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Antisense-Mediated Lowering of Plasma Apolipoprotein C-III By 1408 Diabetes Care Volume 39, August 2016 Andres Digenio,1 Richard L. Dunbar,2 Antisense-Mediated Lowering Veronica J. Alexander,3 Marcus Hompesch,4 Linda Morrow,4 of Plasma Apolipoprotein C-III Richard G. Lee,3 Mark J. Graham,3 Steven G. Hughes,3 Rosie Yu,3 by Volanesorsen Improves Walter Singleton,3 Brenda F. Baker,3 Dyslipidemia and Insulin Sanjay Bhanot,3 and Rosanne M. Crooke3 Sensitivity in Type 2 Diabetes Diabetes Care 2016;39:1408–1415 | DOI: 10.2337/dc16-0126 OBJECTIVE To determine the effects of volanesorsen (ISIS 304801), a second-generation 2’-O-methoxyethyl chimeric antisense inhibitor of apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A randomized, double-blind, placebo-controlled trial was performed in 15 adult patients with type 2 diabetes (HbA1c >7.5% [58 mmol/mol]) and hypertriglycer- idemia (TG >200 and <500 mg/dL). Patients were randomized 2:1 to receive volanesorsen 300 mg or placebo for a total of 15 subcutaneous weekly doses. Glucose handling and insulin sensitivity were measured before and after treat- ment using a two-step hyperinsulinemic-euglycemic clamp procedure. RESULTS Treatment with volanesorsen significantly reduced plasma apoC-III (288%, P = EMERGING TECHNOLOGIES AND THERAPEUTICS 0.02) and TG (269%, P = 0.02) levels and raised HDL cholesterol (HDL-C) (42%, P = 0.03) compared with placebo. These changes were accompanied by a 57% im- provement in whole-body insulin sensitivity (P < 0.001). Importantly, we found a strong relationship between enhanced insulin sensitivity and both plasma apoC-III 1Akcea Therapeutics, Cambridge, MA (r = 20.61, P =0.03)andTG(r = 20.68, P = 0.01) suppression. Improved insulin 2University of Pennsylvania, Philadelphia, PA fi fi 2 P 3Ionis Pharmaceuticals, Inc., Carlsbad, CA sensitivity was suf cient to signi cantly lower glycated albumin ( 1.7%, = 4 fi 2 m P Pro l Institute for Clinical Research, San Diego, 0.034) and fructosamine ( 38.7 mol/L, = 0.045) at the end of dosing and HbA1c CA 2 2 P ( 0.44% [ 4.9 mmol/mol], = 0.025) 3 months postdosing. Corresponding author: Andres Digenio, adigenio@ akceatx.com. CONCLUSIONS Received 20 January 2016 and accepted 9 May Volanesorsen reduced plasma apoC-III and TG while raising HDL-C levels. Impor- 2016. tantly, glucose disposal, insulin sensitivity, and integrative markers of diabetes A.D. and R.L.D. are co–primary authors. also improved in these patients after short-term treatment. Clinical trial reg. no. NCT01647308, clinicaltrials .gov. Insulin resistance states usually seen in the context of obesity and type 2 diabetes This article contains Supplementary Data online are commonly associated with a metabolic dyslipidemia that amplifies cardiovas- at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc16-0126/-/DC1. cular disease risk. Among patients with type 2 diabetes, insulin resistance impairs © 2016 by the American Diabetes Association. the ability to utilize glucose as fuel, prompting a switch toward fat storage that Readers may use this article as long as the work is promotes free fatty acid flux, hepatic triglyceride (TG) synthesis, and secretion of properly cited, the use is educational and not for large VLDL particles (1). Cholesteryl ester transfer protein-mediated exchange of profit, and the work is not altered. care.diabetesjournals.org Digenio and Associates 1409 VLDL-TG for cholesteryl esters in LDL more recent studies, it does not appear euglycemic (HE) clamp trial was conducted and HDL particles promotes atherogenic that apoC-III is directly associated with at a single center in the U.S. (ProfilIn- small-dense LDL and dysfunctional small- the incidence of nonalcoholic fatty liver stitute for Clinical Research, San Diego, dense HDL particles, which are more disease in broader patient populations CA) between 8 August 2012 and 31 Jan- readily catabolized by the kidney. The re- (14). Two recent Mendelian randomiza- uary 2014 to evaluate the effects of sulting metabolic dyslipidemia features tion studies showed that individuals with volanesorsen treatment in adult pa- a triad of high levels of VLDL-TG, low loss-of-function APOC3 variants had tients with type 2 diabetes and hyper- HDL cholesterol (HDL-C), and an in- lower TG concentrations and LDL-C, triglyceridemia. The primary objective creased prevalence of small-dense LDL higher HDL-C, and, compellingly, a 40% of this trial was to determine the effects particles despite normal or even low LDL reduction in risk of coronary heart dis- of volanesorsen versus placebo on fast- cholesterol (LDL-C) levels. The cumulative ease (15,16). While it is unclear whether ing total apoC-III. The secondary objec- result is a significant increase in the risk of the coronary heart disease risk reduction tives were to determine its effects on atherosclerosis (2). is due to suppressed TG, other TRL- other lipid parameters, glycemic con- Recommended treatments include associated factors, or apoC-III per se, trol, and insulin sensitivity. Written in- diet and exercise as well as statins