Volume 3, Number 3, December 2006

EDITORIALEarly and intensive treatment: glycaemic control in type 2 diabetes
Clifford J Bailey

Diabetes Vasc Dis Res 2006;3:145-146.

POPULAR
TOPICREVIEWCardiovascular disease prevention in patients with type 2 diabetes: the role of oral anti-diabetic agents
Ramzi A Ajjan, Peter J Grant

Diabetes Vasc Dis Res 2006;3:147-158.

POPULAR
TOPICREVIEWDipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes
Brian D Green, Peter R Flatt, Clifford J Bailey

Inhibitors of the enzyme dipeptidyl peptidase IV (DPP IV) provide a strategy for the treatment of type 2 diabetes. DPP IV rapidly inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP). Inhibition of DPP IV prolongs and enhances the activity of endogenous GLP-1 and GIP, which serve as important prandial stimulators of insulin secretion and regulators of blood glucose control. In clinical trials DPP IV inhibitors (or 'gliptins') have shown efficacy and tolerability in the management of hyperglycaemia in type 2 diabetes, without causing weight gain or hypoglycaemia.

Diabetes Vasc Dis Res 2006;3:159-165.

POPULAR
TOPICREVIEWFibrates after the FIELD study: some answers, more questions
Anthony S Wierzbicki

Fibrates have a long history in cardiovascular disease. These drugs raise high-density lipoprotein (HDL)-cholesterol, reduce triglycerides and improve small dense low-density lipoprotein (LDL) so would be expected to have large effects in type 2 diabetes, where this is the typical lipid profile. The general trial results with these agents have been confusing, with varying cardiovascular benefits. The Fenofibrate Intervention and Endpoint Lowering in Diabetes (FIELD) study recruited a low-risk population with a lipid profile that would be more usually treated with a statin. FIELD showed a non-significant 11% reduction (p=0.16) in the primary end point of coronary events and a significant 11% benefit on the secondary end point of cardiovascular events and procedures (p=0.04). Most of the benefits were seen in primary prevention and non-fatal myocardial events. Fenofibrate had little effect on HDL-C; the effects of the trial are consistent with the LDL-C reducing potential of this drug.
FIELD, because of unequal statin drop-in, gives little evidence on statin-fibrate combination therapy but does reinforce the available data on the safety of fenofibratestatin combination therapy. In addition, fenofibrate showed possible benefits on microvascular disease end points, including albuminuria and retinopathy.
On current data fenofibrate and gemfibrozil seem to be reasonable second-line agents in type 2 diabetes or secondary prevention with low HDL-C, respectively, based on outcome evidence. In combination therapy, drug-specific safety considerations will affect the exact choice of agent, especially in combination with statins, but the efficacy of combination therapy still requires validation in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

Diabetes Vasc Dis Res 2006;3:166-171.

POPULAR
TOPICREVIEWProtein kinase C beta inhibition: a novel therapeutic strategy for diabetic microangiopathy
Iskandar Idris, Richard Donnelly

Biochemical mechanisms involved in hyperglycaemiainduced vascular damage include alterations in cellular signalling by activation of protein kinase C (PKC). Twelve isoforms of PKC have been characterised according to their structure and co-factor requirements. Activation of PKC is mediated primarily through increased release of diacylglycerol (DAG). Adverse effects of PKC and DAG on vascular function include increased permeability, endothelial cell activation, altered blood flow, leukocyte adhesion and abnormal growth factor signalling.
A highly selective and orally active PKC-beta isoformselective inhibitor, ruboxistaurin, has been developed. Initial studies suggest that this agent decreased the development of sight-threatening macular oedema and the occurrence of visual loss. It did not, however, prevent the progression of diabetic retinopathy.

Diabetes Vasc Dis Res 2006;3:172-178.

REVIEWInhaled insulin (Exubera^®): combining efficacy and convenience
Srikanth Bellary, Anthony H Barnett

The pulmonary route, due to its rich vascularity, large surface area and immunotolerant characteristics, may be an ideal target for drug delivery. Although the inhaled route has been used to deliver drugs used in the management of respiratory disorders, success with peptide delivery has been limited by poor bioavailability. Recent advances in technology have overcome these barriers and have enabled new delivery devices to be developed. Insulin is the first peptide to be delivered successfully by this route and the first of the inhaled insulin delivery devices (Exubera®) has now been approved for clinical use. In clinical trials it has been shown to be effective, apparently safe and a preferred alternative to subcutaneously injected meal-time insulin. This new technology offers great convenience to patients needing insulin treatment. While it will considerably reduce the number of injections needed by people with type 1 and type 2 diabetes, it should also encourage more patients to start insulin treatment earlier. The potential benefits from improved adherence and better glycaemic control with this insulin are also significant.

Diabetes Vasc Dis Res 2006;3:179-185.

ORIGINAL PAPERThe sibutramine metabolite M2 improves muscle glucose uptake and reduces hepatic glucose output: preliminary data
Dawn K Coletta, Sarah H Bates, Robert B Jones, Clifford J Bailey

The satiety agent sibutramine acts in part through a primary amine metabolite, M2. To investigate whether M2 could affect glycaemia independently of satiety and weight loss, groups of normal mice received a single dose of M2 (1 or 10 mg/kg) and food was withheld. Compared with controls (who received vehicle only), M2 (10 mg/kg) decreased basal plasma glucose concentrations, with a maximal decrease of about 25% at 4–8 hours (p<0.05). Soleus muscles were isolated from the mice at intervals: insulin-mediated glucose uptake by the muscles from controls progressively decreased over 24 hours whereas uptake was maintained by muscles from M2-treated mice. Hepatic gluconeogenesis was reduced about 40% by liver snips isolated from M2-treated mice after 24 hours (p<0.05).
These preliminary results suggest that the M2 metabolite of sibutramine can reduce glycaemia, maintain insulin-mediated muscle glucose uptake and reduce hepatic gluconeogenesis independently of satiety and weight loss.

