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Liraglutide is marketed in Europe as Victoza® (1.2 mg/1.8 mg), indicated for glycaemic control in type 2 diabetes, and Saxenda® (3.0 mg), indicated for weight management in adults with obesity. We performed a post-authorization safety study (PASS) to assess the in-market use of Saxenda® and Victoza® according to approved indications and posology.This retrospective, non-interventional study was conducted at 41 sites between December 2016 and May 2019. Via medical record review, physicians at each site identified patients who had been prescribed Saxenda® (Italy) or Victoza® (Italy/Germany) within the 24 months following launch in each country. Pseudonymized data were abstracted on patient and site characteristics, indication for the prescription, posology and duration of usage. Adherence to the approved indications and posology, and to the Saxenda® stopping rule, were assessed. No formal statistical analysis was performed.A total of 440 patients were pre-screened and 225 (51.1%) were enrolled (Saxenda®: N=75, all in Italy; Victoza®: N=75 in Italy; N=75 in Germany). In all, 96% (72/75) of Saxenda® prescriptions, and 98.7% (148/150) of Victoza®, were in accordance with the approved indications. Among the 40 patients treated with Saxenda® for ≥16 weeks, only two (5.0%) were confirmed as non-adherent to the stopping rule. Adherence could not be assessed in 23 (57.5%) patients owing to missing body weight measurements.This retrospective, real-world PASS provides reassurance that Saxenda® and Victoza® are primarily used according to the approved European label, thus their real-world utilization does not raise safety concerns.gov identifier: NCT02967757. This article is protected by copyright. All rights reserved.

Aims Both acute pancreatitis (AP) and pancreatic cancer (PC) have been areas of focus for studies of incretin drugs. This 5‐year prospective cohort study aimed to quantify possible associations between liraglutide and risk of AP and PC as compared to other antidiabetic drugs (ADs). Materials and methods Patients initiating liraglutide or other ADs who were enrolled in a US health plan (2010‐2014) were included. Comparisons of AP and PC incidence rates were made between matched cohorts of liraglutide initiators and initiators of other ADs. Adjudicated AP cases and algorithm‐based PC cases were identified. Propensity score‐matched intention‐to‐treat (ITT) and time‐on‐drug (TOD) analyses were completed using Poisson regression. A latency analysis was performed for PC. Results Median follow‐up was 405 days for AP cohorts (9995 liraglutide, 1:1 matched to all comparators) and 503 days for PC cohorts (35 163 liraglutide, 1:1 matched to all comparators). In the primary AP analysis, “current” use of liraglutide was not significantly associated with elevated risk across comparators (all comparators relative risk [RR] = 1.2; 95% confidence interval [CI], 0.6‐2.3). ITT results were similar where, in the primary analysis, no RRs were significantly associated with PC (all comparators RR = 0.7; 95% CI, 0.3‐1.4); latency and TOD analyses did not alter findings. There was no evidence of a dose‐response effect. Conclusions Liraglutide was not associated with an increased risk of AP or PC, although risk estimates were more variable for AP, and numbers of cases for both outcomes were limited because of the rarity of outcomes.

Donnie Funch,1 Kathleen Mortimer,1 Najat J Ziyadeh,1 John D Seeger,1 Li Zhou,1 Eva Ng,1 Douglas Ross,2,3 Atheline Major-Pedersen,4 Heidrun Bosch-Traberg,5 Helge Gydesen,6 David D Dore1,7 1Optum Epidemiology, Boston, MA, USA; 2Massachusetts General Hospital, Thyroid Associates, Boston, MA, USA; 3Harvard Medical School, Department of Medicine, Boston, MA, USA; 4Global Safety, Novo Nordisk A/S, Copenhagen, Denmark; 5Global Development, Novo Nordisk A/S, Copenhagen, Denmark; 6Epidemiology, Novo Nordisk A/S, Copenhagen, Denmark; 7Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, RI, USACorrespondence: Najat J ZiyadehOptum Epidemiology, 1325 Boylston Street, 11th Floor, Boston, MA, 02215, USAEmail najat.ziyadeh@optum.comBackground: Quantify association between the glucagon-like peptide-1 receptor agonist liraglutide and risk of thyroid cancer (TC) compared to other antidiabetics.Patients and Methods: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US health plan (2010– 2014) and followed for a median of 17 months. Thyroid cancer cases during follow-up were identified via a validated algorithm. Incidence rates of TC among liraglutide and comparators were assessed using relative risks estimated within propensity score-matched cohorts using intention to treat (ITT) and time on drug analyses. Latency effects and potential surveillance bias were evaluated.Results: Relative risks from ITT analyses ranged from 1.00 (95% confidence interval (CI) 0.56– 1.79) versus metformin to 1.70 (95% CI 1.03– 2.81) versus all comparators excluding exenatide. Effect estimates from latency analyses were slightly attenuated. Time on drug analyses suggested no increased risk for either longer duration or higher cumulative dose of liraglutide. Medical record review found 85% were papillary or a follicular variant of papillary or both; 46% were microcarcinomas (≤ 10 millimeters), which were more prevalent in the liraglutide cohort (67% versus 43% in all comparators).Conclusion: Relative risks were elevated for several comparisons, which should be interpreted cautiously because of potential residual confounding and surveillance bias. Liraglutide cases had smaller thyroid nodules and shorter time-to-diagnosis, suggesting increased surveillance for TC among liraglutide initiators, especially shortly after the drug´s approval. After adjusting the primary analyses (ITT) for latency, no significant elevated risk of TC was observed among liraglutide initiators.Keywords: glucagon-like peptide-1 receptor agonist, type 2 diabetes, administrative claims, intention-to-treat, time-on-drug

