Microvascular Outcomes in Patients with Type 2 Diabetes Treated with Vildagliptin vs. Sulfonylurea: A Retrospective Study Using German Electronic Medical Records

Diabetes mellitus is a progressive and chronic disease which is a major healthcare problem worldwide. According to the World Health Organization, 347 million people worldwide have diabetes (both types 1 and 2) [1], and the number is estimated to rise to 592 million by 2035, as forecasted by the International Diabetes Federation [2]. Type 2 diabetes mellitus (T2DM) results from a combination of insulin resistance and insulin deficiency. It is the most prevalent type of diabetes, accounting for 95% or more of all diabetes cases globally [3].

Diabetes can lead to many serious microvascular degenerative complications (e.g., retinopathy, nephropathy, and neuropathy) resulting into an increased risk of morbidity and mortality and with this significant health care system costs [4]. Hence, while, ideally, the treatment of diabetes demands a holistic approach that can address various complications associated with diabetes, the primary target of achieving an adequate blood glucose level as measured by hemoglobin A1c (HbA1c) level seems still essential. In fact, in previous studies in patients with T2DM, an association between the degree of hyperglycemia and a high risk of microvascular complications has been shown [5, 6]. Several prospective observational studies have outlined the role of intensive glucose control in reducing the risk of microvascular complications in diabetes [7, 8]. Some of the important drugs that are widely used in the treatment of T2DM are metformin, sulfonylureas, and thiazolidinediones class of molecules [4].

Dipeptidyl peptidase-4 (DPP-4) inhibitors were introduced in the treatment of T2DM in 2006 [9]. DPP-4 is an endogenous aminopeptidase enzyme which degrades incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors impart their action by increasing the endogenous concentrations of GLP-1 and GIP that are released in response to food intake [10, 11]. The increased concentration of GLP-1 and GIP lead to insulin secretion by pancreatic β-cells, decreased glucagon secretion, and reduction in liver glucose production. Due to their efficacy, good tolerability, low risk of hypoglycemia, and body-weight neutrality, DPP-4 inhibitors have gained importance in the treatment of T2DM [12]. Vildagliptin (Galvus^®; Novartis Pharma AG) is an oral antidiabetic agent from the DPP-4 inhibitor class of drugs. It is indicated in Europe in the treatment of T2DM on its own (monotherapy) in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance; together with metformin, a thiazolidinedione or a sulfonylurea (dual therapy); or together with a sulfonylurea and metformin (triple therapy). Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycemic control [3].

Several studies have indicated importance of sulfonylureas or insulin to reduce the risk of microvascular complications [13]. However, there is no adequate comparative data available on the role of a relatively new molecule, i.e., a DPP-4 inhibitor vildagliptin, in treating the microvascular complications associated with T2DM. In this study, we used real-world evidence to evaluate the role of vildagliptin in treating microvascular complications associated with T2DM and compared it with sulfonylurea. The main objectives were to evaluate the incidence of microvascular complications of diabetes between the two treatment groups, i.e., vildagliptin vs. sulfonylurea, as well as, to investigate time needed for the development of these complications between patients in the above-mentioned populations.

A retrospective cohort observational study was carried out to investigate any advantage of the relatively new DPP-4 inhibitors class of a drug vildagliptin over sulfonylurea in treating microvascular complications associated with T2DM.

Our investigations in the present study indicate that treatment with vildagliptin is associated with lower overall incidences of microvascular events, particularly significant were retinopathy and neuropathy, when compared with sulfonylurea. Microvascular complications associated with T2DM affect the retina, nerves, and kidney leading to the reduced quality of life of patients. Time-to-event analysis based on the IRR demonstrated no statistically significant differences in time required for the occurrence of various microvascular complications between two study groups (vildagliptin vs. sulfonylurea).

