- Email: [email protected]
Lomitapide for homozygous familial hypercholesterolaemia
Comment
Homozygous familial hypercholesterolaemia is an inherited disorder caused mainly by mutations in both LDL-receptor alleles.1 The disorder is difficult to treat. Currently available lipid-modifying therapies, even if combined with LDL-apheresis, rarely achieve optimal LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolaemia, and these patients remain at high cardiovascular risk with substantially reduced life expectancy from premature cardiovascular disease, especially coronary artery disease.2 However, in a retrospective study, lipid-lowering therapy, especially statin therapy, delayed the onset of cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolaemia despite only a modest reduction in LDL cholesterol.3 Even with statin therapy the average age of death is still very young, with few patients surviving beyond the age of 40 years.3 Mipomersen, an antisense inhibitor of ApoB synthesis still under development, when given in combination with maximum tolerated doses of lipid-lowering therapy, can reduce LDL cholesterol by an additional 25% in patients with homozygous familial hypercholesterolaemia, but even the addition of mipomersen does not achieve the recommended target for LDL cholesterol in most patients.4 Microsomal transfer protein (MTP) is a key protein involved in the assembly and secretion of ApoBcontaining lipoproteins in the liver and intestines.5 Complete absence of MTP causes abetalipoproteinaemia, a rare disorder, which is characterised by failure to thrive, steatorrhoea, deficiency of the fat soluble vitamins, and extremely low or undetectable concentrations of ApoB-containing lipoproteins.6 Inhibition of MTP is, therefore, potentially a powerful therapeutic method to reduce the production of ApoB-containing lipoproteins, especially VLDL, the precursors of LDL. In The Lancet, Marina Cuchel and colleagues report on the safety and efficacy of lomitapide, an oral inhibitor of MTP, in a phase 3 study of 29 adult patients with homozygous familial hypercholesterolaemia. At a median dose of 40 mg lomitapide per day, concentrations of LDL cholesterol were reduced by 50% (95% CI –62 to –39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]), and by www.thelancet.com Vol 381 January 5, 2103
38% (–52 to –24) in the 23 patients who completed 78 weeks of treatment.7 However, as would be expected from the drug’s mechanism of action, gastrointestinal side-effects were common, occurring in 80% of patients, and 30% of patients had more than a three-fold elevation in liver enzymes on one or more occasion. At week 26 there was an eight-fold increase in the amount of hepatic fat, from 1% at baseline to almost 9%.7 Despite the limitations of this non-randomised, unmasked, single group study, the reduction in LDL cholesterol is impressive and suggests that lomitapide could be of value as additional therapy in patients with homozygous familial hypercholesterolaemia. Yet the benefit of lomitapide has to be weighed against the potential long-term risks of this therapy. Additionally, the dose of lomitapide is not fixed and must be titrated in individual patients according to gastrointestinal side-effects, liver enzyme elevation, and the amount of hepatic fat accumulation. Use of this drug will therefore probably be restricted to these patients at specialised lipid clinics. The study was relatively short-term, only 78 weeks. As treatment with lomitapide will be lifelong, patients with homozygous familial hypercholesterolaemia receiving this therapy will have to be closely monitored over a much longer period to confirm that the reduction in LDL cholesterol achieved with lomitapide is maintained and, more importantly, to ensure that the accumulation of hepatic fat does not progress to hepatic fibrosis or frank cirrhosis, as can occur in non-alcoholic fatty liver disease.8 However, hepatic fat accumulation due to lomitapide (and mipomersen) results from a different mechanism (or mechanisms) and the long-term consequences remain unknown. In patients with heterozygous familial hypercholesterolaemia, monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently been shown to reduce LDL cholesterol by an additional 50–60% on top of high-dose statins with or without ezetimibe.9 The addition of a PCSK9 inhibitor will probably allow most patients with heterozygous familial hypercholesterolaemia to achieve target concentrations of LDL cholesterol. However, the action of PCSK9 inhibitors is dependent on the
Getty Images
Lomitapide for homozygous familial hypercholesterolaemia
LDL particle Published Online November 2, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61845-5 See Articles page 40
7
Comment
presence of functional LDL receptors, which are absent or substantially defective in patients with homozygous familial hypercholesterolaemia. Whether PCSK9-inhibitor therapy will be effective in these patients is uncertain. Rather than a reduction in LDL cholesterol, the ultimate test of any lipid-modifying therapy is a reduction in cardiovascular events and improved survival, as has been shown with statin therapy.10–12 Ultimately, the addition of lomitapide could improve survival in patients with homozygous familial hypercholesterolaemia, but its use will be limited by its narrow therapeutic window and the need to titrate the dose in individual patients. This will probably restrict the use of lomitapide to patients with this rare, but devastating, disorder. Frederick J Raal Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, 2193 Johannesburg, South Africa [email protected] I declare that I have no conflicts of interest. 1
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 8th edn. New York: McGraw-Hill, 2001: 2863–913.
