5.1 A1C, FPG and HOMA-IR
Metformin and SU are recommended as the first 2 steps of therapy in current treatment algorithms5,6. However, there is no widely agreed consensus on how to intensify therapy in patients with secondary oral agent failure. Our study demonstrated that intensifying an existing dual oral therapy by adding pioglitazone or sitagliptin resulted in a significant and similar improvement in A1C.
Our changes in A1C results of pioglitazone and sitagliptin were similar to previous meta-analysis evaluating antidiabetic drug additions to metformin12. The magnitude of A1C reduction of pioglitazone in our study was somewhat lower than previous reports combining metformin and a SU with pioglitazone9-11,21. This could be due to that we only used pioglitazone 30mg daily lower than previous studies (34.5mg to 45mg daily).
Our results demonstrated superior FPG reductions with pioglitazone verses sitagliptin, despite similar effect on A1C, were consistent with prior studies which pioglitazone or vildagliptin (another brand of DPP-4 inhibitors) were added to patients with metformin monotherapy28. This could be probably due to the different mechanisms of action of the two add-on drugs. Pioglitazone decreases fasting and postprandial plasma glucose by improving hepatic and peripheral insulin sensitivity, whereas
sitagliptin stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner which was considered to be mainly a postprandial treatment18,23,29. Future studies are needed to compare the 24-h glucose profiles with treatment with both drugs.
In agreement with the established effects of pioglitazone on insulin resistance, pioglitazone was associated with significant decrease in HOMA-IR18,19. In contrast, HOMA-IR was not significantly change with sitagliptin, consistent with the observation that DPP4 inhibitors target insulin secretion and do not alter insulin resistance15-17.
5.2 Hs-CRP and lipids
The favourable influence of pioglitazone on TG, HDL-C and hs-CRP is well established18,19. Our results extended the findings and showed that similar lipid and hs-CRP changes can be expected when pioglitazone is added to dual therapy with metformin and a SU. Consistent with previous studies, in which sitagliptin has generally demonstrated a neutral effect on lipid and hs-CRP15,16,23. Whether these differences in lipid and hs-CRP effects translate into differences for the risk of CVD is not clear.
5.3 Safety, tolerability and body weight change
Both combination therapies were general well tolerated, with no difference in the
incidence of overall adverse events. There was a significantly higher incidence of edema in the pioglitazone group compared with the sitagliptin group, consistent with previous results of an increased incidence of edema with pioglitazone9,22. Gastrointestinal adverse events was more common in the sitagliptin and was higher than reports of previous sitagliptin studies (20% vs. 4.3 -12%)13-17. However, most of the events were mild and resolved while patients continued to receive therapy.
Hypoglycemia is always a concern with the antidiabetic drugs. The incidence of hypoglycemia was similar in both groups and none of the episodes was considered to be severe by the investigators and most were associated with precipitating factors, such as delay eating, skipped meals or increased activity.
Another concern with antidiabetic drugs is weight gain. In this study, the mean weight gain was higher in the pioglitazone group compared with the sitagliptin group. Weight gain is a well-known consequence of pioglitazone treatment, while weight neutrality has been observed in sitagliptin studies both in monotherapy and add-on settings13-17,23.
5.4 Subgroup analyses
The treatment effects on A1C were consistent across most subgroups, with only significant interaction noted with regard to gender. Magnitudes of the A1C reduction with sitagliptin were generally consistent across the subgroups in previous clinical
studies (e.g. age, gender, duration of diabetes, BMI, and HOMA-IR)15,17. The efficacy of pioglitazone was different in gender has not been reported in clinical studies, but according to the FDA review, the decrease in AlC was greater in women than in men30. The reasons for sex difference are possibly due to the pharmacological mechanisms based on differences in body fat distribution and in sex hormones and due to the different pharmacokinetic mechanism31-33.
5.5 Limitation
There were some limitations to this study. First, the period of treatment was too short to evaluate long-term glycemic control and adverse event. Second, we may underestimate the efficacy of pioglitazone, as the maximum dose pioglitazone was not used. However, the cost of pioglitazone 30mg is similar to sitagliptin 100mg, so we don’t need to consider cost-effectiveness. Third, our study did not record or measure some potential adverse events including anemia, osteoporosis and urinary tract infection. Finally, Subgroup analyses indicated a slight favour for adding pioglitazone compared with sitagliptin in patients with higher BMI or higher HOMA-IR at baseline, however, our study was not designed with sufficient power to draw statistical conclusions about individual subgroups. Thus, one should be cautious in interpreting the results of subgroup analyses.
5.6 Conclusion
Pioglitazone and sitagliptin achieved similar improvements in overall glycemic control in patients with type 2 diabetes inadequately controlled with metformin and a sulfonylurea. However there were some differences in terms of FPG, lipids, HOMA-IR, body weight change and adverse events. Long term randomized control trials will be required to provide the reference when choosing OAD as combination therapy in patients with type 2 diabetes who had inadequate glycemic control on dual therapy with metformin and a SU.