Relevant patients’ data for the present study were extracted from the IMS Lifelink EMR DA database for the German population. The study design (retrospective cohort study) prevents any claims to have established causal effects based on the observed associations. A further limitation of database studies using EMR data is the suboptimal recording of information by physicians. However, in this study, the assumption could be made that this suboptimal recording affects both exposure groups (vildagliptin vs. sulfonylurea) in the same way, and thus, under-reporting may not be an issue for this real-world evidence comparison. Nevertheless, any conclusion regarding the absolute incidence of each microvascular complication shall be handled with caution. In addition, the under-reporting can potentially reduce the effect size, the amount of which cannot be estimated from the study data. It is likely that patients’ exposure to vildagliptin or sulfonylurea was determined by their profile which, in its turn, affects the development of microvascular complications. We have tried to reduce or eliminate this confounding effect using propensity scoring to generate comparable groups between two treatments. Comparable groups of patients with respect to age, sex, HbA1c level, duration of disease and treatment, and existing co-morbid conditions between two treatments (vildagliptin vs. sulfonylurea) ensured a high internal validity of our findings. In addition, validity and representativeness of the IMS Lifelink EMR DA database have already been investigated for its use in pharmacoepidemiological studies [14].

DPP-4 inhibitors have shown potential for the management of T2DM, as corroborated by conducted clinical trials that have indicated safety and efficacy of vildagliptin and other DPP-4 inhibitors in the treatment of T2DM [15‐20]. Vildagliptin is well-tolerated and produces clinically meaningful reduction in blood glucose level without promoting weight gain or inducing hypoglycemia [21]. Recent studies have shown advantages of vildagliptin in T2DM treatment in elderly [22] and overweight/obese patients [23]. The benefit of DPP-4 inhibitors in addressing cardiovascular risks associated with T2DM when compared with, e.g., the metformin therapy was also investigated in several studies [12, 24, 25].

Considering microvascular complications associated with T2DM, role of intensive glucose control therapies in treating such microvascular complications has been investigated in several trials. In the UK Prospective Diabetes Study (UKPDS) trial (ISRCTN75451837), it was reported that each 1% reduction in mean HbA1c with intensive glucose therapies (sulfonylurea or insulin) was associated with 37% reductions in risk of microvascular complications [7]. An even more pronounced effect with reductions of 54% in microvascular complications was observed in the Diabetes Control and Complications Trial (DCCT; ClinicalTrials.gov identifier: NCT00360815) [26]. Similar observations regarding the benefit of intensive glucose treatment in microvascular complications were reported in Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) [27] and Action to Control Cardiovascular Risk in Diabetes (ACCORD; ClinicalTrials.gov identifier: NCT00000620) [28] trials.

Several pilot studies were also conducted to investigate whether relatively new classes of DPP-4 inhibitors have any effect on microvascular complications associated with T2DM. A recent small (50 patients with T2DM), placebo-controlled, double blind, crossover trial has demonstrated that treatment with saxagliptin (a DDP-4 inhibitor) for 6 weeks could be advantageous in early microvascular changes [29]. In another pilot study, treatment with vildagliptin for 8 weeks in 47 patients with T2DM has shown the significantly reduced decreased albumin/creatinine ratio [30]. Similarly, vildagliptin has shown improved healing features for chronic foot ulcers in patients with T2DM [31]. Several pre-clinical studies also observed the importance of DPP-4 inhibitors in treating microvascular complications associated with diabetes [32‐35]. Most of the studies on humans investigating importance of DPP-4 inhibitors in microvascular complications were preliminary and short-term studies, and further large and long-term trials are required to corroborate these findings. Our present observational study has attempted to fill in the gaps in establishing role of a DPP-4 inhibitor vildagliptin in treating microvascular complications associated with T2DM by directly comparing it with the sulfonylurea treatment.

The comparative evidence basis investigating different available therapeutic options in treating T2DM and its complications is sparse [36]. Hence, there is a high-demand of the comparative effectiveness research between various available treatment options for T2DM. However, lengthy and costly clinical trials limit such comparative effectiveness studies, especially considering the fact that head-to-head comparisons between different treatments result into large number of combinations and permutations of drugs to be investigated. Nevertheless, real-world evidence solutions, as has been implemented in the present study, provide an effective alternative for direct comparisons between different therapeutic options available in the treatment of T2DM and its complications based on patients’ data extracted from real-world settings. Such comparative effectiveness studies based on real-world data will be one step forward toward achieving the tailor-made, patient-centered approach for the treatment of a chronic disease, such as diabetes.