Diabetes Vasc Dis Res 2006;3:186-188.

ORIGINAL PAPERRosiglitazone increases LDL particle size and buoyancy and decreases C-reactive protein in patients with type 2 diabetes on statin therapy
Dahong Yu, Susan J Murdoch, Shamik J Parikh, Santica M Marcovina, Alexander Cobitz, Hongzi Chen, John D Brunzell

Asubstantial number of individuals with type 2 diabetes mellitus (T2DM) demonstrate a predominance of small dense low-density lipoprotein (sdLDL), which is associated with an increased risk of cardiovascular disease (CVD). In some cases, sdLDL persists after treatment with a statin to reduce levels of LDL. The effect of the addition of a thiazolidinedione, rosiglitazone (RSG) (4 mg/day or 8 mg/day) to statin therapy on LDL phenotype and C reactive protein (CRP) levels was investigated in a 12- week, placebo-controlled study of 72 T2DM patients who were well controlled and on a statin, but who had persistently predominant sdLDL.
Addition of RSG 8 mg to statin therapy significantly increased LDL buoyancy (relative flotation +0.014, p=0.003) and LDL particle size (+4.2Å, p=0.001) from baseline and relative to the change with placebo (+0.014 and +3.8Å; p=0.03 and p=0.04, respectively), and was associated with a non-significant decrease in sdLDL. RSG 8 mg moderately, but significantly, increased total cholesterol (by 12.2%, p=0.004), LDL-cholesterol (11.2%, p=0.02) and intermediate-density lipoprotein (IDL)-cholesterol from baseline but did not increase total or LDL apolipoprotein B. RSG 4 mg and 8 mg significantly reduced CRP compared with placebo (-44.9% and -48.0%; p=0.008 and p=0.004, respectively), and significantly reduced insulin resistance and fasting plasma glucose from baseline.
Addition of RSG to statin therapy may further reduce cardiovascular risk by improving the LDL phenotype, as well as reducing insulin resistance and CRP levels. However, the increase in IDL may be proatherogenic and must be considered when assessing the benefits of rosiglitazone.

Diabetes Vasc Dis Res 2006;3:189-196.

ORIGINAL PAPERExercise capacity is a predictor of cardiovascular events in patients with type 2 diabetes mellitus
Berhane Seyoum, Raymond O Estacio, Paulos Berhanu, Robert W Schrier

Peak exercise oxygen consumption (peak VO2), as measured by expired gas analysis, is an accurate, reproducible and reliable method for determining exercise capacity. In this study, a cohort of 468 patients with type 2 diabetes underwent graded exercise testing to measure peak VO₂ at baseline; the cohort was followed for five years for the occurrence of cardiovascular disease (CVD) events. Patients who developed CVD events during the five-year follow-up period were found to have significantly lower baseline peak VO₂, as compared to those who did not (p=0.02). Analysis by gender showed that the mean peak VO₂ in male patients who developed CVD events was significantly lower than the peak VO₂ in those who did not (p<0.03). Multiple Cox regression analysis also showed low peak VO₂ to be an independent factor.
In conclusion, patients with type 2 diabetes mellitus with reduced peak VO₂ during exercise have a greater tendency to develop future CVD events.

Diabetes Vasc Dis Res 2006;3:197-201.

ORIGINAL PAPERBaseline characteristics of the randomised cohort from the Look AHEAD (Action for Health in Diabetes) study
The Look AHEAD Research Group

Objective. The Look AHEAD (Action for Health in Diabetes) study is a 16-centre randomised clinical trial in overweight and obese individuals with type 2 diabetes, designed to evaluate the long-term effects (up to 11.5 years) of intensive weight loss intervention on the time to incidence of major cardiovascular events.
Research design and methods. Eligibility requirements are diagnosis of type 2 diabetes (determined by self-report and verification) in individuals aged 45–74 years and body mass index (BMI) > 25 kg/m² (> 27 kg/m² if currently taking insulin). The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. The study is designed to provide 90% probability of detecting an 18% difference in major cardiovascular disease event rates in patients randomised to the intensive lifestyle intervention compared to the control group receiving standard diabetes support and education.
Results. The 5,145 participants who were randomised between 2001 and 2004 were 63.3% white, 15.6% African-American, 13.2% Hispanic, 5.0% American Indian and 1.0% Asian-American, which closely paralleled the ethnic distribution of diabetes in the National Health and Nutrition Examination Survey (NHANES) 1999–2000 survey. Their average age at entry was 59+ 6.8 years (mean + SD), and 60% were women. There were 31.5% between 45–55 years of age, 51.5% were 56–65, and 17.0% were 66–76 years of age. Some 15.4% of participants were taking insulin at the time of randomisation and 14.0% had a history of cardiovascular disease. More men (21.3%) than women (9.2%) had a history of cardiovascular disease. Few participants (4.4%) were current cigarette smokers, compared to 16.2% in the NHANES 1999–2000 survey. Furthermore, 65.0% of participants had a first-degree relative with diabetes. Overall, BMI averaged 36+5.9 kg/m² at baseline, with 83.6% of the men and 86.1% of women having a BMI > 30 kg/m² and 17.9% of men and 25.4% of women having a BMI > 40 kg/m².
Conclusions. The Look AHEAD study has successfully randomised a large cohort of participants who have type 2 diabetes with a wide distribution of age, obesity, ethnicity and racial background and will examine the effects of lifestyle intervention on the incidence of major cardiovascular events.

Diabetes Vasc Dis Res 2006;3:202-215.