News from American Diabetes Association Scientific Sessions 2009

HDL cholesterol raising with combination fenofibric acid/rosuvastatin in mixed dyslipidemia

Analysis of two phase 2 studies involving 480 patients with type 2 diabetes and mixed dyslipidemia showed that this treatment combination improved achievement of American Diabetes Association (ADA) target lipid levels compared with those taking rosuvastatin monotherapy. In particular, patients receiving combination treatment (fenofibric acid plus 5 mg rosuvastatin) had a 25% increase in high-density lipoprotein (HDL) cholesterol compared with 17% on rosuvastatin monotherapy (p<0.05).

Rosenson RS, Carlson DM, Kelly MT et al. Simultaneous attainment of lipid targets with the combination of fenofibric acid and rosuvastatin in patients with type 2 diabetes mellitus. Abstract 936-P.

Lipid inclusion criteria for the studies were low-density lipoprotein (LDL) cholesterol ³130 mg/dL, HDL cholesterol <40 mg/dL and triglycerides ³ 150 mg/dL. Patients were randomised to treatment with the combination (135 mg fenofibric acid plus 5 mg, 10 mg, or 20 mg rosuvastatin daily), or rosuvastatin (10 mg, 20 mg, or 40 mg) or fenofibric monotherapies for 12 weeks. Overall, patients had a mean age of 58.8 years, 11% had coronary artery disease, and 87.8% had metabolic syndrome according to National Cholesterol Education Program-Adult Treatment Panel III criteria.(1)

In addition, to the HDL cholesterol response, combination fenofibric acid plus 5 mg rosuvastatin lowered triglycerides by 39.9% (versus 23.6% with rosuvastatin monotherapy, p<0.001); and LDL cholesterol by 32.8% (versus 28.1% with rosuvastatin monotherapy). The percentage of patients meeting ADA lipid targets with each treatment is summarized in Table 1.

Commenting on the results, lead author Robert S. Rosenson, MD, State University of New York, Brooklyn said: "The HDL increases occurred early and continued incrementally. As we see this with both niacin and fibrates, I think there are two different sets of genes being activated; one set is activated early to raise HDL and another set is activated long-term."

Reference

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final report. Circulation 2002; 106: 3143-421.

 

 

High density lipoproteins: impact on pancreatic beta-cell insulin secretionApolipoproteins AI and AII, contained with high-density lipoprotein (HDL), increase pancreatic beta-cell secretion at physiologically relevant HDL concentrations, according to results reported at the American Diabetes Association Scientific Sessions, 2009. These data suggest potential therapeutic benefit of HDL raising interventions in type 2 diabetes.

 

Fryirs MA, Barter PJ, Appavoo M et al. High density lipoproteins increase the insulin secretory capacity of pancreatic beta-cells. Abstract 1657-P

 

The authors incubated Min6 beta-cells and primary rabbit islets with discoidal reconstituted HDL (rHDL) containing either apolipoprotein A-I, (A-I)rHDL, or apolipoprotein A-II, (A-II)rHDL, as the only apolipoprotein. The cells were incubated for 1 or 16 hours with rHDL (final apolipoprotein concentration 32 µmol/l) under basal (2.8mmol/l) or high (25 mmol/l) glucose conditions. Lipid-free apoA-I or lipid-free apoA-II (8 mg/kg) were also infused into New Zealand White (NZW) rabbits. Insulin levels were determined by radioimmunoassay. Changes in gene expression were quantitated using real-time PCR and Affymetrix microarray.

 

Incubation with (A‑I)rHDL or (A-II)rHDL for 1 hour, under both basal and high glucose conditions, increased insulin release from Min6 cells and rabbit islets by up to five-fold in a time- and concentration-dependent manner (p<0.05 for both). This effect was attributed to the apolipoproteins and was calcium-dependent. Additionally, infusion of lipid-free apoA-I or lipid-free apoA-II into NZW rabbits also increased insulin secretion.

 

Furthermore, when Min6 cells were incubated for 16 hours with (A-I)rHDL or (A-II)rHDL, insulin secretion increased by 145±41% and 155±42% respectively (p<0.05). The intracellular insulin content was unchanged as a result of an increase in insulin mRNA levels. The ability of apoA-I and apoA-II to increase beta-cell insulin secretion was due, in part, to their ability to efflux cholesterol from beta-cells.

 

Given that patients with type 2 diabetes typically present with low HDL cholesterol (in addition to elevated triglycerides), the authors highlighted the potential benefit on beta-cell function of therapeutic interventions aimed at raising HDL cholesterol.

 

VADT: beneficial role of HDL cholesterol with intensive glycaemic control

A follow-up report from the Veterans Affairs Trial of Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT) indicates that patients with elevated high-density lipoprotein (HDL) cholesterol are more likely to benefit from intensive glucose control. This conclusion contrasts with the initial VADT report last year which indicated no benefit in terms of cardiovascular events, including death, with intensive glucose control.(1) The data were reported at the American Diabetes Association Scientific Sessions, 2009.

According to William C. Duckworth, MD, co-chair of VADT and Director of Diabetes Research, Carl T. Hayden VA Medical Center, Phoenix, Arizona: ‘HDL levels strongly affected primary outcomes and cardiovascular death, with some individuals benefitting by 90%.’ With every 10 mg/dL increase in HDL cholesterol there was 80% decrease in risk of cardiovascular events, 50% decrease in the risk of a first primary event and 55% decrease in all-cause mortality.

The VADT included 1,791 patients from 20 VA medical centres (mean age 60 years, 97% men, 16% were African American, 16% were Hispanic, and 62% non-Hispanic whites). At baseline, 40% of patients had a history of cardiovascular events, mainly myocardial infarction and stroke. Overall, 80% had hypertension, more than 50% had lipid abnormalities, and the majority were obese.

All patients in VADT had already failed initial therapy defined as elevated HbA1c levels while being treated with the maximum dose of at least one oral antidiabetes agent or insulin. The average baseline HbA1c was 9.5%. The goal was to treat until HbA1c levels were below 7%.

Patients were randomized to either intensive- or standard-treatment arms. By the end of the first year of the 7.5-year study, 90% of the intensive-treatment group was taking insulin versus 74% of the standard-treatment group. Patients starting insulin during the trial remained on it throughout the study period. Oral antidiabetic agents were prescribed for 94% of all VADT patients, with most receiving two or three different medications. Average follow-up was 6.25 years. All patients were also treated with maximum lipid and antihypertensive agents and diet and lifestyle modification, which included education and counselling.

Reference

1. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.

 


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