THE EXPANDED HORIZON OF VILDAGLIPTIN BENEFITS

The complexities of diabetes mellitus management extend beyond its clinical implications that negatively affect the outcomes of patients with the disease. Over the years, the positive impact of innovations for diabetes has been dampened by societal and cultural issues, as well as widespread misinformation. This is especially true in the local setting.

This highlights the need for intersectoral collaboration, going beyond the medical and scientific community, to address the multifaceted challenges that hinder the successful uptake of locally available solutions for diabetes. This also warrants revisiting existing solutions whose benefits can be maximized to improve patient outcomes further. Such was the theme for the recent scientific symposium “Tibay ng Bukas: Unang Himig Laban sa Diabetes”, held at the Grand Hyatt Manila, on July 26, 2024.


The scientific symposium made possible through the educational grant from Corbridge, brought together highly regarded experts in diabetes management, headed by Dr Augusto Litonjua, widely recognized as the “father of endocrinology” in the Philippines, professor emeritus at the UP College of Medicine, and a multi-awarded clinician and academician, who gave a lecture on the expanded benefits of a class of antidiabetic agents – the DPP4-inhibitors (DPP4-is).

A closer look at DPP4-inhibitors and the Benefits of Vildagliptin
Dr Augusto Litonjua began his lecture by reviewing the mechanism of action of DPP4-is, focusing on how these molecules increase the amount of physiologically available GLP-1, leading to stimulation of beta cells to release insulin and inhibition of alpha cells from releasing glucagon.^1,2 His discussion then focused on the benefits of a particular DPP4-i which is vildagliptin.

Firstly, Dr Litonjua discussed how DPP4-is increases alpha cell sensitivity. As such, administration of other hypoglycemic agents, when combined with vildagliptin causes less hypoglycemia.

This is exemplified in a study where the combination of insulin with vildagliptin not only resulted in a significant reduction of HbA1c but was also associated with a markedly decreased incidence of hypoglycemia.³ The underlying mechanism of this effect was further explained by findings from another study which showed a greater change in plasma glucagon levels associated with vildagliptin compared to placebo.⁴ Dr Litonjua explains that in this setting, DPP4-is increases the sensitivity of alpha cells, which then release glucagon, resulting in a more robust counter-regulatory response to the hypoglycemia caused by insulin.

The second benefit that can be expected of vildagliptin is the associated improvement of lipid parameters. Specifically, vildagliptin was associated with a significantly decreased total cholesterol, as well as LDL and non-HDL cholesterol levels.³ This effect of vildagliptin results from both an increase in postprandial lipolysis,⁵ and reduced levels of ApoB48⁶ – the protein needed to absorb cholesterol in the intestines.

Dr Litonjua further talks about how the compound effect of these two benefits results in the third advantage associated with the use of vildagliptin, which is the achievement of a favorable weight profile of patients.⁷Given these benefits to vildagliptin administration, Dr Litonjua also explored the advantage of switching from sulfonylureas(SUs) to DPP4-is, specifically vildagliptin. He presented existing evidence showing a similar degree of HbA1c reduction achieved with vildagliptin compared to SUs, such as glimepiride andgliclazide.^7,8 The same study also demonstrated lesser hypoglycemic episodes associated with vildagliptin compared to glimepiride.⁸

Considering that diabetes is a multi-morbid condition, at times accompanied by abnormalities in blood pressure, Dr Litonjua also stresses the importance of Vildagliptin's effect on hypertension.⁹

Vildagliptin vs. Sitagliptin: A head-to-head comparison
In his discussion, Dr Litonjua also highlights the features of vildagliptin that give it an edge even over other locally availableDPP4-is. Among the most notable differences of vildagliptin compared to other DPP4-is is its slower dissociation rate from the DPP-4 enzyme, translating to a longer DPP-4 inhibition.¹⁰

A head-to-head comparison further reveals other advantages of vildagliptin over sitagliptin, which include better GLP-1 preservation profile, better plasma glucagon suppression, and superior amelioration of pancreatic dysfunction.¹¹ Glycemic variability, measured as the mean amplitude of glycemic excursion (MAGE), was also notably less in vildagliptin compared to sitagliptin. MAGE is as equally important as the degree of glycemic control because glycemic variability, resulting from glucose swings and post-prandial spikes in blood sugar, is linked to the generation of oxidative stress, which is one of the mechanisms by which diabetes complications develop.^11,12

