Our cost-effectiveness analysis, conducted with a validated model of type 2 diabetes and informed by a recent mixed treatment comparison meta-analysis and Canadian cost data, indicated that the addition of a sulphonylurea would be the most cost-effective second-line therapy in patients with type 2 diabetes inadequately controlled by metformin monotherapy. This conclusion was unaltered in sensitivity analyses, where model inputs were varied over their plausible ranges, and over a relevant range of willingness-to-pay thresholds. Since the initial preparation of this report, the prices of sulphonylureas have been halved in some provinces, which would further improve the cost-effectiveness of this class.
Our finding that second-line agents led to a modest reduction in glycosylated hemoglobin, similar to that achieved with metformin monotherapy, is consistent with other systematic reviews.40
Where there were slight differences between treatments, they translated into only very minor differences in long-term complications. With similar glycemic control, second-line agents with greater treatment costs would require additional clinical benefits for them to be considered cost-effective. Relative differences in the risk of hypoglycemia favoured thiazolidinediones, dipeptidyl peptidase-4 inhibitors and α-glucosidase inhibitors, but this did not make these drug classes more cost-effective than sulphonylureas, even when large decrements in quality of life were assigned to hypoglycemia. This relatively minor effect was partly due to the low absolute risk of severe hypoglycemia associated with sulphonylureas,14,15
which resulted in small differences in absolute risk. Similarly, although differences in weight change were noted, they were typically less than 3 to 4 kg and did not have a substantial effect on model results, even when a disutility associated with weight gain was incorporated.41,42
We attempted to use our model to accurately capture the effect of all relevant health outcomes, but uncertainty exists regarding the disutility associated with insulin use,43–45
Sensitivity analyses over plausible ranges did not alter results in the base case, but further research is needed to better define the impact of insulin use, weight gain and hypoglycemia on quality of life.
As expected, inclusion of other adverse events in the model, such as congestive heart failure for thiazolidinediones, made certain agents less attractive. Unlike sulphonylureas, which have an established safety profile because of their longevity on the market, greater uncertainty exists regarding the long-term safety of newer drugs. For example, the safety profile of dipeptidyl peptidase-4 inhibitors is still emerging, because they were introduced relatively recently. If future trials demonstrate clinical benefit or adverse outcomes with newer antihyperglycemic agents, their cost-effectiveness ratios may be altered.
First, our assumption that patients stay on the same therapy indefinitely does not reflect the progressive nature of the disease or clinical practice. However, sensitivity analyses in which failure of second-line treatment (glycosylated hemoglobin ≥ 9%) would eventually result in addition of insulin did not fundamentally alter our conclusions. Second, estimates of clinical benefit were limited by generally poor methodologic quality, short duration of studies and use of the surrogate of glycosylated hemoglobin.11
Although these limitations are considerable, the burden of proof lies with newer, more costly agents to demonstrate clinically relevant benefits relative to standard care in future randomized controlled trials.
Gradual loss of glycemic control is observed in patients with type 2 diabetes,6
and there is speculation that newer agents such as the incretins (i.e., dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues) may prolong glycemic control by slowing the decline of β-cell function and could thereby delay the initiation of insulin. However, the evidence supporting this proposed benefit is limited.46
In fact, a recent randomized controlled trial46
suggested that dipeptidyl peptidase-4 inhibitors do not confer benefits in terms of sustained glycemic control. Nevertheless, if future long-term studies demonstrate differences in glycemic durability between agents over time, or in other clinically important outcomes, cost-effectiveness estimates will have to be updated.
The results of this cost effectiveness analysis are generalizable to patients with type 2 diabetes in Canada. However, analogous conclusions are likely to be reached in other countries with similar price gradients among second-line agents. Indeed, other independent groups such as the National Institute for Health and Clinical Excellence have reported similar findings.47
In our model, we found that the addition of a sulphonylurea to metformin was associated with the most favourable cost-effectiveness results. This finding was primarily driven by the low cost of sulphonylureas relative to other drugs, marginal differences in glycemic control and long-term complications between sulphonylureas and other agents, and the low absolute risk of severe hypoglycemic episodes requiring health care resource use. Given the increasing prevalence of type 2 diabetes, the optimal use of antihyperglycemic therapies is of paramount importance. Although individualization of therapy is required for all patients, the addition of a sulphonylurea to metformin has similar efficacy to the addition of other antihyperglycemic drugs and represents the most cost-effective use of health care resources. Widespread use of newer, more expensive oral antihyperglycemic drugs or insulin as second-line therapy in patients with type 2 diabetes would lead to significant increases in drug expenditure without necessarily resulting in significant improvements in patient health. These funds would be better used in providing more cost-effective interventions for the treatment of type 2 diabetes.