Background: Generation of real-world cardiovascular drug safety evidence in patients with type 2 diabetes (T2D) warrants robust methodology. Regulatory authorities are increasingly seeking to support their decision making through real-world evidence. At the time of marketing authorization, this study was required by regulatory authorities to further characterize the liraglutide safety profile in routine real-world clinical practice (external validity). Safety outcomes were compared to those of other non-insulin antidiabetic (NIAD) treatments in patients with T2D initiating NIADs in a UK real-word setting. The design was endorsed by health regulatory authorities. This paper analyzes the methodology and study results, and postulates that it was the differences in patient characteristics at NIAD initiation, not the treatment itself, that modulated the observed differences in cardiovascular risk between NIAD cohorts.Methods: Data were obtained from linked UK electronic repositories: the Clinical Practice Research Datalink primary care database (CPRD GOLD) and Hospital Episode Statistics (HES). Risks of selected outcomes with current liraglutide use were compared to current use of other NIADs. Rates of each outcome and corresponding crude and adjusted incidence rate ratios were examined using Poisson regression analysis. Results: Overall, 149 788 patients met the study inclusion criteria; of these, 3432 initiated liraglutide. Components of the metabolic syndrome were more common among liraglutide initiators than those initiating other NIADs. The risk of some macrovascular conditions was increased in liraglutide initiators versus other NIAD initiators; following stepwise adjustment, this was only seen in liraglutide initiators when compared to biguanide initiators (incidence rate ratio: 1.33 [99% confidence interval (CI): 1.11;1.59]).Conclusions: The observed increase of macrovascular outcomes in liraglutide initiators compared with other NIAD initiators emphasizes the importance of countering potential selection bias when designing studies comparing cardiovascular outcomes across treatment initiator cohorts in heterogenous populations, such as patients with T2D. Baseline differences in the NIAD cohort may have modulated cardiovascular outcomes and likely explain the observed increased cardiovascular risk in liraglutide initiators. Selection bias, channeling bias and residual confounding, inherent in such observational studies, must be considered early when designing the study if the real-world data are to support decision-making.

Author(s): Major-Pedersen, Atheline; McCullen, Mary Kate; Sabol, Mary Elizabeth; Adetunji, Omolara; Massaro, Joseph; Neugut, Alfred I; Sosa, Julie Ann; Hollenberg, Anthony N | Abstract: PurposeTo share better practice in establishing data monitoring committees (DMCs) for observational, retrospective safety studies with joint-industry sponsorship.MethodsA DMC model was created to monitor data from an observational, retrospective, post-authorization safety study investigating risk of medullary thyroid cancer in patients treated with long-acting glucagon-like peptide-1 receptor agonists (LA GLP-1RAs) (NCT01511393). Sponsors reviewed regulatory guidelines, best practice and sponsors' standard operation procedures on DMCs. Discussions were held within the four-member consortium, assessing applicability to observational, retrospective, real-world studies. A DMC charter was drafted based on a sponsor-proposed, adapted DMC model. Thereafter, a kick-off meeting between sponsors and DMC members was held to receive DMC input and finalize the charter.ResultsDue to this study's observational, retrospective nature, assuring participant safety - central for traditional explanatory clinical trial models - was not applicable to our DMC model. The overall strategy and key indication for our real-world model included preserving study integrity and credibility. Therefore, DMC member independence and their contribution of expert knowledge were essential. To ensure between-sponsor data confidentiality, all study committees/corporations and sponsors, besides the DMC, received blinded data only (adapted to refer to data blinding that revealed the specific marketed LA GLP-1RA/sponsor). Communication and blinding/unblinding of these data were facilitated by the contract research organization, which also provided crucial operational oversight.ConclusionsTo our knowledge, we have established the first DMC model for joint industry-sponsored, observational, retrospective safety studies. This model could serve as a precedent for others performing similar post-marketing, joint industry-sponsored pharmacovigilance activities.

