Volume 4, Number 3, September 2007

EDITORIALLearning from tesaglitazar
Clifford J Bailey

Diabetes Vasc Dis Res 2007;4:161-162.

REVIEWImprovement of postprandial lipid handling and glucose tolerance in a non-diabetic population by the dual PPARa/g agonist, tesaglitazar
Bjorn Fagerberg, Herbert Schuster, Grethe Støa Birketvedt, Serena Tonstad, Karl Peter Öhman, Ingrid Gause-Nilsson On Behalf Of The Sir Study Group

This study examined the effect of tesaglitazar (GALIDA™), a dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist, on postprandial metabolism.
This investigation was part of the Study in Insulin Resistance (SIR) (SH-SBT-0001), a randomised, double-blind, placebo-controlled study that reported improvements in fasting lipid and glucose values with tesaglitazar (0.1, 0.25, 0.5 or 1 mg once daily for 12 weeks) in hypertriglyceridaemic, abdominally obese, non-diabetic patients. A subgroup of 222 patients underwent postprandial lipid and glucose testing at baseline and treatment end.
Tesaglitazar 0.25, 0.5 and 1 mg reduced postprandial area under the curve (AUC) for triglycerides by 20% (p=0.003), 30% (p<0.0001) and 41% (p<0.0001), respectively. Free fatty acid (FFA) levels were reduced by 17% with tesaglitazar 0.5 mg (p=0.002) and by 29% with tesaglitazar 1 mg (p<0.0001). Tesaglitazar significantly improved glucose tolerance and increased the proportion of patients with normal glucose tolerance as measured by the oral glucose tolerance test (OGTT).
To conclude, postprandial dyslipidaemia and hyperglycaemia, indicators of increased vascular risk, were significantly improved by tesaglitazar treatment in these non-diabetic, hypertriglyceridaemic, abdominally obese subjects.

Diabetes Vasc Dis Res 2007;4:174-180.

POPULAR
TOPICREVIEWA double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus
Harold Bays, Jennifer Mcelhattan, Brian S Bryzinski On Behalf Of The Gallant 6 Study Group

The efficacy and safety of tesaglitazar (0.5 and 1 mg) and pioglitazone (15, 30 and 45 mg) were compared in a 24-week, randomised, double-blind study in 1,707 patients with type 2 diabetes mellitus.
Tesaglitazar 1 mg was non-inferior to pioglitazone 45 mg for change from baseline in glycosylated haemoglobin (HbA_1C) at 24 weeks (difference: -0.056 [95% confidence intervals -0.161, 0.049], pNI<0.001 for non-inferiority hypothesis). Tesaglitazar 1 mg improved triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels compared with all pioglitazone doses at 24 weeks (p<0.001). Low-density lipoprotein cholesterol (LDL-C) was lower with tesaglitazar for all pioglitazone comparisons (p<0.05), except for tesaglitazar 0.5 mg versus pioglitazone 15 mg. Tesaglitazar 1 mg decreased LDL particle number, when compared with all pioglitazone doses (p<0.01). Both agents increased body weight and peripheral oedema in a dose-dependent manner, but only tesaglitazar increased serum creatinine. In summary, tesaglitazar provided similar glycaemic control to pioglitazone, was associated with significant improvement in lipid and lipoprotein variables, and increased serum creatinine in a dose-dependent manner.

Diabetes Vasc Dis Res 2007;4:181-193.

POPULAR
TOPICREVIEWTesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes
John PH Wilding, Ingrid Gause-Nilsson, Anders Persson On Behalf Of The Gallant 7 Study Group

