Amarin Corp Plc (AMRN)

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The more I research the AdCom panel the more I am starting to believe the AdCom is really about the label and how broad it should be. I think the fact that it is before the Endocrinologic Committee will end up being a blessing. Think broad label. The ADA guidelines/recommendation should be quite helpful and convincing for us.

Dr. Cecilia Low Wang is one member of the committee. She focuses on Diabetes and is particularly interested in cardiovascular disease. When you have a chance review this paper she co-authored. It is filled with many nuggets. Suffice it to say I think she will be in our corner. Especially considering she recognizes not everyone can tolerate statins. See this section below on Statins & Diabetes (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.022194):

Statins and Diabetes Mellitus
Although there are clear benefits of statins to reduce cardiovascular events and mortality in patients with or at risk for ASCVD,183,184 statins also modestly accelerate the development of diabetes mellitus in individuals with preexisting risk factors.186–189 In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which involved participants without diabetes mellitus but with LDL cholesterol levels <3.4 mmol/L (130 mg/dL) and high-sensitivity C-reactive protein concentrations of 2.0 mg/L or higher, the hazard ratio for newly diagnosed diabetes mellitus was increased 25% in the rosuvastatin group compared to the placebo group.186 Despite the increase in the risk of new-onset diabetes mellitus, the participants previously considered to be at low cardiovascular risk had clinically important cardiovascular event reductions over a median follow-up period of only 1.9 years, with a hazard rate 44% lower with rosuvastatin in comparison with placebo for the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Almost two-thirds of participants had ≥1 major risk factor for developing diabetes mellitus: metabolic syndrome as defined by the 2005 American Heart Association/National Heart, Lung, and Blood Institute consensus criteria, impaired fasting glucose (as defined by fasting serum glucose of equal to or >100 and <126 mg/dL [5.55–7.00 mmol/L]), BMI 30 kg/m2 or higher, or HbA1c >6%.190 As expected, incident diabetes mellitus was 28% higher those with than without any major diabetes mellitus risk factor, and statins accelerated the average time to diagnosis of diabetes mellitus by 5.4 weeks. However, statin allocation reduced the risk for the primary end point both in participants with and without a major risk factor for diabetes mellitus, such that in patients with ≥1 risk factor for diabetes mellitus, in total 54 new cases of diabetes mellitus were diagnosed, whereas 93 first major cardiovascular events or deaths, or 134 total cardiovascular events or deaths were avoided.

Several meta-analyses have now been performed examining the risk of developing diabetes mellitus in statin-treated individuals, and relative risks are somewhat lower overall than that found in the index JUPITER trial.187–189 Diabetes mellitus relative risk was 13% higher with no heterogeneity across 5 trials (including HPS [Heart Protection Study],191 LIPID [Long-Term Intervention with Pravastatin in Ischemic Disease],192 ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial],193 JUPITER,186 and CORONA [Controlled Rosuvastatin Multinational Trial in Heart Failure]194) with a total of 57?593 patients, mean follow-up of 3.9 years, and 2082 incident cases of diabetes mellitus.187 Addition of WOSCOPS (West of Scotland Coronary Prevention Study)195 to the analysis introduced significant heterogeneity and attenuated risk, which no longer retained statistical significance as WOSCOPS reported a protective effect of pravastatin versus placebo on the incidence of diabetes mellitus. In a second meta-analysis, a 9% increase in risk for incident diabetes mellitus was found (odds ratio [OR], 1.09, 95% CI, 1.02–1.17), including 13 trials with 91?140 participants and development of diabetes mellitus in 4278 patients over a mean of 4 years.188 Investigators were contacted to obtain unpublished data regarding incident diabetes mellitus resulting in 7 additional trials (and both JUPITER and WOSCOPS) included as compared with the other meta-analysis. In this analysis little heterogeneity was found across trials despite the inclusion of WOSCOPS, potentially attributable to different criteria used to diagnose diabetes mellitus. Statin-associated diabetes mellitus risk may be slightly higher in women.196 A meta-regression analysis showed the highest diabetes mellitus risk was associated with older age, but not baseline BMI or LDL cholesterol level.188 One extra case of diabetes mellitus resulted from treating 225 (95% CI, 150–852) patients with statins for 4 years, whereas 5.4 vascular events were prevented. In the larger context, given that statins are used by approximately 24 million Americans, the population-attributable risk of statin-associated diabetes mellitus is not small. However, considering the many treatments for diabetes mellitus and the importance of cardiovascular event reduction, providers should not avoid using statins when indicated solely because of concern for risk of diabetes mellitus.

