- Email: [email protected]
PCSK9 inhibition in type 2 diabetes: so far so good, but not there yet
Comment
PCSK9 inhibition in type 2 diabetes: so far so good, but not there yet Alirocumab and evolocumab, both fully human monoclonal antibodies that bind to plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), were recently approved for the treatment of hypercholesterolaemia in Europe and the USA. PCSK9 is mainly synthesised by the liver and binds to LDL receptors, thereby precluding their recycling to the hepatocyte surface, reducing LDL clearance from plasma, and thus increasing the concentration of LDL cholesterol.1 Type 2 diabetes is associated with an increased lifetime risk of cardiovascular disease, and practice guidelines recommend intensive LDL cholesterol-lowering treatment to prevent major atherosclerotic events.4 Patients with type 2 diabetes have therefore become a natural population in which to test PCSK9 inhibitors. In The Lancet Diabetes & Endocrinology, Naveed Sattar and colleagues5 present the results of a meta-analysis of three 12-week phase 3 trials that compared evolocumab with placebo, ezetimibe (a cholesterol absorption inhibitor), or both to manage plasma lipids. The studies included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. The study populations were similar to patients seen in contemporary clinical practice, with one in three patients with diabetes presenting with coronary artery disease, most patients receiving statins, and most presenting with high concentrations of LDL cholesterol, non-HDL cholesterol, and triglycerides, and a low concentration of HDL cholesterol. Despite the fact that some enrolled patients had familial hypercholesterolaemia, the patients were representative of patients with diabetes in clinical practice. After 12 weeks of evolocumab therapy, the results from patients with type 2 diabetes showed mean reductions in LDL cholesterol (60% relative to placebo [absolute reduction 1·74 mmol/L] and 39% relative to ezetimibe [absolute reduction 1·13 mmol/L]), non-HDL cholesterol (55% relative to placebo and 34% relative to ezetimibe), lipoprotein(a) (31% relative to placebo and 26% relative to ezetimibe), and triglycerides (23% relative to placebo and 17% relative to ezetimibe), while the concentration of HDL cholesterol increased with evolocumab therapy (8% relative to placebo and
ezetimibe). No heterogeneity in the lipid-lowering effects of evolocumab were found between patients with and without type 2 diabetes, and the effects of evolocumab were not affected by use of insulin, presence of previous cardiovascular disease, baseline renal function, or baseline blood glucose control status. Safety and tolerability were similar among studied groups. This study extends previous evidence1,3 of the robust cholesterol-lowering effects of PCSK9 inhibitors to patients with type 2 diabetes. These effects were seen in patients who were already taking modern statin therapy, and evolocumab was superior to ezetimibe and well tolerated. If sustained in the long term, the absolute mean reduction in LDL cholesterol with evolocumab of 1·74 mmol/L could have important clinical implications if PCSK9 inhibitors follow the pattern described for statins by the Cholesterol Treatment Trialists,6 whereby every 1 mmol/L reduction in LDL cholesterol was associated with a relative 22% reduction in major atherosclerotic cardiovascular events. Despite the safety and tolerability profile of evolocumab being no different from that seen in a longer-duration study,3 the main limitation of Sattar and colleagues5 analysis is the short duration of the included studies, precluding adequate assessment of possible side-effects caused by the drug. Furthermore, whether PCSK9, which is also present in the pancreas, could affect glucose homeostasis, is a controversial issue.7–9 PCSK9 knockout mice have reduced insulin concentrations in their pancreas and present with hypoinsulinaemia, hyperglycaemia, and glucose intolerance.7 This finding, together with changes in β-cell histology in PCSK9 knockout mice, suggests that PCSK9 might be important for pancreatic function. In human beings, evidence suggests that plasma PCSK9 concentrations are positively associated with fasting serum glucose, insulin, and homeostasis model assessment insulin resistance.8 However, the p.R46L PCSK9 loss-of-function mutation, which leads to reduced LDL cholesterol concentration, was not associated with dysglycaemia or increased diabetes risk in a prospective study.9 This controversy will probably last a long time, since it took
www.thelancet.com/diabetes-endocrinology Published online February 8, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00014-0
Lancet Diabetes Endocrinol 2016 Published Online February 8, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)00014-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(16)00003-6
1
Comment
decades of use and a huge number of patients enrolled in clinical trials to show that statins can have unfavourable, modest effects on glucose homeostasis.10 Therefore, ongoing trials and post-marketing surveillance will be of utmost importance to definitely show whether or not PCSK9 inhibitors can disturb glucose homeostasis. Because of their high cost (more than US$12 000 dollars per year in the USA2), the absence of robust evidence for reduction of cardiovascular events,3 and the need to prove long-term safety, PCSK9 inhibitors should initially be reserved for patients who are at the highest risk of cardiovascular disease and whose hypercholesterolaemia persists despite the use of other lipid-lowering treatments (eg, patients with familial hypercholesterolaemia or those who are statin intolerant).1,2 Ultimately, the costeffectiveness of widespread PCSK9 treatment, which could potentially be used by millions of patients with diabetes worldwide, will be determined by the absolute cardiovascular risk of these patients, by the extent of residual uncontrolled LDL cholesterol concentrations despite use of statins and ezetimibe, and by the future costs of these drugs. First and foremost, cardiovascular benefits and safety of PCSK9 inhibitors must be proven in robust randomised clinical trials that include patients with diabetes, such as FOURIER (NCT01764633), ODYSSEY (NCT01663402), SPIRE-1 (NCT01975389), and SPIRE-2 (NCT01975376). For the moment, PCSK9 inhibition in type 2 diabetes is promising, but not yet ready for widespread use.
