0378] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of β cell function, i.e. HOMA-β, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced β cell activity rather than improved insulin resistance.
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Affiliation(s)
- Tamotsu Neda
- Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama 350-0495, Japan
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Vega GL, Dunn FL, Grundy SM. Effect of colesevelam hydrochloride on glycemia and insulin sensitivity in men with the metabolic syndrome. Am J Cardiol 2011; 108:1129-35. [PMID: 21813109 DOI: 10.1016/j.amjcard.2011.06.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Revised: 06/06/2011] [Accepted: 06/06/2011] [Indexed: 12/26/2022]
Abstract
Colesevelam hydrochloride (colesevelam) lowers low-density lipoprotein (LDL) cholesterol and glycated hemoglobin in patients with type 2 diabetes mellitus. The present study examined the effects of colesevelam treatment in nondiabetic men with metabolic syndrome. Twenty men completed the study, which consisted of two 8-week phases of treatment with colesevelam (3.75 g/day) or placebo and a 6-week washout between study phases. Of the 20 men, 17 took statins throughout. The fasting plasma LDL cholesterol, triglyceride, glucose, and glycated hemoglobin levels were measured in the last 2 weeks of each study phase. Nonesterified fatty acids and 3-hydroxybutyrate, insulin, and glucose were measured hourly for 5 hours during fasting and during an extended glucose tolerance test. The colesevelam treatment reduced LDL cholesterol from 96 ± 28 mg/dl to 78 ± 32 mg/dl (p <0.006) and non-high-density lipoprotein cholesterol by 8.2% (p = 0.07). Triglycerides increased by 17% (p <0.02). The fasting plasma glucose was reduced by 5 mg/dl (p <0.03), and glycated hemoglobin remained unchanged by colesevelam. No significant treatment changes were noted for the 2-hour glucose test or insulin sensitivity. The fasting nonesterified fatty acid level was significantly reduced with treatment but the 3-hydroxybutyrate level was unchanged. Insulin-mediated suppression of nonesterified fatty acids during extended glucose tolerance test was significantly less effective during treatment than during placebo. In conclusion, colesevelam significantly reduced the LDL cholesterol levels, even though the baseline LDL cholesterol level was low owing to statin treatment. The fasting and postprandial blood glucose level but not the glycated hemoglobin level was lowered by colesevelam therapy. The effect on fasting glucose was unrelated to the changes in insulin resistance or fatty acid oxidation. Finally, an increase in triglycerides with colesevelam therapy might have been related to a lesser suppression of nonesterified fatty acids levels in the postprandial state.
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Affiliation(s)
- Gloria Lena Vega
- The Metabolic Unit, Lipid, and Diabetes Clinics of the Veterans Affairs North Health Care System, Dallas, Texas, USA.
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20
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Brunetti L, Campbell RK. Clinical Efficacy of Colesevelam in Type 2 Diabetes Mellitus. J Pharm Pract 2011; 24:417-25. [DOI: 10.1177/0897190011406125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Purpose: The clinical experience and role in therapy of colesevelam in type 2 diabetes mellitus (T2DM) is discussed. Summary: Colesevelam HCl is a bile acid sequestrant (BAS) with proven efficacy in reducing elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia. Colesevelam HCl gained food and drug administration (FDA) approval in 2008 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. In randomized controlled studies, colesevelam (add-on therapy with metformin, sulfonylureas, and insulin) has shown significant percentage reductions in glycosylated hemoglobin A1c (HbA1c) ranging from 0.5% to 0.54%. Reductions in LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) ranging from –12.8% to –16.7% and –4.0% to –10.3%, respectively, were also observed. Although no direct comparisons have been made, the safety and tolerability profile of this agent appears to be better than other BAS, with the most common side effects being gastrointestinal related. Conclusion: Colesevelam is effective as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Due to its effects upon LDL-C and glycemic parameters and favorable safety profile, colesevelam can play a role in an array of T2DM patients.
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Affiliation(s)
- Luigi Brunetti
- Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, NJ, USA
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21
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Jacobson TA. Opening a new lipid "apo-thecary": incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin Proc 2011; 86:762-80. [PMID: 21803958 PMCID: PMC3146376 DOI: 10.4065/mcp.2011.0128] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce low-density lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins' cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B-lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease.
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Affiliation(s)
- Terry A Jacobson
- Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University, Atlanta, GA 30303, USA.
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22
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Ashrafian H, Athanasiou T, Li JV, Bueter M, Ahmed K, Nagpal K, Holmes E, Darzi A, Bloom SR. Diabetes resolution and hyperinsulinaemia after metabolic Roux-en-Y gastric bypass. Obes Rev 2011; 12:e257-72. [PMID: 20880129 DOI: 10.1111/j.1467-789x.2010.00802.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux-en-Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long-term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti-diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight-independent and weight-dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta-cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease-specific procedures including 'diabetes surgery'. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.
