Why does welchol raise triglycerides

In contrast to using two or more drugs from the same therapeutic class, the combined use of drugs from different therapeutic classes, working by different mechanisms of action on the same endpoint in this case LDL-C lowering , will in general demonstrate at least pharmacodynamic additivity. Exceptions of course include synergy, where the measured benefit exceeds that which would be predicted by additivity alone, and antagonism where the mechanism of action of one agent presumably interferes in some manner with the mechanism of action of the second agent.

With inhibition by statins of HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, there is a decrease in the cytoplasmic concentration of cholesterol. Decreased intracellular cytoplasmic cholesterol concentration, however, also results in less direct enzyme feedback inhibition as well as less enzyme degradation by polyubiquitination — both effects mediated via cholesterol binding to a sterol sensing domain of the HMGCoA reductase enzyme itself.

These latter two effects along with the upregulation of HMGCoA reductase described above, limit the utility of serum cholesterol lowering with statin monotherapy. BAS lower hepatocyte cytoplasmic concentration of cholesterol differently by upregulating Cyp7A1 and thereby increasing synthesis of bile acid from cholesterol as previously described.

The increased utilization of cholesterol for bile acid synthesis engendered by BAS, coupled with the continued strong inhibition of the rate-limiting enzyme in cholesterol biosynthesis by statins, produces an additive effect upon LDL-receptor protein synthesis and a further lowering of serum cholesterol.

Five studies have examined the combined use of ezetimibe and colesevelam HCl. In all of these, the dose of ezetimibe was 10 mg. The remaining two trials were randomized, double-blind, placebo-controlled, add-on studies where colesevelam 3.

A type II error secondary to inadequate sample size only nine subjects actually received active dual therapy might explain the latter result. While both ezetimibe and colesevelam HCl are intestinally active agents, their mechanism of action is quite distinct. Ezetimibe, and more importantly its active metabolite ezetimibe glucuronide, binds to the Niemann-Pick C1-like-1 receptor at the jejunal epithelial cell brush border, preventing formation of the clathrin-coated vesicles which allow endocytosis of the cholesterol Niemann-Pick C1-like-1 receptor complex.

Currently, the combination of colesevelam HCl and nicotinic acid is not FDA approved for the management of dyslipidemia. The proposed mechanisms of action of nicotinic acid with regards to lipid modulation are complex.

With regards to its LDL-C-lowering effects, binding to the G protein-coupled receptorA of adipocytes results in inhibition of hormone sensitive lipase with decreased free fatty acid release into the circulation. This coupled with direct inhibition of the enzyme diacylglycerol O-acyltransferase-2 results in a decrease in triglyceride synthesis, resulting in accelerated hepatic Apo B degradation, resulting in decreased release of VLDL particles into the circulation.

While there are no reports of the use of gemfibrozil with colesevelam, there are reports of the use of gemfibrozil with the first-generation BAS cholestyramine and colestipol. A single, randomized, double-blind, placebo-controlled, add-on study examined the effect of adding 3.

Also, the addition of colesevelam to fenofibrate therapy further reduced the levels of non-HDL-C and Apo B without statistically affecting the triglyceride-lowering effects of fenofibrate. These results are consistent with the reported lack of pharmacokinetic interactive effects when these drugs are administered together.

The latter, however, does not appear to be significant, perhaps related to fibrate-mediated upregulation of the adenosine triphosphate-binding cassette subfamily G member-5 gene coding for sterolin-1, resulting in increased secretion of cholesterol into bile, lowering hepatocellular content of free cholesterol. Consistent with this explanation, the addition of cholestyramine, with its upregulating effects upon Cyp7A1, to gemfibrozil in patients with familial combined hyperlipidemia has been shown to decrease the cholesterol saturation of bile.

Phytosterols, being more hydrophobic than cholesterol, are thought to displace cholesterol from micelles and on that basis decrease cholesterol absorption by the intestine. At week 16, treatment with colesevelam 3. At week 26, treatment with colesevelam 3. Additional studies with similar design have been performed in patients with prediabetes mean HbA 1c 6.