Potential effects, if any, of statin-induced diabetes mellitus on the development of long-term microvascular complications remain unknown, but current epidemiological data are reassuring. With recent lower lipid target goals and increasing use of statins, as well as improved screening, early detection, and multifactorial interventions, the age-adjusted percentage of adults with diabetes mellitus reporting visual impairment197 and the incidence of end-stage renal disease in adults with diabetes mellitus198 have decreased over the past few decades. Furthermore, the 10-year risk of myocardial infarction or stroke (˜25%) is markedly higher than that of blindness or renal failure (approximately 1%–2%) for patients with recent-onset diabetes mellitus impacting risk-to-benefit considerations.199

The risk of developing diabetes mellitus appears to be related to statin potency200 and dose.189 Cellular mechanisms underlying the increased incidence of diabetes mellitus remain incompletely understood. Genome-wide studies do not reveal associations between genes that regulate HMG-CoA reductase or LDL cholesterol metabolism and type 2 diabetes mellitus. Statins may interfere with ß-cell insulin secretion either by decreasing Ca2+-dependent insulin secretion or by interfering with isoprenylation of guanosine triphosphate–binding proteins.201 Statin inhibition of isoprenoid biosynthesis may lead to lower expression of insulin signaling proteins in adipocytes and to reduced glucose transporter expression or translocation.202 Fasting insulin levels may increase modestly, suggesting that insulin resistance may be increased, but euglycemic hyperinsulinemic clamp studies do not show consistent changes in insulin sensitivity.203 Other off-target effects may also be involved.

Overall, the risk of incident diabetes mellitus with statin therapy is present but largely outweighed by the actual cardiovascular benefits.204 Patients should be educated regarding the risk of incident diabetes mellitus with statins as with other risk–benefit of all therapies.132 Lifestyle modification should be encouraged to lower cardiovascular risk and that for developing diabetes mellitus.205 Patients on statins at higher risk for but without preexisting type 2 diabetes mellitus should undergo periodic screening for diabetes mellitus with fasting glucose and HbA1c, and if type 2 diabetes mellitus develops, standard of care and national guidelines should be used to manage diabetes mellitus.206,207


From the paper:

What Is on the Horizon?
A number of new approaches for glucose lowering are under development and may provide agents with dual benefit for diabetes mellitus and the diabetic heart. Additionally, drugs that are developed for cardiovascular risk reduction may also lower glycemia. In the meantime, cardiovascular outcome trials will provide useful information on cardiovascular safety of use of diabetes mellitus drugs in patients with established heart disease or at high risk for events and additional exposure, information that may reveal previously unrecognized positive or negative effects. These trials may help to better address the question of the impact of specific glucose-lowering drugs and pharmacological class agents on the diabetic heart.

Conclusions
The long-term treatment of diabetes mellitus is challenging because of diverse goals: to address metabolic derangements and to reduce risks for both micro- and macrovascular adverse outcomes. Management of hyperglycemia has resulted in substantial reductions in risks for retinopathy with associated preservation of vision, and nephropathy with prevention of end-stage renal disease when combined with aggressive blood pressure control. Progress in prevention and amelioration of these microvascular complications has conversely resulted in a shift in the major causes of long-term morbidity and mortality in diabetes mellitus, which now consists of cardiovascular risk with associated ischemic heart disease, ischemic stroke, peripheral artery disease, and congestive heart failure. Diabetes mellitus clearly exacerbates mechanisms of atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately fully modulated or addressed by focusing solely on optimal glycemic control. Fortunately, aggressive management of cardiovascular risk factors, particularly lowering of LDL cholesterol concentration and blood pressure along with glycemic management, provides substantial improvements in cardiovascular outcomes. Therefore, we prioritize recommendations for management of cardiovascular and heart failure risk to focus on the most effective therapies, as summarized in Table 1.

Multiple areas of further investigation remain. Potential cardiovascular benefits versus risks of new glucose-lowering agents and timing of (early or prolonged) glucose-targeting interventions are incompletely understood. Evidence for a more effective antiplatelet regimen than aspirin in moderate to high risk patients with diabetes mellitus without ischemic heart disease is necessary. Recommended blood pressure goals are also not fully evidence-based, and the role of new potent lipid-lowering therapies (PCSK9 inhibitors) and lipid-lowering drugs that target triglycerides and HDL cholesterol needs further study. Another unaddressed issue is the ultimate risk–benefit ratio for polypharmacy that occurs when physicians add multiple drugs to achieve an optimal level of glycemic control and cardiovascular risk management. These are pragmatic concerns wherein the use of multiple medications can result in less overall medication compliance and increased risk of drug–drug interactions. Although the overall management of diabetes mellitus has improved substantially over the past 2 decades, there is a large unmet need for cardiovascular prevention.