2
Raul D Santos Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital and Preventive Medicine Centre and Cardiology Program, Hospital Israelita Albert Einstein, São Paulo, SP 05403, Brazil [email protected] I have received honoraria for consulting and speaking fees from AstraZeneca, Aegerion, Akcea, Amgen, Eli Lilly, Boehringer Ingelheim, Biolab, Cerenis, Genzyme, Kowa, Merck, Pfizer, Praxis, Sanofi, Regeneron, Torrent, and Unilever. 1 2
3
4
5
6
7
8
9
10
Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet 2015; 385: 307–10. Weintraub WS, Gidding SS. PCSK9 inhibitors: a technology worth paying for? PharmacoEconomics 2015; published online Dec 21. DOI:10.1007/s40273015-0355-y. Sabatine MS, Giugliano RP, Wiviott SD, et al, for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500–09. Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ 2014; 349: g4356. Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol 2016; published online Feb 8. http://dx.doi.org/10.1016/S22138587(16)00003-6. Cholesterol Treatment Trialists’ (CTT) Collaboration. 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. Mbikay M, Sirois F, Mayne J, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 2010; 584: 701–06. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009; 94: 2537–43. Bonnefond A, Yengo L, Le May C, et al. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia 2015; 58: 2051–55. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735–42.
www.thelancet.com/diabetes-endocrinology Published online February 8, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00014-0
PCSK9 inhibition in type 2 diabetes: so far so good, but not there yet Alirocumab and evolocumab, both fully human monoclonal antibodies that bind to plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), were recently approved for the treatment of hypercholesterolaemia in Europe and the USA. PCSK9 is mainly synthesised by the liver and binds to LDL receptors, thereby precluding their recycling to the hepatocyte surface, reducing LDL clearance from plasma, and thus increasing the concentration of LDL cholesterol.1 Type 2 diabetes is associated with an increased lifetime risk of cardiovascular disease, and practice guidelines recommend intensive LDL cholesterol-lowering treatment to prevent major atherosclerotic events.4 Patients with type 2 diabetes have therefore become a natural population in which to test PCSK9 inhibitors. In The Lancet Diabetes & Endocrinology, Naveed Sattar and colleagues5 present the results of a meta-analysis of three 12-week phase 3 trials that compared evolocumab with placebo, ezetimibe (a cholesterol absorption inhibitor), or both to manage plasma lipids. The studies included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. The study populations were similar to patients seen in contemporary clinical practice, with one in three patients with diabetes presenting with coronary artery disease, most patients receiving statins, and most presenting with high concentrations of LDL cholesterol, non-HDL cholesterol, and triglycerides, and a low concentration of HDL cholesterol. Despite the fact that some enrolled patients had familial hypercholesterolaemia, the patients were representative of patients with diabetes in clinical practice. After 12 weeks of evolocumab therapy, the results from patients with type 2 diabetes showed mean reductions in LDL cholesterol (60% relative to placebo [absolute reduction 1·74 mmol/L] and 39% relative to ezetimibe [absolute reduction 1·13 mmol/L]), non-HDL cholesterol (55% relative to placebo and 34% relative to ezetimibe), lipoprotein(a) (31% relative to placebo and 26% relative to ezetimibe), and triglycerides (23% relative to placebo and 17% relative to ezetimibe), while the concentration of HDL cholesterol increased with evolocumab therapy (8% relative to placebo and
ezetimibe). No heterogeneity in the lipid-lowering effects of evolocumab were found between patients with and without type 2 diabetes, and the effects of evolocumab were not affected by use of insulin, presence of previous cardiovascular disease, baseline renal function, or baseline blood glucose control status. Safety and tolerability were similar among studied groups. This study extends previous evidence1,3 of the robust cholesterol-lowering effects of PCSK9 inhibitors to patients with type 2 diabetes. These effects were seen in patients who were already taking modern statin therapy, and evolocumab was superior to ezetimibe and well tolerated. If sustained in the long term, the absolute mean reduction in LDL cholesterol with evolocumab of 1·74 mmol/L could have important clinical implications if PCSK9 inhibitors follow the pattern described for statins by the Cholesterol Treatment Trialists,6 whereby