These findings suggest that both the absolute, as well as relative decrease in FBS affected by colesevelam, may be dependent upon the baseline degree of glycemia. Possibly due to the number of transgenic animal models examined and the potential differences in comparison to type 2 DM in man, the literature appears at times to be contradictory.

A detailed discussion of the multiple hypotheses generated by this work is beyond the scope of this review and the reader is referred to a number of excellent monographs.

Peripheral insulin resistance as measured by the hyperinsulinemic euglycemic clamp method appears unaltered during colesevelam administration. Fasting and postprandial glucagon-like peptide-1 levels are increased in man with colestimide 93 and colesevelam treatment, 89 and this result is consistent with animal experiments. CCK, by delaying gastric emptying, may also independently further ameliorate postprandial hyperglycemia.

While BAS are contraindicated in patients with complete biliary obstruction, in which bile is not secreted into the intestine, there are otherwise no special considerations in patients with hepatic impairment. Pooled analyses of clinical studies has revealed a small, but statistically significant, increase in the level of liver transaminase as well as alkaline phosphatase, which have, however, remained within the normal reference range. During postmarketing surveillance, bowel obstruction with cholestyramine, while extremely rare, has been reported.

Use of colesevelam of course is contraindicated in patients with a history of bowel obstruction. Pooled analyses from studies with a relatively small number of patients have revealed a small, but statistically significant, decrease in the blood levels of fat soluble vitamins, which have, however, remained within the normal reference range. It is currently recommended that individuals taking supplements of the above vitamins take them at least 4 hours before or after taking colesevelam.

The oral suspension formulation of colesevelam described previously does contain 48 mg of phenylalanine per 3. Abbreviations: DM, diabetes mellitus; Rx, prescription. While originally perceived as merely biological detergents aiding in the solubilization and absorption of dietary fats, over the past decade it has been demonstrated that bile acids, through their known agonist activity at the nuclear FXR transcription factor, act as hormones involved in multiple different physiological systems as previously described in this manuscript.

An example of the latter might be the triglyceride elevation associated with their use in certain patients. Statins, first available in the United States 25 years ago, remain the backbone of lipid-lowering therapy due to their potency as well as proven efficacy in decreasing morbid cardiovascular disease events. Recent data obtained in both primary and secondary prevention settings, have also revealed a dose related increase in new onset type 2 DM in patients on chronic statin therapy.

In addition, postmarketing surveillance has confirmed the rare side effect of mild cognitive decline in statin users, which had been previously suggested.

Ideally, the agent should demonstrate pharmacodynamic additivity or synergy in lowering LDL-C compared to statin monotherapy. It should be free of systemic side effects, free of significant drug—drug and drug—food interactions, and be safe and well tolerated by all patient groups, including diabetics as well as those with chronic kidney and liver disease.

National Center for Biotechnology Information , U. Journal List Core Evid v. Core Evid. Published online Jul Michael James Zema. Author information Copyright and License information Disclaimer. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC.

Keywords: colesevelam, bile acid sequestrants, cholesterol, low-density lipoprotein. Open in a separate window. Introduction The very first rigorous proof of the lipid hypothesis ie, lowering the level of cholesterol, a previously known atherosclerotic risk factor, reduces risk for future development of hard clinical cardiovascular morbid events in man was published over 25 years ago, comparing the use of the bile acid sequestrant BAS cholestyramine with placebo in over patients with hypercholesterolemia who were all partaking in a moderately low cholesterol diet.

The colesevelam molecule Colesevelam hydrochloride HCl is poly allylamine HCl crosslinked with epichlorohydrin and alkylated with 1-bromodecane and 6-bromohexyl -trimethylammonium bromide to form allylamine polymer with 1-chloro-2,3- epoxypropane 6-allylaminohexyl trimethylammonium chloride and N-allyldecylamine, HCl.