This randomised, double-blind, parallel-group, multicentre study investigated the effects of the dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar (0.5 and 1 mg), as add-on treatment in 568 patients with type 2 diabetes that was poorly controlled with sulphonylurea therapy titrated to the highest tolerated dose.
There was a significant placebo-corrected reduction in glycosylated haemoglobin (HbA_1C) from baseline to week 24 with tesaglitazar 0.5 mg and 1 mg (mean [95% confidence interval]: -0.93% [-1.09, -0.77] and -1.3% [-1.46, -1.14]; p<0.0001). Significant reductions were observed in insulin, fasting plasma glucose (FPG), triglyceride (all p<0.001) and non-high-density lipoprotein (HDL) cholesterol (p<0.001). Tesaglitazar increased levels of HDL-cholesterol (p<0.0001), adiponectin (p<0.0001) and leptin (p<0.001), but was associated with dose-dependent increases in serum creatinine and decreases in haemoglobin.
This study showed improvements in glycaemic control and dyslipidaemia in patients with type 2 diabetes poorly controlled with existing sulphonylurea therapy. Although tesaglitazar has now been discontinued from clinical development, these results remain relevant to future research into PPAR agonists.

Diabetes Vasc Dis Res 2007;4:194-203.

REVIEWThe effects of tesaglitazar as add-on treatment to metformin in patients with poorly controlled type 2 diabetes
Burkhard Göke, Ingrid Gause-Nilsson, Anders Persson On Behalf Of The Gallant 8 Study Group

This study assessed the effects of tesaglitazar (0.5 or 1 mg/day), a dual peroxisome proliferator-activated receptor a/g agonist, when added to maximally tolerated metformin (2–2.5 g/day) in patients with poorly controlled type 2 diabetes. The primary end point of this 24-week, randomised, placebo-controlled study was the absolute change from baseline in glycosylated haemoglobin (HbA1C).
Tesaglitazar significantly reduced HbA1C, fasting plasma glucose and insulin levels compared with placebo (p<0.0001 for all) when added to metformin. Triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels also improved with tesaglitazar treatment (p<0.0001 for all). Adverse events were generally similar across treatments, except for higher frequencies of peripheral oedema and weight gain in the tesaglitazar 1 mg group. Although reversibility was not fully evaluated, dose-dependent changes in mean serum creatinine levels and haematology measures tended to return towards baseline at follow-up.
Despite the clinical discontinuation of tesaglitazar, this study has demonstrated the potential benefits of dual PPAR agonism as add-on therapy to metformin, in patients with poorly controlled type 2 diabetes.

Diabetes Vasc Dis Res 2007;4:204-213.

REVIEWEfficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes
Robert E Ratner, Shamik Parikh, Conrad Tou On Behalf Of The Gallant 9 Study Group

This randomised, double-blind, parallel-group study assessed the effects of addition of the dual peroxisome proliferator-activated receptor (PPAR) a/g agonist, tesaglitazar, for 24 weeks to the therapeutic regimen of 392 poorly controlled (glycosylated haemoglobin [HbA1C] 7.5–10%) insulin-treated, type 2 diabetes patients. At 24 weeks, tesaglitazar 0.5 mg resulted in a 0.66% (95% confidence intervals: -0.85, -0.47; p<0.0001) reduction from baseline in HbA1C, and reduced fasting plasma glucose (p<0.0001) and daily insulin dose (p=0.014) versus placebo. After 24 weeks, tesaglitazar caused greater improvements from baseline in triglycerides (p<0.0001), high-density lipoprotein cholesterol (HDL-C) (p<0.001), non-HDL-C (p<0.05), apolipoprotein (apo)A-I (p<0.05) and apoB levels (p<0.01) than placebo. Tesaglitazar was generally well tolerated but was associated with a greater increase in serum creatinine level than placebo. The clinical development of tesaglitazar is no longer continuing; its effects on the glucose and lipid abnormalities of type 2 diabetes suggest that the concept of dual PPARa/g agonism is worthy of further investigation. Diabetes Vasc Dis Res 2007;4:214–21

Diabetes Vasc Dis Res 2007;4:214-221.

POPULAR
TOPICREVIEWThe PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events): what does it mean for primary care physicians?
Vanitha Singaram, Richard Pratley

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular disease (CVD). This complication accounts for much of the increased morbidity, mortality and costs of care associated with diabetes. Hypertension, dyslipidaemia, a pro-inflammatory phenotype, abnormal fibrinolysis and platelet activation, insulin resistance and high blood glucose concentrations all contribute to the increased risk of macrovascular disease in diabetes. Although reducing low-density lipoprotein (LDL)-cholesterol, controlling blood pressure, angiotensin-converting enzyme (ACE) inhibitors and aspirin have been shown to decrease CVD in diabetes, it is less clear that lowering glucose levels decreases risk. The PROactive trial was undertaken to test whether treatment with the thiazolidinedione pioglitazone could decrease the number of CVD events in high-risk patients with T2DM.