Donnie Funch,1 Kathleen Mortimer,1 Ling Li,1 Heather Norman,1 Atheline Major-Pedersen,2 Anne Helene Olsen,3 Margit S Kaltoft,4 David D Dore1,5 1Optum Epidemiology, Boston, MA, USA; 2Global Safety, Novo Nordisk A/S, Copenhagen, Denmark; 3Epidemiology, Novo Nordisk A/S, Copenhagen, Denmark; 4Global Development, Novo Nordisk A/S, Copenhagen, Denmark; 5Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, RI, USA Background: Liraglutide is a human glucagon-like peptide-1 receptor agonist approved for treatment of adults with type 2 diabetes mellitus at a maximum dose of 1.8 mg/day (Victoza®) and more recently at 3.0 mg/day for weight management (Saxenda®). During the evaluation of liraglutide for approval in weight management, a minor imbalance in the numbers of reported breast neoplasms was observed, motivating the present study. Our objective was to quantify the association between liraglutide and incidence of breast cancer (BC) among women in a real-world setting. Patients and methods: Women initiating liraglutide or other antidiabetic therapies and who were enrolled in a large US health plan (2010–2014) were included. Comparisons of BC incidence rates were made between matched cohorts of initiators of liraglutide and cohorts of initiators of exenatide, metformin, pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors separately and as two “all comparators” groupings: with or without exenatide. Women with two or more claims with BC diagnosis codes within 61days of each other were identified as possible cases, with additional confirmation by clinician review of comprehensive claims listings. Propensity score matched intention-to-treat (ITT) and time-on-drug (TOD) analyses were completed via Poisson regression. A latency analysis was performed. Results: Relative risks for BC for liraglutide vs comparators from the ITT analyses ranged from 0.90 (95% CI: 0.67–1.22) for both the “all comparator” and “all comparator except exenatide” cohorts to 1.46 (95% CI: 0.96–2.22) relative to exenatide. Latency analyses excluding the first year of follow-up yielded slightly attenuated point estimates. The TOD analyses of cumulative use of liraglutide suggested no increased risk of BC. Conclusion: Neither the ITT (overall or latency analysis) nor cumulative TOD analyses suggested an elevated risk of BC among liraglutide initiators. Short length of follow-up and the potential for confounding by unmeasured factors limit the full assessment of long-term risk. Keywords: glucagon-like peptide-1 receptor agonist, type 2 diabetes, administrative claims, intention-to-treat, time-on-drug

Background. Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood. Objectives. 1) To investigate the influence of parental history of type 2 diabetes (T2DM) on offspring birthweight and adult offspring glucose tolerance status in non-diabetic offspring of patients with T2DM and 2) to study the associations of birthweight with measures of pancreatic beta-cell function and insulin sensitivity. Design. Family cohort study. Population. Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes. Methods. Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in nondiabetic offspring. Birthweight and length obtained from birth records. Results. Among 122 offspring with maternal history of T2DM, 14.8% had diabetes compared to 8.0% in 137 offspring with paternal history of diabetes, p=0.09. Offspring with maternal history of T2DM had a mean birthweight 196g higher than offspring with paternal T2DM (3 651±640g (mean±SD) vs. 3 456±472g (p=0.01)). Nondiabetic offspring with birthweights in the lowest tertile had significantly higher plasma glucose levels after an oral glucose tolerance test (OGTT) [Area under the curveglucOGTT, mean (95%CI), 1 795 (1 725‐1 866) vs. 1 683 (1 613‐1 753) mmol/L/min, p=0.02], and lower insulin sensitivity index calculated from a frequentlysampledintravenousglucosetolerancetest‐Si9.60[10 ‐5 (min ∗ pmol/L) ‐1 ] (8.23‐10.97)vs.11.79(10.41‐13.18),p=0.02‐inadulthoodcomparedtooffspring with birthweights in the upper tertile. Conclusions. Offspring with a family history of maternal T2DM have higher birthweights than those with paternal T2DM. Low birthweight associates with elevated plasma glucose levels after an oral glucose load and decreased insulin sensitivity in adulthood. Abbreviations: AIR, acute serum insulin responses; AUC, area under the curve; BMI, body mass index; FSIGT, frequently sampled intravenous glucose tolerance test;OGTT,oralglucosetolerancetest;Sg,glucoseeffectiveness;Si,insulinsensitivity index; T2DM, type 2 diabetes