Figure 1. Table 2 Pharmacodynamic additivity. Figure 2. Bile acids as hormones in the regulation of metabolic processes. Colesevelam triglycerides — clinical With regards to placebo-corrected change in serum triglycerides, there has been wide variation in the reported results of three clinical trials in patients with type IIa hyperlipoproteinemia referenced above.

Colesevelam high-sensitivity C-reactive protein — clinical With regards to inflammatory markers, as monotherapy, colesevelam 3. Clinical use in combination lipid-lowering therapy Use with statin therapy — clinical Due to overwhelmingly positive outcome studies in patients treated for hypercholesterolemia with HMGCoA reductase inhibitors statins , these agents remain the backbone of lipid-lowering therapy.

Use with statin therapy — putative mechanism In contrast to using two or more drugs from the same therapeutic class, the combined use of drugs from different therapeutic classes, working by different mechanisms of action on the same endpoint in this case LDL-C lowering , will in general demonstrate at least pharmacodynamic additivity. Use with ezetimibe therapy — clinical Five studies have examined the combined use of ezetimibe and colesevelam HCl. Use with ezetimibe therapy — putative mechanism While both ezetimibe and colesevelam HCl are intestinally active agents, their mechanism of action is quite distinct.

Use with nicotinic acid therapy — putative mechanism The proposed mechanisms of action of nicotinic acid with regards to lipid modulation are complex. Use with fibrate therapy — clinical While there are no reports of the use of gemfibrozil with colesevelam, there are reports of the use of gemfibrozil with the first-generation BAS cholestyramine and colestipol.

Use with phytosterol phytostanol therapy — putative mechanism Phytosterols, being more hydrophobic than cholesterol, are thought to displace cholesterol from micelles and on that basis decrease cholesterol absorption by the intestine. Table 3 Adverse effects of colesevelam hydrochloride. Conclusion Statins, first available in the United States 25 years ago, remain the backbone of lipid-lowering therapy due to their potency as well as proven efficacy in decreasing morbid cardiovascular disease events.

References 1. Reduction in incidence of coronary heart disease. Efficacy and safety of cholesterol-lowering treatment; prospective meta-analysis of data from 90, participants in 14 randomised trials of statins. Sign Up Now. Previous: Inflammatory Lesions on Every finger. Jul 15, Issue. Synopsis Colesevelam WelChol is a nonabsorbed binder of bile acids in the intestine, and thereby impedes the reabsorption of this source of endogenously produced cholesterol.

Safety The risk of systemic toxicity is low because colesevelam is not absorbed. Tolerability Side effects are infrequent and rarely result in discontinuation. Effectiveness Colesevelam has been studied in several short-term trials, alone and in combination with statins. Simplicity Each solid tablet contains mg of colesevelam. Bottom Line Colesevelam lowers LDL cholesterol levels a small amount 7 to 16 percent when used alone and provides additional cholesterol lowering when added to statin therapy.

Read the full article. Get immediate access, anytime, anywhere. Choose a single article, issue, or full-access subscription. Earn up to 6 CME credits per issue. Purchase Access: See My Options close. Best Value! To see the full article, log in or purchase access. Email Alerts Don't miss a single issue. Sign up for the free AFP email table of contents. Take the medicine with food and a full glass of water as soon as you can, but skip the missed dose if it is almost time for your next dose.

Do not take two doses at one time. Health Topics. Health Tools. Welchol Colesevelam. Generic Name: Colesevelam. Reviewed: September 24, You should not take colesevelam if you are allergic to it, or if you have: very high levels of triglycerides a type of fat in your blood; diabetic ketoacidosis call your doctor for treatment ; a history of bowel obstruction; or a history of pancreatitis caused by high triglycerides.

Tell your doctor if you have ever had: trouble swallowing; blockage in your digestive tract stomach or intestines ; slow digestion; surgery on your stomach or intestines; or a vitamin A, D, E, or K deficiency. Side Effects. Side Effects What are the side effects of Welchol Colesevelam? Stop using colesevelam and call your doctor at once if you have: severe constipation; severe stomach pain; or pancreatitis --severe pain in your upper stomach spreading to your back, nausea and vomiting.

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