Colesevelam - a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia.

INTRODUCTION: Low density Lipoprotein cholesterol)LDL-C) levels show a clear relationship with cardiovascular disease (CVD). Statins are first line agents to reduce LDL-C and CVD risk. However, combination lipid-lowering therapy is often required to achieve large reductions in LDL-C. AREA COVERED: Colesevelam HCl is a bile acid sequestrant (BAS), which reduces LDL-C by 16-22% in monotherapy and adds a further 12-14% reduction in LDL-C when combined with other lipid-lowering drugs. Like statins, colesevelam reduces C-reactive protein levels by 16% in monotherapy and additional 6% when added to statins. Colesevelam also reduced HbA1c by 4 mmol/mol (0.5%) when used alone and added to other hypoglycemic drugs in studies of patients with diabetes . EXPERT OPINION: Bile acid sequestrants reduce LDL-C and HbA1c and have some CVD outcome evidence. The uses of these agents are limited in patients with gastrointestinal disease or high triglycerides due to adverse effects on gut function and raising triglycerides and they interfere with the absorption of lipid-soluble drugs. Colesevelam has a higher bile acid binding capacity, and fewer adverse effects than other BAS. Colesevelam may be useful as a third line agent for treatment of hypercholesterolemia with some additional specific benefits on glycemic control.

Hypertriglyceridaemia: an update.

Triglycerides (TGs) form part of the standard lipid profile. Elevations in TGs are associated with increased cardiovascular disease risk through triglyceride-rich lipoprotein particles found as part of non-HDL cholesterol. Many elevations of TGs are secondary to other causes, but primary hypertriglyceridaemia syndromes need to be identified. The genetic causes of hypertriglyceridaemia range from familial combined hyperlipidaemia through the autosomal recessive remnant hyperlipidaemia (related to apolipoprotein E variants) and familial chylomicronaemia syndromes. Patients with primary hypertriglyceridaemia >10 mmol/L require characterisation and specific intervention. Simple lipid profiles do not provide adequate information for detailed diagnosis and additional assays such as apolipoprotein (apo)B100, apoE genotype and next-generation sequencing may be useful. Management of raised TGs includes optimising diet, reducing exacerbating factors as well as lipid-lowering medications such as statins, fibrates, niacin and omega-3 fatty acids. Novel medications for orphan disease indications such as familial chylomicronaemia syndrome include volanesorsen, evinacumab and other antisense therapeutics. Extreme hypertriglyceridaemia syndromes, especially chylomicronaemia syndromes, which can be exposed by pregnancy or other factors are a medical emergency and require admission and specialist management sometimes including plasma exchange.

Triglycerides and cardiovascular disease.

PURPOSE OF REVIEW: Triglycerides (TGs) are measured as part of routine lipid profiles but their relationship to cardiovascular disease (CVD) risk has been controversial and overshadowed by high-density lipoprotein cholesterol (HDL-C). RECENT FINDINGS: Epidemiological studies show a clear relationship of TG-containing lipoproteins including remnant particles with CVD risk with the effect being most clearly demonstrated through the excess risk captured by non-HDL-C compared with low-density lipoprotein-cholesterol (LDL-C). Mendelian randomisation studies show a consistent relationship of gene variants linked to TG metabolism with rates of CVD. Furthermore, meta-analyses of intervention trials with statins and other nonstatin drugs also suggest that reducing TGs is associated with benefits on rates of CVD events. Historical subgroup data from fibrate trials suggest benefits in patients with high TG:HDL ratios but seem to add little to optimized statin therapy. Recent trials with omega-3 fatty acids (specifically eicosapentaenoic acid) have suggested that high-dose formulations in contrast to low dose formulations have benefits on CVD outcomes. SUMMARY: Further studies with newer agents are required to determine the place of TG-lowering drugs in therapeutic pathways. Trials with agents such as pemafibrate and vupanorsen may finally answer these questions.

Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy.

Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70-80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.