ObjectiveTo examine the association between selected glucose-lowering medications and left ventricular (LV) diastolic function in patients with diabetes.DesignRetrospective cohort study (years 2005–2008).MethodsEchocardiograms of 242 patients with diabetes undergoing coronary angiography were analyzed. All patients had an LV ejection fraction (LVEF) ≥20% and were without atrial fibrillation, bundle branch block, valvular disease, or cardiac pacemaker. Patients were grouped according to the use of metformin (n=56), sulfonylureas (n=43), insulin (n=61), and combination treatment (n=82).ResultsMean age (66±10 years) and mean LVEF (45±11%) were similar across the groups. Mean isovolumic relaxation time (IVRT) was 66±31, 79±42, 69±23, and 66±29 ms in metformin, sulfonylureas, insulin, and combination treatment groups respectively (P=0.4). Mean early diastolic longitudinal tissue velocity (e′) was 5.3±1.6, 4.6±1.6, 5.3±1.8, and 5.4±1.7 cm/s in metformin, sulfonylureas, insulin, and combination treatment groups (P=0.04). In adjusted linear regression models, the use of metformin was associated with a shorter IVRT (parameter estimate −9.9 ms, P=0.049) and higher e′ (parameter estimate +0.52 cm/s, P=0.03), compared with no use of metformin. The effects of metformin were not altered by concomitant use of sulfonylureas or insulin (P for interactions >0.4).ConclusionsThe use of metformin is associated with improved LV relaxation, as compared with no use of metformin.

Aim: We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme. Methods: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models. Results: The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81–1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26–1.60). Conclusion: We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

Britt Falskov1, Thomas Steffen Hermann1, Christian Rask-Madsen2, Atheline Major-Pedersen1, Buris Christiansen1, Jakob Raunsø1, Lars Køber3, Christian Torp-Pedersen1, Helena Dominguez41Department of Cardiology, Gentofte Hospital, Denmark; 2Joslin Diabetes Center, Boston (MA), USA; 3Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; 4Department of Cardiology, Herlev Hospital, Herlev, DenmarkAim: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes.Methods: Twenty-three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion.Results: Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% ± 6.16%, 23.50% ± 8.32%, and 22.29% ± 10.77% at the three doses respectively, compared to the healthy control group 45.96% ± 11.56%, 67.40% ± 18.11% and 84.57% ± 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% ± 7.81%, -2.35% ± 11.76%, and 5.82% ± 17.70% at the three doses of serotonin, respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co-existence of diabetes (P = 0.08).Conclusion: Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive.Keywords: insulin resistance, diabetes, heart failure, endothelial function

Links are well established between both family history of diabetes and reduced birthweight and increased risk of diabetes in adulthood.1) To investigate the influence of parental history of type 2 diabetes (T2DM) on offspring birthweight and adult offspring glucose tolerance status in non-diabetic offspring of patients with T2DM and 2) to study the associations of birthweight with measures of pancreatic beta-cell function and insulin sensitivity.Family cohort study.Offspring of patients with verified T2DM diagnosed after age 40 years with a spouse without known diabetes.Oral glucose tolerance tests and frequently sampled intravenous glucose tolerance tests (FSIGT) in non-diabetic offspring. Birthweight and length obtained from birth records.Among 122 offspring with maternal history of T2DM, 14.8% had diabetes compared to 8.0% in 137 offspring with paternal history of diabetes, p=0.09. Offspring with maternal history of T2DM had a mean birthweight 196 g higher than offspring with paternal T2DM (3,651 ± 640 g (mean ± SD) vs. 3,456 ± 472g (p=0.01)). Non-diabetic offspring with birthweights in the lowest tertile had significantly higher plasma glucose levels after an oral glucose tolerance test (OGTT) [Area under the curve(glucOGTT) , mean (95%CI), 1 795 (1 725-1 866) vs. 1 683 (1 613-1 753) mmol/L/min, p=0.02], and lower insulin sensitivity index calculated from a frequently sampled intravenous glucose tolerance test - Si 9.60 [10(-5) (min*pmol/L)(-1) ] (8.23-10.97) vs. 11.79 (10.41-13.18), p=0.02 - in adulthood compared to offspring with birthweights in the upper tertile.Offspring with a family history of maternal T2DM have higher birthweights than those with paternal T2DM. Low birthweight associates with elevated plasma glucose levels after an oral glucose load and decreased insulin sensitivity in adulthood.

