The Role of Bile Acid Sequestrants in the Management of Type 2 Diabetes Mellitus: Summary and Future Directions

Introduction

T he obesity explosion of recent years has been followed by further development of diabetes and prediabetes, which has reached epidemic proportions in the United States and globally. Type 2 diabetes mellitus (T2DM) is a cardiovascular risk equivalent and is associated with premature cardiovascular disease (CVD), hypertension, and dyslipidemia. CVD is the leading cause of death in people with T2DM. In recent years there has been a significant decline in mortality from coronary heart disease (CHD) in the United States, primarily due to improvement in the prevention and treatment of coronary risk factors like low-density lipoprotein cholesterol (LDL-C), hypertension, and smoking. However this trend in mortality reductions has been offset by the increase prevalence of diabetes and its associated CVD.

Special Issue Summary

In his article, Philip Levy describes that the treatment of prediabetes and diabetes requires a comprehensive approach focusing on weight, glucose, hypertension control, and management of dyslipidemia. Lifestyle modification is key in the management of diabetes; however, it usually needs to be accompanied by the aid of pharmacologic agents addressing all aspects of diabetes—hyperglycemia, elevated blood pressure, dyslipidemia, and hypercoagulopathy.

After many years of having only two types of diabetes medications—insulin and sulfonylurea—we now have 11 different classes of medications to control the hyperglycemia of diabetes, as reviewed by Ganda. The bile acid sequestrant (BAS) colesevelam hydrochloride (HCl) is a recent addition to the growing list of medications for diabetes, having received the indication in 2008 from the Food and Drug Administration (FDA) to improve glycemic control in adults with T2DM. Colesevelam HCl, which has been available for the past 10 years to reduce LDL-C in adults with primary hyperlipidemia, is the only drug that is indicated to treat both hyperglycemia and LDL-C.

Colesevelam HCl, like the other BASs, is not absorbed by the intestines; its action in reducing LDL-C was believed to be like an intestinal detergent. Prawitt and Staels in their elegant article describe the potential mechanism of BAS and especially that of colesevelam HCl to improve glycemic control. The bile acids seem to regulate hepatic glucose metabolism, peripheral insulin sensitivity, and energy metabolism by affecting the nuclear receptors farnesoid X receptor (FXR)- and TGR5-dependent pathways. Another mechanism implies the induction of the fibroblast growth factor 19 (FGF19) in the intestines. FGF19, which is induced by intestinal FXR, affects energy and glucose metabolism. Studies have shown that an increase in glucagon-like peptide-1 (GLP1) levels following the administration of colesevelam HCl seems to be a mediated TGR5 increase of GLP1 secretion by intestinal L cells. This presents a powerful mechanism by which changes in bile acid metabolism can modulate glucose and perhaps lipid homeostasis.

Philip Levy describes the studies with colesevelam HCl that spanned throughout the life cycle of diabetes. The “real-to-life” studies were: (1) metformin based, seemingly early diabetes; (2) sulfonylurea based, intermediate diabetes; and (3) insulin based, perhaps representing late-stage diabetes. The reduction in glycosylated hemoglobin (HbA1c) was consistent throughout the studies, ranging between 0.5% and 0.7%, regardless of whether colesevelam was the second, third, or even the fourth drug added. In all of these studies, the LDL-C reduction was consistent at approximately 15%. Other cardio-vascular risk markers affected by colesevelam HCl and showing a reduction, were non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB) levels, and high-sensitivity C-reactive protein (hsCRP) levels. Levy also described a study treating high cholesterol in people with prediabetes that also resulted in reducing hyperglycemia, ¹ underscoring the values of the drug in the entire life cycle of diabetes. In his article, Levy also points out the safety of the drug both in the studies as well as in the observed approximately 10 years of postmarketing data.

In his article, Ganda highlights the need to address all cardiovascular risk factors when treating people with diabetes. Ganda points out that colesevelam HCl is effective in combinations, and in fact adding it to a statin may be more efficacious than increasing the dose of the statin. He concludes that it makes sense to add the drug for people who are already treated for both hyperglycemia and hyperlipidemia and who are not at their goals. Adding colesevelam HCl may get them to both glucose and lipid goals, as otherwise they would have needed two drugs to reach both goals; however, its effect on cardiovasular morbidity and mortality has not been determined. Dr Ganda goes on to describe the implication of the results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and VA Diabetes Trial (VADT) studies as well as the other epidemiologic and clinical trial data, such as United Kingdom Prospective Diabetes Study (UKPDS). He suggests that these studies point out the need to institute individualized treatment. He suggests that having safe drugs allow for early intensive glycemic control that can be initiated soon after the diagnosis of diabetes to achieve near-normal HbA1c levels, a desired goal if achieved safely without recurrent hypoglycemia. He also points out the need to develop and use cardiovascular safe drugs because many of the existing medications are potentially risky cardiovascularly, causing hypoglycemia, edema, weight gain, and congestive heart failure (CHF).

Future Role of BASs

BASs like colesevelam HCl have an attractive and growing role in the treatment of diabetes. The recent American Association of Clinical Endocrinologists (AACE) consensus algorithm for glycemic control ² highlights the direction of the future choice of medications in the treatment of diabetes. This choice is in clear contrast to the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus for the medical management of hyperglycemia in T2DM. ³ This consensus promotes the use of seemingly “inexpensive” medications, yet with apparent total disregard to their potential negative side effects. The ADA/EASD consensus endorsed sulfonylurea and insulin, which may cause hypoglycemia, obesity, and edema, whereas the AACE algorithm endorses seemingly more expensive medications, although the total cost of treatment may prove to be less. Safer medications that do not cause hypoglycemia, weight gain, and obesity will eventually be not just more beneficial but less expensive in the long run.

I predict that the use of medications like the BAS colesevelam HCl in combination with other anti-diabetic medications will increase over time because it can be used in early disease with less risk of hypoglycemia as well as in late disease when other medications cannot be used, for example, metformin in the presence of kidney disease or thiazolidinediones (TZDs) in CHF. Colesevelam HCl may offer a unique opportunity in prediabetes, a condition that currently has no approved medication. However, it is recommended to treat the LDL-C of people with prediabetes to below 100 mg/dL, ⁴ and adding colesevelam HCl to statins is a logical step that may have the benefit of also reducing hyperglycemia in this population. ¹

Recognizing that most people with diabetes have CVD, from which they are likely to die, future treatment recommendations for diabetes will address all risk factors. It is becoming clear that treating diabetes is not just about controlling glucose. The future endocrinologist diabetes expert will be the specialist in the comprehensive care of diabetes, be able to control glucose, dyslipidemia, hypertension, coagulopathy and other cardiovascular risk factors. Future guidelines and algorithms by the AACE, and perhaps the ADA and others, will focus on the comprehensive care of diabetes, promoting medications to control all the above conditions. The newly developed medications will be indicated for more than one condition and they will be safe and cardioprotective. We should anticipate drugs that will reduce glucose levels and weight; others that are designed for cardiovascular risk and inflammation will also reduce glucose. In other words, medications like colesevelam are the characteristic prototype for future drugs for diabetes and will be able to address the requirement and recommendations that will be set by the leading medical societies.