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5 6 7
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10 11
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Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012; 223: 262–68. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011; 124: 2202–07. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 998–1006. Wetterau JR, Lin MC, Jamil H. Microsomal triglyceride transfer protein. Biochim Biophys Acta 1997; 1345: 136–50. Di Leo E, Lancellotti S, Penacchioni JY, et al. Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia. Atherosclerosis 2005; 180: 311–18. Cuchel M, Meagher EA, Theron HdT, et al, for the Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2012; published online Nov 2. http://dx.doi.org/10.1016/S01406736(12)61731-0. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with non-alcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7: 234–38. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380: 29–36. Grundy SM. Is lowering low-density lipoprotein an effective strategy to reduce cardiac risk? Circulation 2008; 117: 569–73. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376: 1670–81.
What videos can tell us about falling Published Online October 17, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61724-3 See Articles page 47
8
In 2004, a videotape of a fall by Fidel Castro, then Cuban President, gained extensive press coverage and elicited a range of reactions.1 The sequence captured a key shot for researchers who study falls. In the film, Castro, after one of his exhausting speeches and probably dazzled by lights, misses a step, starts falling after an unsuccessful stepping attempt, and turns in the air to reduce the impact of his head on the ground at the expense of an upper limb; the fall resulted in a broken shoulder and patella. Falls and fall-related injuries are a major health burden. Despite many epidemiological studies of predisposing risk factors,2 many assumptions and decisions about falls are still based on subjective and often biased information.3 Fewer than 10% of falls are witnessed and, even when reports are available, they often do not provide detailed and objective information about the context and circumstances of
the fall, or what happened during the fall. This absence of understanding is one of the reasons why efforts to prevent falls have had little success, although some progress has been achieved.4–6 In The Lancet, Stephen Robinovitch and colleagues7 present results of an observational study of videotaped falls. They extensively studied falls in two long-term care institutions in British Columbia, Canada, between 2007 and 2010, using more than 200 public video cameras that were preinstalled for safety purposes. With a well-defined protocol, they were able to match staff incident reports of falls to video footage, making this a unique study. The researchers recorded 227 falls by 130 individuals whose mean age was 78 years (SD 10). Studies of this type are important because falls by elderly people are much more frequent in long-term care facilities than in the community; more than 90% of all hip fractures are caused by falls, www.thelancet.com Vol 381 January 5, 2013
Homozygous familial hypercholesterolaemia is an inherited disorder caused mainly by mutations in both LDL-receptor alleles.1 The disorder is difficult to treat. Currently available lipid-modifying therapies, even if combined with LDL-apheresis, rarely achieve optimal LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolaemia, and these patients remain at high cardiovascular risk with substantially reduced life expectancy from premature cardiovascular disease, especially coronary artery disease.2 However, in a retrospective study, lipid-lowering therapy, especially statin therapy, delayed the onset of cardiovascular events and prolonged survival in patients with homozygous familial hypercholesterolaemia despite only a modest reduction in LDL cholesterol.3 Even with statin therapy the average age of death is still very young, with few patients surviving beyond the age of 40 years.3 Mipomersen, an antisense inhibitor of ApoB synthesis still under development, when given in combination with maximum tolerated doses of lipid-lowering therapy, can reduce LDL cholesterol by an additional 25% in patients with homozygous familial hypercholesterolaemia, but even the addition of mipomersen does not achieve the recommended target for LDL cholesterol in most patients.4 Microsomal transfer protein (MTP) is a key protein involved in the assembly and secretion of ApoBcontaining lipoproteins in the liver and intestines.5 Complete absence of MTP causes abetalipoproteinaemia, a rare disorder, which is characterised by failure to thrive, steatorrhoea, deficiency of the fat soluble vitamins, and extremely low or undetectable concentrations of ApoB-containing lipoproteins.6 Inhibition of MTP is, therefore, potentially a powerful therapeutic method to reduce the production of ApoB-containing lipoproteins, especially VLDL, the precursors of LDL. In The Lancet, Marina Cuchel and colleagues report on the safety and efficacy of lomitapide, an oral inhibitor of MTP, in a phase 3 study of 29 adult patients with homozygous familial hypercholesterolaemia. At a median dose of 40 mg lomitapide per day, concentrations of LDL cholesterol were reduced by 50% (95% CI –62 to –39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]), and by www.thelancet.com Vol 381 January 5, 2103
