Achieving and maintaining adequate glycaemic control in patients with type-2 diabetes markedly reduces incidence of micro- and macrovascular complications. When lifestyle intervention followed by metformin monotherapy fail to achieve or sustain glycaemic control, the ADA/EASD guidelines recommend addition of either a sulphonylurea, a thiazolidinedione (pioglitazone or rosiglitazone - 'glitazones') or initiation of insulin therapy.1
Goal-orientated treatment of type-2 diabetes is often associated with weight gain. This is somewhat counterintuitive when the first step in diabetes management is to reduce weight to improve glycaemic control and cardiovascular risk.
This article focuses on weight gain associated with glitazone treatment, with the aim of helping clinicians understand its implications for treatment.
Weight gain as an adverse effect of glitazone treatment affects approximately 1-10 per cent of patients. Patients typically experience an average weight gain of 3-4kg over the first six months of treatment; however the rate of weight gain decreases and stabilises after the first 6-12 months of treatment.2
The magnitude of weight gained with glitazone monotherapy is comparable to that seen with a sulphonylurea and insulin, but greater than the increase seen in metformin-treated patients.3 The effect is exacerbated when combined with insulin or sulphonylureas, and is reduced or absent when used in combination with metformin.2
It is also worth noting that weight gained does not appear to impact upon the sustainability of glycaemic control over continued glitazone treatment, whereas sustainability is often diminished in patients taking a sulphonylurea over the longer term.4
Weight gain observed with glitazones involves a re-distribution of fat away from the central, visceral depot and liver/skeletal muscle towards the subcutaneous depot, leading to a significant reduction in waist-to-hip ratio (see figure).2
Increases in weight may present a psychological barrier to treatment compliance, which can hinder achievement of adequate glycaemic control. Furthermore, the association between obesity and an increased risk of cardiovascular disease in those with type-2 diabetes has led to some concerns that the weight gain associated with glitazones may exacerbate this risk.
However, as described above the fat redistribution that occurs results in fat deposits associated with a lower cardiovascular risk than centrally distributed fat.5
The effects of glitazones on other cardiovascular risk factors, apart from weight gain, also need to be considered in order to balance the implications of this intervention with patient outcomes.
For example, despite the mean 3.6kg weight gain, the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study, in more than 5,000 patients, has demonstrated that treatment with pioglitazone is associated with improvements in insulin resistance, BP, lipid profiles and cardio-vascular outcomes, regardless of weight gain.6
NICE advises that glitazones should not be used in patients with evidence of heart failure.
The use of pharmacological weight loss agents such as orlistat and sibutramine may help limit weight gain, but these have not been studied in combination with glitazones. The best method to prevent significant weight gain with the glitazones is regular dietetic advice.
The weight gain associated with the glitazones tends to occur in the first few months of therapy and stabilises after approximately 12 months of therapy.
In addition, this weight gain is comparable with that observed in patients given a sulphonylurea and can be limited with appropriate lifestyle interventions.
While weight gain associated with any antidiabetic agent appears to be counterintuitive to risk factor management, importantly, the weight gain associated with pioglitazone in particular is not linked to adverse cardiovascular events and the redistributed weight is itself not a risk factor for cardiovascular disease.
Newer antidiabetic agents such as the dipeptidyl peptidase-4 inhibitors appear to be weight neutral and the glucogon-like peptide-1 agonists can give rise to significant weight reduction. However, clinical experience with these agents is limited.
For the time-being, the glitazones are a worthy option in the battle for tight glycaemic control and cardiovascular risk reduction and the associated weight gain should not be seen as a barrier to their use in the type-2 diabetes treatment algorithm, especially when they are used in combination with metformin.
3. Barnett A, Allsworth J, Jameson K, Mann R. A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies. Curr Med Res Opin 2007; 23: 1,493-507.
4. Tan M, Baksi A, Krahulec B et al. Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type-2 diabetes. Diabetes Care 2005; 28: 544-50.
5. Sam S, Haffner S, Davidson M et al. Relationship of abdominal visceral and subcutaneous adipose tissue with lipoprotein particle number and size in type-2 diabetes. Diabetes 2008; 57: 2,022-7.
6. Dormandy J, Charbonnel B, Eckland D et al. Secondary prevention of macrovascular events in patients with type-2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1,279-89.