Abstract: Six RCTs ranging from 8 to 26 weeks investigating 1450 participants met the inclusion criteria. Overall, the risk of bias of these trials was unclear or high. All RCTs compared the effects of colesevelam with or without other antidiabetic drug treatments with placebo only (one study) or combined with antidiabetic drug treatments. Colesevelam with add-on antidiabetic agents demonstrated a statistically significant reduction in fasting blood glucose with a mean difference (MD) of -15 mg/dL (95% confidence interval (CI) -22 to - 8), P < 0.0001; 1075 participants, 4 trials, no trial with low risk of bias in all domains. There was also a reduction in glycosylated haemoglobin A1c (HbA1c) in favour of colesevelam (MD -0.5% (95% CI -0.6 to -0.4), P < 0.00001; 1315 participants, 5 trials, no trial with low risk of bias in all domains. However, the single trial comparing colesevelam to placebo only (33 participants) did not reveal a statistically significant difference between the two arms - in fact, in both arms HbA1c increased. Colesevelam with add-on antidiabetic agents demonstrated a statistical significant reduction in low-density lipoprotein (LDL)-cholesterol with a MD of -13 mg/dL (95% CI -17 to - 9), P < 0.00001; 886 participants, 4 trials, no trial with low risk of bias in all domains. Non-severe hypoglycaemic episodes were infrequently observed. No other serious adverse effects were reported. There was no documentation of complications of the disease, morbidity, mortality, health-related quality of life and costs. Colesevelam added on to antidiabetic agents showed significant effects on glycaemic control. However, there is a limited number of studies with the different colesevelam/antidiabetic agent combinations. More information on the benefit-risk ratio of colesevelam treatment is necessary to assess the long-term effects, particularly in the management of cardiovascular risks as well as the reduction in micro- and macrovascular complications of type 2 diabetes mellitus. Furthermore, long-term data on health-related quality of life and all-cause mortality also need to be investigated.

Plain-language summary: A total of 1450 patients took part in six studies investigating colesevelam. These studies lasted 8 to 26 weeks. Only one small study compared colesevelam directly to placebo, the other five studies investigated a combination of colesevelam with other antidiabetic agents versus a combination of placebo with other antidiabetic agents. There were no two studies with the same intervention and comparison group. When added to other antidiabetic agents colesevelam showed improvements in the control of blood glucose and blood lipids. However, it is difficult to disentangle the effects of colesevelam from the other antidiabetic agents used because only one study compared colesevelam to placebo. The same is true for adverse effects: three studies reported on just a few non-severe hypoglycaemic episodes, no other serious side effects were observed. No study investigated mortality; complications of type 2 diabetes such as eye disease, kidney disease, heart attack and stroke; health-related quality of life; functional outcomes and costs of treatment. Therefore, long-term data on the efficacy and safety of colesevelam are necessary.