38% (–52 to –24) in the 23 patients who completed 78 weeks of treatment.7 However, as would be expected from the drug’s mechanism of action, gastrointestinal side-effects were common, occurring in 80% of patients, and 30% of patients had more than a three-fold elevation in liver enzymes on one or more occasion. At week 26 there was an eight-fold increase in the amount of hepatic fat, from 1% at baseline to almost 9%.7 Despite the limitations of this non-randomised, unmasked, single group study, the reduction in LDL cholesterol is impressive and suggests that lomitapide could be of value as additional therapy in patients with homozygous familial hypercholesterolaemia. Yet the benefit of lomitapide has to be weighed against the potential long-term risks of this therapy. Additionally, the dose of lomitapide is not fixed and must be titrated in individual patients according to gastrointestinal side-effects, liver enzyme elevation, and the amount of hepatic fat accumulation. Use of this drug will therefore probably be restricted to these patients at specialised lipid clinics. The study was relatively short-term, only 78 weeks. As treatment with lomitapide will be lifelong, patients with homozygous familial hypercholesterolaemia receiving this therapy will have to be closely monitored over a much longer period to confirm that the reduction in LDL cholesterol achieved with lomitapide is maintained and, more importantly, to ensure that the accumulation of hepatic fat does not progress to hepatic fibrosis or frank cirrhosis, as can occur in non-alcoholic fatty liver disease.8 However, hepatic fat accumulation due to lomitapide (and mipomersen) results from a different mechanism (or mechanisms) and the long-term consequences remain unknown. In patients with heterozygous familial hypercholesterolaemia, monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently been shown to reduce LDL cholesterol by an additional 50–60% on top of high-dose statins with or without ezetimibe.9 The addition of a PCSK9 inhibitor will probably allow most patients with heterozygous familial hypercholesterolaemia to achieve target concentrations of LDL cholesterol. However, the action of PCSK9 inhibitors is dependent on the
Getty Images
Lomitapide for homozygous familial hypercholesterolaemia
LDL particle Published Online November 2, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61845-5 See Articles page 40
7
Comment
presence of functional LDL receptors, which are absent or substantially defective in patients with homozygous familial hypercholesterolaemia. Whether PCSK9-inhibitor therapy will be effective in these patients is uncertain. Rather than a reduction in LDL cholesterol, the ultimate test of any lipid-modifying therapy is a reduction in cardiovascular events and improved survival, as has been shown with statin therapy.10–12 Ultimately, the addition of lomitapide could improve survival in patients with homozygous familial hypercholesterolaemia, but its use will be limited by its narrow therapeutic window and the need to titrate the dose in individual patients. This will probably restrict the use of lomitapide to patients with this rare, but devastating, disorder. Frederick J Raal Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, 2193 Johannesburg, South Africa [email protected] I declare that I have no conflicts of interest. 1
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 8th edn. New York: McGraw-Hill, 2001: 2863–913.
2
3
4
5 6 7
8 9
10 11
12
Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012; 223: 262–68. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011; 124: 2202–07. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 998–1006. Wetterau JR, Lin MC, Jamil H. Microsomal triglyceride transfer protein. Biochim Biophys Acta 1997; 1345: 136–50. Di Leo E, Lancellotti S, Penacchioni JY, et al. Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia. Atherosclerosis 2005; 180: 311–18. Cuchel M, Meagher EA, Theron HdT, et al, for the Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2012; published online Nov 2. http://dx.doi.org/10.1016/S01406736(12)61731-0. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with non-alcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7: 234–38. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380: 29–36. Grundy SM. Is lowering low-density lipoprotein an effective strategy to reduce cardiac risk? Circulation 2008; 117: 569–73. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376: 1670–81.
What videos can tell us about falling Published Online October 17, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61724-3 See Articles page 47
8
In 2004, a videotape of a fall by Fidel Castro, then Cuban President, gained extensive press coverage and elicited a range of reactions.1 The sequence captured a key shot for researchers who study falls. In the film, Castro, after one of his exhausting speeches and probably dazzled by lights, misses a step, starts falling after an unsuccessful stepping attempt, and turns in the air to reduce the impact of his head on the ground at the expense of an upper limb; the fall resulted in a broken shoulder and patella. Falls and fall-related injuries are a major health burden. Despite many epidemiological studies of predisposing risk factors,2 many assumptions and decisions about falls are still based on subjective and often biased information.3 Fewer than 10% of falls are witnessed and, even when reports are available, they often do not provide detailed and objective information about the context and circumstances of
the fall, or what happened during the fall. This absence of understanding is one of the reasons why efforts to prevent falls have had little success, although some progress has been achieved.4–6 In The Lancet, Stephen Robinovitch and colleagues7 present results of an observational study of videotaped falls. They extensively studied falls in two long-term care institutions in British Columbia, Canada, between 2007 and 2010, using more than 200 public video cameras that were preinstalled for safety purposes. With a well-defined protocol, they were able to match staff incident reports of falls to video footage, making this a unique study. The researchers recorded 227 falls by 130 individuals whose mean age was 78 years (SD 10). Studies of this type are important because falls by elderly people are much more frequent in long-term care facilities than in the community; more than 90% of all hip fractures are caused by falls, www.thelancet.com Vol 381 January 5, 2013