Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. Results: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P <0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P <0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship‚ and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P <0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3x elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). Conclusions: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic f at fraction.

BACKGROUND AND OBJECTIVESBecause there is no recent update on the state of diabetes and its concomitant complications in Saudi Arabia, we undertook a study of the prevalence of health complications in patients with type 2 diabetes mellitus admitted to our institution.METHODSWe conducted a retrospective review of medical records of adult Saudi patients with type 2 diabetes who were seen in clinics or admitted to the Security Forces Hospital, Riyadh, Saudi Arabia, between January 1989 and January 2004.RESULTSOf 1952 patients, 943 (48.3%) were males. For the whole study population the mean age at enrollment was 58.4±14.2 years, the mean age at onset of diabetes was 48.1±12.8 years, the mean duration of diabetes was 10.4±7.5 years, and the mean duration of follow-up was 7.9±4.6 years. Nephropathy was the most prevalent complication, occurring in 626 patients (32.1%). Acute coronary syndrome occurred in 451 (23.1%), cataracts in 447 (22.9%), retinopathy in 326 (16.7%), and myocardial infarction in 279 (14.3%), Doubling of serum creatinine was seen in 250 (12.8%) and 79 (4.0%) went into dialysis. Hypertension was present in 1524 (78.1%) and dyslipidemia in 764 (39.1%). Overall mortality was 8.2%. Multiple complications were frequent. Males had higher prevalence of complications than females (P<.05). Mortality was significantly higher in males 92 (9.8%) than females 69 (6.8%) (P=.024). The prevalence of complications significantly increased with duration of diabetes and age (P<.05).CONCLUSIONAmong Saudis, the prevalence of concomitant diabetic complications is high, with cardiovascular and renal complications the most frequent. Many patients had multiple complications. Early and frequent screenings in the patients with type 2 diabetes are desirable to identify patients at high risk for concomitant complications and to prevent disabilities.

BACKGROUND AND OBJECTIVESBecause there is no recent update on the state of diabetes and its concomitant complications in Saudi Arabia, we undertook a study of the prevalence of health complications in patients with type 2 diabetes mellitus admitted to our institution.METHODSWe conducted a retrospective review of medical records of adult Saudi patients with type 2 diabetes who were seen in clinics or admitted to the Security Forces Hospital, Riyadh, Saudi Arabia, between January 1989 and January 2004.RESULTSOf 1952 patients, 943 (48.3%) were males. For the whole study population the mean age at enrollment was 58.4±14.2 years, the mean age at onset of diabetes was 48.1±12.8 years, the mean duration of diabetes was 10.4±7.5 years, and the mean duration of follow-up was 7.9±4.6 years. Nephropathy was the most prevalent complication, occurring in 626 patients (32.1%). Acute coronary syndrome occurred in 451 (23.1%), cataracts in 447 (22.9%), retinopathy in 326 (16.7%), and myocardial infarction in 279 (14.3%), Doubling of serum creatinine was seen in 250 (12.8%) and 79 (4.0%) went into dialysis. Hypertension was present in 1524 (78.1%) and dyslipidemia in 764 (39.1%). Overall mortality was 8.2%. Multiple complications were frequent. Males had higher prevalence of complications than females (P<.05). Mortality was significantly higher in males 92 (9.8%) than females 69 (6.8%) (P=.024). The prevalence of complications significantly increased with duration of diabetes and age (P<.05).CONCLUSIONAmong Saudis, the prevalence of concomitant diabetic complications is high, with cardiovascular and renal complications the most frequent. Many patients had multiple complications. Early and frequent screenings in the patients with type 2 diabetes are desirable to identify patients at high risk for concomitant complications and to prevent disabilities.

Aim To compare the efficacy and safety of colesevelam and ezetimibe as second‐line low density lipoprotein‐cholesterol (LDL‐c)‐lowering options in type 2 diabetes (T2D). Materials and Methods GOAL‐RCT is a 24‐week, open‐label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%‐10%) and LDL‐c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL‐c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. Results Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL‐c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon‐inferiority < .001, Psuperiority = .41). LDL‐c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL‐c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (−0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. Conclusions Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL‐c and HbA1c within target), with ezetimibe recording a greater LDL‐c reduction and better tolerability than colesevelam.

BACKGROUND: Lipid-lowering therapies are often added to statin drugs in patients with type 2 diabetes (T2D) who fail to achieve target LDL cholesterol. Our objective was to compare the efficacy and safety of two second-line LDL lowering options: colesevelam (COL) vs. ezetimibe (EZE) in T2D. METHODS: GOAL-RCT is the first randomized controlled trial comparing COL vs. EZE in T2D patients with uncontrolled A1c (7-10%) and LDL cholesterol (>2 mmol/L) (NCT02682680). The 6-month trial enrolled 200 patients randomized to either COL (3.75g daily) or EZE (10 mg daily. T2D medications as well as statin dose were unchanged during the trial. The primary outcome was the proportion of patients achieving A1c 7.0% and LDL 2 mmol/L. RESULTS: GOAL-RCT enrolled subjects with comparable baseline characteristics: mean age 59AE10 years, mean A1c 8.0% and mean LDL 2.5 mmol/L. T2D therapies included metformin (88%), insulin (85%), DPP-4 inhibitor (63%), and SGLT2i (52%). 97% of the enrolled subjects were on statin medications. Three month data were available for 85 COL patients and 98 EZE patients (Table 1). The proportion of patients achieving A1c 7.0% and LDL 2 mmol/L in the COL arm (14%) was non-inferior compared to the EZE arm (9%) (p-value < 0.01 for non-inferiority; p-value ¼ 0.28 for superiority). The COL arm had a lesser reduction in both LDL (-0.28 vs-0.65 mmol/L; p < 0.01) and non-HDL (-0.32 vs-0.74, P < 0.01) but a greater reduction in A1c (-0.4% vs. 0%; p < 0.01) compared to EZE, respectively. No significant differences were noted between fasting plasma glucose, triglycerides, HDL and CRP levels. Fifteen COL patients and 6 EZE patients discontinued study treatment (7 and 5 subjects due to adverse effects, respectively).

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