In agreement with a previous meta-analysis, that was conducted on DPP-4 inhibitors including four studies on alogliptin
, this meta-analysis has demonstrated a significant reduction of HbA1c and FPG in patients treated with either alogliptin 12.5 mg or alogliptin 25 mg. Moreover, addition of either dose of alogliptin to a previously prescribed antidiabetic drug(s), in patients with inadequately controlled type 2 diabetes, has shown a statistically significant reduction in HbA1c and FPG - better than the previously prescribed antidiabetic drug(s) alone. Since the FPG reflects the hepatic glucose production, which depends on insulin secretory capacity of the pancreas
, while the HbA1c provides information about the degree of long-term glycemic control
, the finding of reduction in both markers with alogliptin probably indicates its short and long term efficacy.
Although heterogeneity testing showed a statistically significant dissimilarity in the results of the included studies, sensitivity analysis has shown the stability of the overall odds ratios with the withdrawal of any of the study from the analysis without a significant improvement of the heterogeneity. Thus, the credibility of the results of this meta-analysis did not seem compromised. This is because; when the number of included studies is small and heterogeneity is large, the robustness of the results is best assessed with a sensitivity analysis
Meta-regression showed a negative relation between the duration of alogliptin therapy and its efficacy (HbA1c reduction become minimal). However, this does not necessarily mean that alogliptin is ineffective after 12 weeks of therapy. Rather, its long term efficacy needs further investigation. From the subgroup analysis, the effect of alogliptin add-on therapy (alogliptin plus other antidiabetic drug) in lowering HbA1c does not appear superior to alogliptin monotherapy. However, this finding should be interpreted very cautiously. This is because; two of the studies in the alogliptin monotherapy subgroup recruited patients with type 2 diabetes who were naïve to antidiabetic drugs
[22, 25]. As a result, patients with type 2 diabetes who were not antidiabetic drug experienced could probably respond better to alogliptin therapy. Additionally, prior study on a combination of other DPP-4 inhibitor (sitagliptin) with metformin has shown better glycemic control than DPP-4 inhibitor monotherapy
On the other hand, the achievement of HbA1c ≤ 7% and HbA1c reduction by ≥ 1% brought further evidence in support of alogliptin efficacy in lowering elevated HbA1c. However, the reason for a significantly higher reduction of HbA1c in studies which were conducted in one country (all in Japan) than studies which were conducted in multiple countries is not exactly known. The possible explanation could be: 1) the shortness of the duration of therapies; i.e. unlike the other multi-country studies included in this meta-analysis (with a minimum duration of therapy 26 weeks), Japanese studies that were included in this meta-analysis have duration of therapy only 12 weeks. In support of this assumption, the meta-regression has shown more reduction in HbA1c in the 12 weeks therapy than the 26 weeks therapy. 2) The sample sizes of the studies which were conducted in Japan were relatively smaller than other studies which were conducted in multiple countries. It is known that small sample size studies have low power to establish the true research finding
. 3) There may be difference in ethnic and cultural background, which may have an influence on the treatment outcomes. Accordingly, Japanese patients with type2 diabetes could respond better to alogliptin than others. In support of our opinion, previous studies on other drugs have shown that there was difference between Japanese and Caucasians in pharmacokinetic and pharmacogenetic parameters for unknown reason
This meta-analysis also showed a significant reduction in FPG level among alogliptin treated groups, that is a desirable effect of any antidiabetic drug. From the theorized causes of diabetes mellitus complications, the widely accepted is persistent hyperglycemia that leads to spontaneous glycosylation of amino acids, lipids and nucleic acid
. As a result, the major goals in the therapy of diabetes mellitus is to keep the plasma glucose level below 110 mg/dl and maintain HbA1c < 7%
[36, 37]. This meta-analysis demonstrated the efficacy of alogliptin even in poorly controlled diabetes with other antidiabetic drug(s). In other words, four of the included studies in FPG and five studies in the HbA1c analyses were conducted in patients who were on other antidiabetic drugs but with poorly controlled diabetes.
Patients with type 2 diabetes are usually overweight or obese
. Unluckily, some other antidiabetic drugs like sulfonylureas, meglitinides, thiazolidinediones and insulin are known to be associated with weight gain, and may aggravate the already gained weight
[39, 40]. However, the effect of alogliptin 25 mg on body weight was not different from the controls (placebo or other antidiabetic drug treated). But, the pooled analysis on body weight change among the alogliptin 12.5 mg treated group demonstrated a significant weight gain. The result should be considered with great caution and needs further investigation. This is because, previous meta-analysis on the effect of DPP-4 inhibitors on body weight showed that DPP-4 inhibitors were weight neutral agents
Till proved otherwise, alogliptin is safe and effective in treating type 2 diabetes as add-on or monotherapy. The number of patients who discontinued their medication due to adverse events while receiving either doses of alogliptin was not different from the number patients who were receiving placebo or other antidiabetic drugs. Similarly, alogliptin treated patients with type 2 diabetes did not experience alogliptin related adverse events and there were no significant changes in serum lipids level. However, the authors of this meta-analysis share the concerns of other investigators on the possible adverse events of incretin-based therapies, such as pancreatitis, anaphylaxis and Steven Johnson’s syndrome
[42–45], which were not assessed in this meta-analysis due to lack of data.
As limitations, this meta-analysis has noted a high degree of heterogeneity among the included studies. The possible explanation for the inconsistencies across studies could be: the variation in the duration of therapies, the difference in the sites of the studies, the type of antidiabetic drugs used with alogliptin and for controls, patients’ difference in their antidiabetic drug experience and the type of anidiabetic drugs used before the start of alogliptin therapy. Secondly, all the included studies were sponsored by a pharmaceutical company, in which the findings might ave been manipulated as noted by other authors
[46, 47]. Thirdly, since the included studies for meta-analyses of adverse events and change in serum lipids were few and these studies were not primarily designed to assess adverse events and lipid profile change, the findings might not be conclusive. This is because; sample sizes of the individual studies included in a meta-analysis did not provide adequate power to test rare adverse events
. Fourthly, this meta-analysis was not able to incorporate studies written in other languages.