This post hoc analysis was conducted to assess the effectiveness of DPP-4 inhibitor vildagliptin- versus SU-based regimens in reducing HbA1c levels in relation to the duration of type 2 diabetes. The results showed a more pronounced reduction in HbA1c with vildagliptin-treated patients compared with SU-treated patients across the duration of the disease in a real-life setting.
Typically individuals develop impaired glucose tolerance as a result of increased insulin resistance, which in turn increases the stress on β-cells to secrete more insulin to combat the increased peripheral insulin resistance. As the disease progresses, multiple pathophysiological defects such as increased hepatic glucose production, increased insulin resistance, and decrease in β-cell function due to various putative biological processes including endoplasmic reticulum (ER) stress result in increasing hyperglycemia and HbA1c. Durability of response to an agent will depend on its ability to target the multiple pathophysiological defects. One explanation for durable efficacy of a DPP-4 inhibitor versus SUs may be the progressive β-cell decline  throughout the course of diabetes duration. SUs target deficient insulin secretion by working on β-cells, whereas glucagon-like peptide-1 (GLP-1)-based medications (DPP-4 inhibitors and GLP-1 receptor agonists) additionally work on the pancreatic α-cells, regulating glucagon release, and thereby results in sustained efficacy even at later stages of type 2 diabetes . A study by Kozlovski et al. reported that the response of the β-cell, but not the HbA1c reduction, with vildagliptin is dependent on the duration of type 2 diabetes. The authors conclude that glycemic durability is maintained with vildagliptin as glucagon suppression may be compensating the reduced β-cell function . Furthermore, there are reports which suggest that GLP-1 receptor activation improves survival of β-cells exposed to chemically induced ER stress .
In this analysis, we found superiority in efficacy with the DPP-4 inhibitor at all stages of the disease duration, after an observational period of 12 months. The reason might be that the treatment effectiveness is retained in real-life with the DPP-4 inhibitor, whereas the same is not observed in SUs, possibly because of the fear of hypoglycemia and thus not always the optimal recommended doses are being used . Our study contributes to the knowledge that the difference in efficacy between SUs and the DPP-4 inhibitor vildagliptin increases over the years of diabetes duration, favoring DPP-4 inhibitors. The choice of an efficient second-line OAD might prevent further intensification to a triple therapy or to a therapy with injectable antidiabetes medication. On the contrary, a retrospective, cohort study reported better durability of glycemic response (reaching HbA1c <7.0%) with SU as add-on therapy in patients failing on metformin monotherapy versus DPP-4 add-on. The disparity in the results can be attributed to differences in baseline HbA1c and duration of diabetes which are strong drivers of the response .
Our secondary endpoint, reaching the goal of HbA1c <7.0% (53.0 mmol/mol) without hypoglycemia or weight gain, also demonstrated better efficacy and tolerability with vildagliptin, when compared with SUs, over the course of the disease duration. This might be of particular importance for the elderly population and for patients with renal impairment. Both groups often have prolonged duration of type 2 diabetes in general and are more vulnerable to adverse side effects, especially hypoglycemia . Furthermore, the favorable extrapancreatic effects of DPP-4 inhibitors such as decrease in blood pressure and improvement in lipid profile which positively influences various diabetic complications are also important clinical considerations when choosing an appropriate second-line agent [20,21,22].
Despite a substantial decline in diabetes-related complications in the past two decades , the continued increase in the prevalence of type 2 diabetes is alarming . Furthermore, with the age of disease manifestation being shifted to younger years, we are likely to see more patients with a prolonged duration of diabetes. Hence it is of utmost importance to know about efficacy of different diabetes medications, preferably without tolerability issues. This study demonstrates that with increased duration of type 2 diabetes, the effectiveness of SUs decreases significantly compared to DPP-4 inhibitor and that a higher percentage of patients on DPP-4 inhibitor are able to reach their glycemic/HbA1c targets without hypoglycemia or weight gain.
The large patient population (N = 36,164) and real-life setting are the key strengths of this study. Another strength is the comparison of two clinically, often used second-line therapies, DPP-4 inhibitor and SUs. The current analysis accentuates the fact that the variance in treatment effectiveness between SU and DPP-4 inhibitor in reducing HbA1c with increasing duration of type 2 diabetes might be pronounced in patients in real-life, adding one more factor in facilitating clinical judgment. This could be of special importance to individuals with a prolonged duration of type 2 diabetes and/or for the elderly population with diabetes.
This paper has certain limitations: We compared only the DPP-4 inhibitor vildagliptin with SUs. Effectiveness of other OADs, especially SGLT-2 inhibitors, over the course of diabetes duration has not been reported as SGLT-2 inhibitors were not on the market during EDGE study initiation. The duration of type 2 diabetes is based on verbally reported values by the patients, and cannot be confirmed; hence, it may not truly reflect the actual diabetes duration. Another limitation of the current study is the fact that baseline BMI affects the change in HbA1c, albeit minimally, and was not taken into account while assessing the impact of diabetes duration on the HbA1c-lowering potential of vildagliptin- and SU-based regimens.