Diabetes Vasc Dis Res 2007;4:237-240.

POPULAR
TOPICREVIEWEffects of perindopril in hypertensive patients with or without type 2 diabetes mellitus, and with altered insulin sensitivity
Michel Marre, Abdoulaye Leye

Impaired insulin sensitivity and hypertension are risk factors for atherosclerosis, which in turn leads to a variety of cardiovascular diseases. In both conditions, the risks of morbidity and mortality appear to be further increased. Impaired insulin sensitivity is also a precursor for diabetes. The renin-angiotensin-aldosterone system (RAAS) is implicated in the development of both hypertension and insulin resistance. Antihypertensive agents that act by blocking the RAAS, such as angiotensin-converting enzyme (ACE) inhibitors, may improve insulin sensitivity and therefore prevent the deleterious consequences of insulin resistance, including type 2 diabetes. ACE inhibitors appear to improve insulin sensitivity in patients with hypertension and insulin resistance, including diabetes. This review assesses the literature surrounding the use of the ACE inhibitor perindopril in patients with hypertension and varying degrees of insulin resistance, including the effects of perindopril in preventing the development of diabetes and subsequent cardiovascular morbidity and mortality. Diabetes Vasc Dis Res 2007;4:163–73 doi:10.3132/dvdr.2007.037 Key words: cardiovascular diseases, diabetes mellitus, hypertension, insulin resistance, perindopril.

Diabetes Vasc Dis Res 2007;4:163-173.

ORIGINAL PAPEREffect of glucose-insulin-potassium (GIK) infusion on biomarkers of cardiovascular risk in ST elevation myocardial infarction (STEMI): insight into the failure of GIK
Shailja V Parikh, Shuaib M Abdullah, Ellen C Keeley, Joaquin E Cigarroa, Tayo A Addo, John J Warner, Amit Khera, James A De Lemos, Darren K Mcguire

Glucose-insulin-potassium (GIK) infusion favourably affects several biomarkers associated with risk in the setting of myocardial infarction (MI). In the context of a recent trial demonstrating no benefit of GIK, we assessed the impact of GIK on inflammation, neurohormonal activation and myonecrosis in ST elevation myocardial infarction (STEMI).
In a local substudy of an international randomised trial, 25 patients with STEMI were randomised to receive a 24-hour infusion of GIK vs. no GIK. C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T (TnT) were assayed at baseline and at 24 hours.
The two groups were well matched for baseline characteristics and infarct location. There were no statistically significant differences at baseline or at 24 hours in levels of hs-CRP, NT-proBNP or cTnT, with similar and significant increases in all three biomarkers by 24 hours in both groups.
In conclusion, GIK had no discernible effect on biomarkers associated with inflammation, neurohormonal activation or myonecrosis, three pathways associated with adverse outcomes in STEMI.

Diabetes Vasc Dis Res 2007;4:222-225.

ORIGINAL PAPERLong-term effects of pioglitazone versus gliclazide on hepatic and humoral coagulation factors in patients with type 2 diabetes
Gabriele Perriello, Simone Pampanelli, Paolo Brunetti, Cinzia Di Pietro, Segundo Mariz, On Behalf Of The Italian Pioglitazone Study Group

This study compared the long-term effects of pioglitazone and gliclazide on the production of coagulation factors in patients with type 2 diabetes. Patients (n=283) with glycosylated haemoglobin > 7.5% were randomised to receive either pioglitazone (30–45 mg/day) or gliclazide (80–320 mg/day) for one year. Coagulation factors were measured at baseline and at six and 12 months. While both pioglitazone and gliclazide induced a comparable improvement in glycaemic control, only pioglitazone improved insulin sensitivity. Pioglitazone significantly (p<0.001) decreased circulating levels of von Willebrand factor (-9.7%, -9.4%) and plasminogen activator inhibitor-1 (-16.8 ng/ml, -12.3 ng/ml), and increased levels of antithrombin-III (+1.3 mg/dL, +1.5 mg/dL) after six and 12 months, respectively. The beneficial effects of pioglitazone on glycaemic control, lipid homeostasis, and coagulation and thrombosis, may improve vascular outcomes in patients with type 2 diabetes.