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Affiliation(s)
- H Ashrafian
- The Department of Surgery and Cancer, Imperial College London, London, UK.
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Garg SK, Ritchie PJ, Moser EG, Snell-Bergeon JK, Freson BJ, Hazenfield RM. Effects of colesevelam on LDL-C, A1c and GLP-1 levels in patients with type 1 diabetes: a pilot randomized double-blind trial. Diabetes Obes Metab 2011; 13:137-43. [PMID: 21199265 DOI: 10.1111/j.1463-1326.2010.01320.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
AIM colesevelam is indicated to lower low density lipoprotein cholesterol (LDL-C) in hyperlipidaemia and improve glycaemic control in adults with type 2 diabetes. This short-term pilot study evaluates its effects in type 1 diabetes. METHODS this double-blind, randomized, investigator-initiated, single-centred, 12-week pilot study evaluated 40 adults (age = 36.4 ± 9.4 years) with type 1 diabetes (duration = 20.4 ± 8.5 years) and hyperlipidaemia. It was powered to show a treatment difference of >10% LDL-C reduction. Subjects received 3.75 g/day colesevelam (n = 20) or placebo (n = 20) for 12 weeks. LDL-C and haemoglobin A1c (A1c) levels were assessed at screening (week 2), baseline (week 0) and every 4 weeks throughout the treatment duration. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during 4-h meal (Boost Plus, Nestle HealthCare Nutrition Inc., Florham Park, New Jersey, USA) challenge tests (MCT) at baseline and 12 weeks. RESULTS colesevelam treatment resulted in a significant reduction in LDL-C values at 4 weeks [-12.1% (95% CI: -20.1 to -4.1), p = 0.004] which was sustained for the study duration (p = 0.005 at 12 weeks). The treatment group also showed a significant change in A1c from baseline at week 4; however, this was not significant for the study duration. There was a significant median increase in GLP-1 levels during the first 2 h of the baseline MCT in the treated group but no difference at 12 weeks. CONCLUSIONS during this short-term pilot study, colesevelam treatment effectively lowered LDL-C in patients with type 1 diabetes. Improvements in A1c seen at week 4 were not sustained. Effects on glycaemic control in subjects with type 1 diabetes may be related to a postprandial rise in GLP-1 levels and require further clinical study.
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Affiliation(s)
- S K Garg
- Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
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Handelsman Y, Goldberg RB, Garvey WT, Fonseca VA, Rosenstock J, Jones MR, Lai YL, Jin X, Misir S, Nagendran S, Abby SL. Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study. Endocr Pract 2010; 16:617-28. [PMID: 20634176 DOI: 10.4158/ep10129.or] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To assess the effect of the bile acid sequestrant colesevelam hydrochloride in patients with hypercholesterolemia and prediabetes. METHODS In this 16-week, randomized, double-blind study, adults with untreated prediabetes (2-hour postoral glucose tolerance test [OGTT] glucose > or =140 to 199 mg/dL, fasting plasma glucose [FPG] > or =110 to 125 mg/dL, or both), low-density lipoprotein cholesterol (LDL-C) > or =100 mg/dL, and triglycerides <500 mg/dL were randomly assigned to receive colesevelam (3.75 g/d) or placebo. The primary end point was percent change in LDL-C from baseline to week 16 with last observation carried forward. Secondary end points included change in FPG, hemoglobin A1c (A1C), and 2-hour post-OGTT glucose level from baseline to week 16 and attainment of LDL-C and FPG targets. RESULTS In total, 216 patients were randomized (colesevelam, 108; placebo, 108). In comparison with placebo, colesevelam significantly reduced LDL-C (mean treatment difference, -15.6%), non-high-density lipoprotein cholesterol (-9.1%), total cholesterol (-7.2%), apolipoprotein B (-8.1%) (P<.001 for all the foregoing), FPG (median, -2.0 mg/dL; P = .02), and A1C (mean, -0.10%; P = .02). Colesevelam did not significantly change 2-hour post-OGTT glucose (-1.9 mg/dL; P = .75) or high-density lipoprotein cholesterol (-0.5%; P = .80). In addition, colesevelam significantly increased triglyceride levels relative to placebo (median, 14.3%; P<.001). The proportion of patients achieving target levels with colesevelam versus placebo, respectively, was as follows: LDL-C <100 mg/dL (29% versus 11%; P<.001), A1C <6.0% (37% versus 25%; P = .05), FPG <110 mg/dL (48% versus 56%; P = .97), and normalization of glucose (FPG <100 mg/dL [40% versus 23%; P = .06]). Colesevelam had a weight-neutral effect and was well tolerated. CONCLUSION Colesevelam is an option for managing the lipid profile and normalizing glucose levels in patients with hypercholesterolemia and prediabetes. Further study is warranted to determine whether colesevelam slows or prevents progression of prediabetes to type 2 diabetes.