Aim Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes. Method 24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period. Results Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% ± 17.89 (at the highest serotonin dosages) before treatment and -33.80% ± 23.38 after treatment (p = 0.007). Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups. Conclusion This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes. Trial registration Current Controlled Trials NCT00497003

The aim of the study is to determine if attenuation of postprandial hyperglycemia, by acutely and chronically enhancing postprandial insulin secretion in insulin-resistant individuals, improves the endothelial dysfunction. We assessed postoral glucose-load endothelial function in 56 insulin-resistant subjects with the Flow-Mediated-Dilation (FMD) technique. We randomized subjects to intervention/control group, and examined the acute and chronic effect of nateglinide, an oral antidiabetic drug of rapid action. In the intervention group, postoral glucose-load (post-OGL) FMD delta values deteriorated when compared to pre-OGL values, most significantly at 3 h post-OGL, on the following days: on the first study day termed "Baseline day" (p=0.04); on both days after 3 months of nateglinide treatment [with nateglinide administered on study-day "acute+chronic" (p=0.01); and without nateglinide on study-day "Closing day", p=0.001]. Post-OGL changes in the control group were nonsignificant both at Baseline and on Closing day. After a single dose of nateglinide "Acute day", post-OGL FMD deterioration was abolished. There was an increment in post-OGL FMD delta values most significant at 2 h post-OGL (p=0.02). Insulin concentrations increased while glucose concentrations decreased on study-days with nateglinide when compared to study-days without (p=

Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism.Twenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation was studied during serotonin or sodium nitroprusside infusion in the diabetic patients and in 15 healthy subjects. Endothelial function, insulin-stimulated endothelial function, and insulin-stimulated glucose uptake were measured before and after quinapril treatment. Blood flow was measured by venous occlusion plethysmography. Gene expression was measured by real-time PCR.Quinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0.001). Systolic and diastolic blood pressures were reduced by quinapril (P0.001). Quinapril increased adiponectin gene expression in vascular tissue obtained from sc adipose biopsies.Quinapril treatment increases insulin-stimulated endothelial function in patients with type 2 diabetes. Increased vascular adiponectin gene expression may contribute to this beneficial effect.

OBJECTIVE—The increased risk of coronary heart disease associated with type 2 diabetes may be partially explained by dyslipidemia characterized by high plasma triacylglycerol (TAG), low HDL cholesterol, and a predominance of atherogenic small dense LDLs. Fish oil reduces plasma TAG and has previously been shown to improve the distribution of LDL subclasses in healthy subjects and might, therefore, be a good nonpharmacological treatment for type 2 diabetic patients. In the present study, we investigate the effect of fish oil supplementation on the fasting lipid profile, including LDL and HDL subclasses. RESEARCH DESIGN AND METHODS—A total of 42 type 2 diabetic patients were randomized to supplementation (capsules) with 4 g daily of either fish oil (n = 20) or corn oil (n = 22) for 8 weeks preceded by a 4-week run-in period of corn oil supplementation. Blood was drawn before and after the 8-week intervention period. Plasma lipoproteins, including LDL and HDL subclasses, were separated by ultracentrifugation. RESULTS—Fish oil lowered TAG (group difference: P = 0.025) and raised HDL-2b cholesterol (P = 0.012) and HDL-2a cholesterol (P = 0.007) concentrations as compared with corn oil. We observed no significant effects of fish oil on LDL cholesterol, HDL cholesterol, or the concentration of small dense LDL particles. CONCLUSIONS—Fish oil supplementation may partially correct the dyslipidemia of type 2 diabetic patients. However, the putative very important aspect of diabetic dyslipidemia—the predominance of small dense LDL particles—was unaffected by fish oil.

Background Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF. Methods Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period. Results Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate. Conclusion Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF. Trial registration Current Controlled Trials NCT00497003