A Systematic Review of Newer Drugs for Glucose Control

The four classes include the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones.  

The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites.  

Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software.

The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycemic control, reflected by glycated hemoglobin (HbA1c) level, hypoglycemic episodes, changes in weight, adverse events, quality of life and costs. Modeling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model. 

The results showed that, exenatide improved glycemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycemic control but had modest advantages in terms of hypoglycemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in the meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 612 dollars and 729 dollars. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 693 and 765 dollars respectively.

Exenatide was more expensive, with an annual cost of around 693 dollars. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with an NPH-based regimen having an annual cost of around 743 dollars for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 1,006 dollars and 1,136 dollars, respectively. Comparisons of sitagliptin and rosiglitazone, and of vildagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 2,856 dollars. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 4,285 dollars and 4,126 dollars. 

The limitations of the analysis included the UKPDS Outcomes Model which does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycemic events and the fear of severe hypoglycemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios.

From the results it was concluded that, exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for Type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycemic control and costs, and appeared to have fewer long-term side effects. 

Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of Type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.