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Levy P. Review of Studies on the Effect of Bile Acid Sequestrants in Patients with Type 2 Diabetes Mellitus. Metab Syndr Relat Disord 2010; 8 Suppl 1:S9-13. [DOI: 10.1089/met.2010.0087] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Ganda OP. The role of bile acid sequestrants in the management of type 2 diabetes mellitus. Metab Syndr Relat Disord 2010; 8 Suppl 1:S15-21. [PMID: 21034179 DOI: 10.1089/met.2010.0095] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The prevalence of type 2 diabetes (T2DM) and cardiovascular disease (CVD) continues to escalate globally. There is now abundant clinical trial evidence that the optimal treatment of CVD risk factors, with lifestyle changes aimed at weight loss in most patients, and pharmacologic management of dyslipidemia and hyperglycemia, can help mitigate the CVD burden. Yet more than 50% of patients are still not achieving glycosylated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C) goals. Over the past 15 years, many novel and emerging drugs have made it possible to achieve optimal glycemic control, generally in combination therapy, without untoward effects of weight gain, hypoglycemia, and other adverse effects with traditional agents. Although the long-term efficacy and safety of some of the newer classes of agents are yet to be determined, bile acid sequestrants represent a unique long-standing class of agents. These drugs have the dual efficacy in glycemic control and LDL-C reduction, and an established record of long-term safety. Colesevelam HCl is the only drug approved for this dual indication and is an adjunct in the treatment of both hyperglycemia and hypercholesterolemia that frequently co-exist in adults with T2DM.
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Affiliation(s)
- Om P Ganda
- Lipid Clinic, Joslin Diabetes Center and Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, USA.
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Jialal I. Bile acid sequestrants and diabetes: introduction and overview to the supplement. Metab Syndr Relat Disord 2010; 8 Suppl 1:S1-2. [PMID: 20973745 DOI: 10.1089/met.2010.1500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Diabetes is a global epidemic. The recommended goals for glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and blood pressure are achieved only in a very small minority of patients. In this supplement to Metabolic Syndrome and Related Disorders, we review the data showing that the bile acid sequestrant colesevelam lowers both HbA1c and LDL-C in patients with diabetes. These data make colesevelam an attractive therapy to get more patients to achieve their LDL-C and HbA1c goals.
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Affiliation(s)
- I Jialal
- Laboratory for Atherosclerosis and Metabolic Research, University of California Davis Medical Center, Sacramento, California, USA
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Brunetti L, Hermes-DeSantis ER. The Role of Colesevelam Hydrochloride in Hypercholesterolemia and Type 2 Diabetes Mellitus. Ann Pharmacother 2010; 44:1196-206. [DOI: 10.1345/aph.1m728] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Objective: To evaluate the safety and efficacy of colesevelam hydrochloride for the treatment of hypercholesterolemia and type 2 diabetes mellitus. Data Sources: Literature retrieval was accessed through MEDLINE/PubMed (1950–March 2010), Web of Science (1980–March 2010), and International Pharmaceutical Abstracts (1977–March 2010) using the terms colesevelam, dyslipidemia, hypercholesterolemia, and type 2 diabetes mellitus. References from publications identified were reviewed for additional resources. In addition, abstracts presented at the most recent (2009) American Diabetes Association, American Association of Clinical Endocrinologists, and European Association for the Study of Diabetes annual meetings were searched for relevant original research. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated. All relevant studies evaluating the safety and efficacy of colesevelam in hypercholesterolemia and/or type 2 diabetes mellitus were included. Priority was placed on data obtained from human randomized controlled trials. Data Synthesis: Seventeen clinical trials were reviewed and evaluated. Of the clinical trials evaluating colesevelam in hypercholesterolemia, 3 evaluated monotherapy, 4 evaluated combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and 6 evaluated combination therapy with other lipid-lowering therapies. In the type 2 diabetes mellitus trials, colesevelam was evaluated in combination with metformin, sulfonylureas, insulin, and rosiglitazone and sitagliptin. A review of the clinical trials provided evidence that colesevelam monotherapy effectively reduces low-density lipoprotein cholesterol (LDL-C). Additionally, the use of colesevelam in combination with other lipid-lowering therapies further reduces LDL-C. Colesevelam also effectively reduces hemoglobin A1c in patients with type 2 diabetes mellitus. The safety and tolerability of colesevelam appear to be improved from that of older-generation bile acid sequestrants, with adverse effects similar to those with placebo in monotherapy and type 2 diabetes mellitus trials. Conclusions: Colesevelam is a safe and effective option for the treatment of hypercholesterolemia and type 2 diabetes mellitus. It can fulfill a useful role in combination with HMG-CoA reductase inhibitors for hypercholesterolemia and should be considered in patients with type 2 diabetes mellitus with concomitant hypercholesterolemia.
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Affiliation(s)
- Luigi Brunetti
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Somerville, NJ
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