Diabetes Vasc Dis Res 2007;4:226-230.

POPULAR
TOPICORIGINAL PAPERVascular inflammatory markers in early-onset obese and type 2 diabetes subjects before and after three months’ aerobic exercise training
Mensud Hatunic, Francis Finucane, Nicole Burns, Declan Gasparro, John J Nolan

Early-onset type 2 diabetes (T2DM) may lead to very early vascular complications. Cardiovascular mortality is two to five times higher in adults with diabetes than in people without diabetes. The cardiovascular risk of young people with T2DM is unknown. T2DM in young people is associated with marked visceral obesity, insulin resistance and microalbuminuria. We recently showed that these subjects did not improve in either fitness (maximum volume of oxygen consumption, VO2max) or glucose disposal after exercise training.
Seven subjects with early-onset T2DM (aged 26.1+0.9 years, body mass index [BMI] 35.6+1.2 kg/m²) and 14 age-matched obese subjects with normal glucose tolerance (aged 25.6+0.9 years, BMI 34.3+1.4 kg/m²) underwent aerobic training for 12 weeks. Serum vascular inflammatory markers (high-sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule [sICAM-1], soluble vascular cell adhesion molecule [sVCAM-1], E-Selectin and P-Selectin) were measured before and after the training programme.
At baseline, plasma concentrations of vascular inflammatory markers were significantly elevated in both groups. They did not improve after exercise.

Diabetes Vasc Dis Res 2007;4:231-234.

LETTERCoexistence of smoking and metabolic syndrome among middle-aged patients with diabetes in the UK: a cross-sectional analysis
Uditha Bulugahapitiya, Sajith Siyambalapitiya, Jabulani Sithole, Devaka Fernando, Iskandar Idris

Diabetes Vasc Dis Res 2007;4:241.

SHORT REPORTAssociation of the T54 allele of the FABP2 gene with cardiovascular risk factors in obese Mexican subjects
Erika Martínez-López, Bertha Ruíz-Madrigal, Iván Hernández-Cañaveral, Arturo Panduro

Genetic predisposition to cardiovascular risk may vary between different ethnic groups. We studied the effect of the FABP2 A54T polymorphism on biochemical and anthropometric cardiovascular risk factors in 114 obese Mexican subjects. The mean age of the patients studied was 36.8+13.3 years. Insulin resistance was present in 47%, hypercholesterolaemia in 49% and hypertriglyceridaemia in 45%.
Frequency of the FABP2 genotype was 39% AA, 54.8% AT and 6.2% TT. The AT/TT group showed an increase in body mass index (34+7.1 vs. 31+4.8 kg/m²), waist circumference (101+15.7 vs. 96.5+15.8 cm), triglycerides (145+60.8 vs. 127+79.4 mg/dL; 1.64+0.67 vs. 1.43+0.89 mmol/L), total cholesterol (176+39.4 vs. 164+38.2 mg/dL; 4.55+1.02 vs. 4.24+0.99 mmol/L), LDL (121+24.2 vs. 111+25.9 mg/dL; 3.13+0.62 vs. 2.88+0.67 mmol/L) and VLDL (28.8+12.1 vs. 25.1+16.1 mg/dL; 0.74+0.31 vs. 0.64+0.41 mmol/L) compared to the AA group (p<0.05). The AT/TT group had greatly increased cardiovascular risk, with an OR of 7.56 (95% CI, 1.82–36.24; p<0.001) compared to the AA group. Our results suggest that A54T polymorphism of the FABP2 gene is associated with cardiovascular disease risk in obese subjects.

Diabetes Vasc Dis Res 2007;4:235-236.