that the aforementioned cardioprotective formed consent was obtained from all have the strongest evidence for im- properties suggest that apoC-III is an participants prior to participation in the provement of this condition (3–5). Be- attractive therapeutic target (17). study. The protocol was approved by cause the TG-reducing effect of statins is Potent second-generation antisense the institutional review board and con- modest at best, patient-centered guide- oligonucleotides (ASOs) have been de- ducted in compliance with the stan- lines also recommend a second drug veloped to reduce apoC-III expression dards of Good Clinical Practice and such as fibric acid derivatives, niacin, in animals and humans (18). In mice, guidelines of the 2002 Declaration of or n-3 fatty acids (3). In support of this administration of a species-specific Helsinki. approach, meta-analyses of five large tri- apoC-III ASO led to dose-dependent re- Eligible patients were 18–65 years als assessing the impact of fibrates on car- ductions in hepatic apoC-III mRNA and old; had hypertriglyceridemia (TG diovascular end points revealed benefits plasma apoC-III protein. In dyslipidemic .200 mg/dL and ,500 mg/dL) and among patients with the lipid triad (6). rodent models, this led to .50% reduc- type 2 diabetes that had been diag- While it is well established that insulin tions in both fasting and postprandial nosed for at least 6 months; had uncon- resistance drives dyslipidemia, there is plasma TG. Recapitulating preclinical trolled hyperglycemia (HbA1c .7.5% growing evidence that the elevation in models, treating normolipidemic and [58 mmol/mol]); and were on a stable plasma TGs and reduction in HDL-C ac- hypertriglyceridemic human subjects dose of metformin $1,000 mg/day. Pa- companying insulin resistance states with the human-specificapoC-IIIASO, tients with uncontrolled high blood may exacerbate the insulin-resistant volanesorsen (ISIS 304801), profoundly pressure, heart failure New York Heart phenotype, albeit by yet-to-be-defined reduced plasma apoC-III protein and Association III and IV, recent episode of mechanisms (7). In preclinical models, plasma TG levels (18,19). This included angina, prior acute myocardial infarction, HDL may improve insulin sensitivity, in- subjects with familial chylomicronemia recent coronary bypass surgery, severe di- sulin secretion through the b-cells, and syndrome (FCS), who have extreme abetes microvascular complications, kid- b-cell survival (8). Clinically, elevations hypertriglyceridemia due to loss-of- ney or liver disease, hypothyroidism, or in TG-rich lipoprotein (TRL) levels have function mutations leading to absent low platelet count were excluded from been shown to exacerbate the pathol- LPL activity (20). This latter study dem- participation in the study. Acceptable con- ogy of insulin resistance. Therefore, re- onstrates that apoC-III also inhibits an traceptive methods were required during ducing TG and increasing HDL may not LPL-independent pathway of TRL dosing and in the follow-up period. Lipid only reduce cardiovascular risk but also clearance. and blood pressure medications were al- improve insulin sensitivity and delay Given evidence that hypertriglyceri- lowed provided that they were stable b-cell failure (1,9). demia may worsen insulin sensitiv- before dosing. Oral antidiabetes medi- Apolipoprotein (apo)C-III has been ity and the data suggesting a role for cation other than metformin was pro- identified as a key modulator of plasma apoC-III in mediating insulin resistance, hibited. Men had to restrict alcohol TG concentrations in animal models and we reasoned that an intervention that intake to 2 drinks and women to 1 drink in humans. ApoC-III affects TG metabo- robustly suppressed apoC-III and plasma daily. All patients received glucose- lism by inhibiting lipoprotein lipase TG would lead to improved insulin sen- monitoring instructions and dietary ed- (LPL) activity and by interfering with sitivity. Thus, we conducted a clinical ucation based on the American Diabetes receptor-mediated uptake of TRLs by trial that allowed us to test the mecha- Association guidelines. the liver (10,11). Mice overexpressing nistic hypothesis that aggressively lower- The trial consisted of three periods apoC-III not only have high plasma TG ing TG by apoC-III ASO treatment would (Supplementary Fig. 1): screening, dos- but also display increased insulin resis- improve insulin sensitivity in patients ing (13 weeks, days 1–85), and post- tance (12). In East Indian Asians, an with diabetes with high TGs. treatment/follow-up (13 weeks, days APOC3 genotype associated with in- 86–176). Eligible patients were random- creased plasma TG is also associated with RESEARCH DESIGN AND METHODS ized 2:1 to receive volanesorsen 300 mg: insulin resistance and nonalcoholic fatty Clinical Trial Design and Participants placebo for a total of 15 subcutaneous liver disease, the hepatic manifestation of A randomized, double-blind, placebo- doses (days 1, 3, 5, 8, 15, 22, 29, 35, 42, the metabolic syndrome (13).
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