every 1 mmol/L reduction in LDL cholesterol was associated with a relative 22% reduction in major atherosclerotic cardiovascular events. Despite the safety and tolerability profile of evolocumab being no different from that seen in a longer-duration study,3 the main limitation of Sattar and colleagues5 analysis is the short duration of the included studies, precluding adequate assessment of possible side-effects caused by the drug. Furthermore, whether PCSK9, which is also present in the pancreas, could affect glucose homeostasis, is a controversial issue.7–9 PCSK9 knockout mice have reduced insulin concentrations in their pancreas and present with hypoinsulinaemia, hyperglycaemia, and glucose intolerance.7 This finding, together with changes in β-cell histology in PCSK9 knockout mice, suggests that PCSK9 might be important for pancreatic function. In human beings, evidence suggests that plasma PCSK9 concentrations are positively associated with fasting serum glucose, insulin, and homeostasis model assessment insulin resistance.8 However, the p.R46L PCSK9 loss-of-function mutation, which leads to reduced LDL cholesterol concentration, was not associated with dysglycaemia or increased diabetes risk in a prospective study.9 This controversy will probably last a long time, since it took
www.thelancet.com/diabetes-endocrinology Published online February 8, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00014-0
Lancet Diabetes Endocrinol 2016 Published Online February 8, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)00014-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(16)00003-6
1
Comment
decades of use and a huge number of patients enrolled in clinical trials to show that statins can have unfavourable, modest effects on glucose homeostasis.10 Therefore, ongoing trials and post-marketing surveillance will be of utmost importance to definitely show whether or not PCSK9 inhibitors can disturb glucose homeostasis. Because of their high cost (more than US$12 000 dollars per year in the USA2), the absence of robust evidence for reduction of cardiovascular events,3 and the need to prove long-term safety, PCSK9 inhibitors should initially be reserved for patients who are at the highest risk of cardiovascular disease and whose hypercholesterolaemia persists despite the use of other lipid-lowering treatments (eg, patients with familial hypercholesterolaemia or those who are statin intolerant).1,2 Ultimately, the costeffectiveness of widespread PCSK9 treatment, which could potentially be used by millions of patients with diabetes worldwide, will be determined by the absolute cardiovascular risk of these patients, by the extent of residual uncontrolled LDL cholesterol concentrations despite use of statins and ezetimibe, and by the future costs of these drugs. First and foremost, cardiovascular benefits and safety of PCSK9 inhibitors must be proven in robust randomised clinical trials that include patients with diabetes, such as FOURIER (NCT01764633), ODYSSEY (NCT01663402), SPIRE-1 (NCT01975389), and SPIRE-2 (NCT01975376). For the moment, PCSK9 inhibition in type 2 diabetes is promising, but not yet ready for widespread use.
2
Raul D Santos Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital and Preventive Medicine Centre and Cardiology Program, Hospital Israelita Albert Einstein, São Paulo, SP 05403, Brazil [email protected] I have received honoraria for consulting and speaking fees from AstraZeneca, Aegerion, Akcea, Amgen, Eli Lilly, Boehringer Ingelheim, Biolab, Cerenis, Genzyme, Kowa, Merck, Pfizer, Praxis, Sanofi, Regeneron, Torrent, and Unilever. 1 2
3
4
5
6
7
8
9
10
Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet 2015; 385: 307–10. Weintraub WS, Gidding SS. PCSK9 inhibitors: a technology worth paying for? PharmacoEconomics 2015; published online Dec 21. DOI:10.1007/s40273015-0355-y. Sabatine MS, Giugliano RP, Wiviott SD, et al, for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500–09. Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ 2014; 349: g4356. Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol 2016; published online Feb 8. http://dx.doi.org/10.1016/S22138587(16)00003-6. Cholesterol Treatment Trialists’ (CTT) Collaboration. 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. Mbikay M, Sirois F, Mayne J, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 2010; 584: 701–06. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009; 94: 2537–43. Bonnefond A, Yengo L, Le May C, et al. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia 2015; 58: 2051–55. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735–42.
www.thelancet.com/diabetes-endocrinology Published online February 8, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00014-0