The major cause of morbidity and mortality in patients with T2DM is cardiovascular disease. It has previously been shown in both the Collaborative Atorvastatin Diabetes Study (CARDS)5
and Heart Protection Study6
that statin therapy results in significant reduction in LDL-C and cardiovascular events. However, statin therapy does not appear to have a benefit with regard to glycemia. Also, recently the UK Prospective Diabetes Study (UKPDS) Study7
has reported a legacy effect with good early glycemic control and reduction in future cardiovascular events. Thus, therapies targeting both LDL-C and glycemia become attractive strategies for forestalling vascular complications in patients with diabetes. In the Glucose Lowering Effect of Welchol Study (GLOWS) study, it was previously reported by Zieve et al. that COL therapy resulted in a reduction in both LDL-C and HbA1c.1
However, this study suffered from a small sample size of n
65. In the present analysis, which includes 1018 patients, the effects seen in the GLOWS study were confirmed in patients on metformin therapy, sulfonylurea therapy, or insulin therapy. In all three of these studies in monotherapy and combination thereapy, COL resulted in a significant reduction in both LDL-C and HbA1c. With regard to the side-effect profile in this pooled analysis, it appears that the major side effect that occurred in all three studies was gastrointestinal side effects, mainly constipation. Thus, this pooled analysis of large sample size confirms the efficacy of COL therapy as an attractive strategy in patients with diabetes who are not at the HbA1c goal of <7.0% or LDL-C goal of <100
mg/dL. The advantage of the COL therapy is that it can be used safely in combination with the other antidiabetic therapies, as shown in these three studies in this pooled analysis.2–4
Furthermore, the efficacy of combination of COL with statin therapy is clearly safe and results in greater reduction in LDL and non-HDL-C.
It is important to appreciate in these three studies that in addition to reduction in LDL-C with COL therapy, there was significant reduction in non-HDL-C and ApoB levels in spite of the modest increase in plasma TGs because both LDL-C and non-HDL-C are targets for treatment.8
It is also possible in future guidelines that ApoB will also become a target for treatment. Whereas the reduction in LDL is related to bile acid sequestration induced by COL, the precise mechanism for the glucose-lowering effect remains to be elucidated. Numerous mechanisms have been proposed; the most attractive appears to be with respect to the interactions of bile acids with nuclear receptors. Bile acids are endogenous ligands of the farnesoid X receptor. This might be a potential mechanism for the reduction in glucose levels.9
The modest increase in TG of 15.0% should be interpreted in conjunction with the benefit of COL therapy in reducing LDL-C, non-HDL-C, and ApoB levels.
Recently, the Jupiter study10
showed the benefit of statin therapy in patients with elevated CRP and normal LDL-C. Also, there is much data suggesting that CRP could contribute to atherothrombosis.11
It has been previously been shown12
and confirmed in this pooled analysis that COL reduces CRP levels. In the future, CRP could emerge as a target for treatment; it is elevated in patients with diabetes. This would make COL therapy even more attractive because, in addition to reduction in LDL-C, ApoB, non-HDL-C, and HbA1c, it would help in reduction in CRP levels.
In conclusion, this pooled analysis confirms that COL therapy in patients with T2DM results in a significantly greater reduction in both LDL-C and HbA1c and should seriously be considered as a viable strategy in obtaining the goals recommended by American Diabetes Association in type 2 diabetic patients.