Dr. Litonjua’s discussion also highlighted the applicability of vildagliptin to a wide variety of patients. Owing to its pharmacokinetics, vildagliptin does not require dose adjustment when administered to patients with renal impairment. Furthermore, vildagliptin’s glucose-dependent effect allows for its administration to elderly and very elderly patients. Vildagliptin has been demonstrated to affect a significant drop in HbA1c in the very elderly without clinically significant changes in body weight, or increased incidence of hypoglycemia. These effects were consistent whether vildagliptin was given as a monotherapy or as an add-on medication.¹³

In terms of adverse events, clinical evidence shows that vildagliptin was not associated with pancreatitis, infections, or hepatic adverse events. Additionally, animal studies evaluating vildagliptin’s potential carcinogenicity yielded no signals for the development of pancreatic cancer.¹⁴

Above and Beyond: Vildagliptin’s role in addressing insulin resistance in T2DM
Based on existing clinical evidence, vildagliptin is the only DPP4-i that has been demonstrated to improveinsulin sensitivity. It does so by enhancing islet cell function, as well as reducing fasting lipolysis.¹⁵

The only other drug group that has been shown to address insulin resistance is thiazolidinediones (TZDs), and thus far, vildagliptin is the only DPP4-is that has been appropriately compared with a TZD.^16,17 Vildagliptin is comparable with rosiglitazone in terms of change in HbA1c from baseline. Similarly, vildagliptin has been shown to as effective pioglitazone in terms of HbA1c reduction, but without the associated weight gain.¹⁷

Dr Litonjua ended his lecture by identifying patient profiles who are most likely to benefit from Vildagliptin therapy, either as a monotherapy or as an add-on to other anti-diabetic medications. This included patients newly diagnosed with diabetes mellitus, patients on SUs who are gaining weight or with increased risk of hypoglycemia, patients on TZDs with weight gain, or those who are on metformin, TZD, or SUs who are not achieving their target blood sugar levels.

Translating Clinical Evidence to Real-World Benefits
Following his lecture, Dr Litonjua was joined by reactors in the persons of Dr Maria Honolina Gomez, a retired tenured full professor at the UST Faculty of Medicine and Surgery and active endocrinology consultant at UST hospital and Capitol Medical Center, and Dr Araceli Panelo, Chairman of the Board of Trustees at the Institute for Studies on Diabetes Foundation. The session was facilitated by Dr Sjoberg Kho, who is the Head of the UST Hospital Diabetes Center and Chairman of the UST Hospital Department of Medicine.



Dr Panelo shared her first-hand clinical experience and reiterated the dangers of hypoglycemia, which led to her appreciation of vildagliptin’s efficacious glucose-lowering effects on the background of decreased incidence of hypoglycemia. She also related the discussion to the local healthcare climate – where most patients are managed in a resource-limited setting – and brought attention to the need for diabetes solutions to be more accessible to patients.

Dr Gomez on the other hand related the discussion points to real-world implications. She emphasized that the degree of Hba1c reduction with vildagliptin observed in RCTs was consistent with data yielded from real-world studies, further solidifying confidence in the efficacy of vildagliptin. She also zeroed in on the data presented earlier by Dr Litonjua showing that higher baseline HbA1c was associated with a greater decrease in HbA1c levels resulting from vildagliptin administration. She explains that this is of particular importance especially in patients with markedly elevated HbA1c upon initial diagnosis, as they may garner the greatest benefit from starting vildagliptin. Finally, she also underscored the implications of vildagliptin’s capacity to preserve beta-cell function, since patients with diabetes are expected to have a significant decline in beta-cell function upon initial diagnosis.

The discussion among the speaker and the reactors also highlighted the utility of vildagliptin in resource-limited settings. This is of particular interest especially in the local setting where accessibility of medications is a major concern. Fortunately, the increasing availability of these medications in the market at more affordable price points, made possible through the collaboration between healthcare providers and pharmaceutical partners, make it more accessible to patients who need it most. Furthermore, the benefits of vildagliptin, especially its role in reducing morbidity and complications in patients with diabetes, ultimately translate to better quality of life and productivity, equating to a more cost-effective strategy in diabetes management.

Conclusion
Diabetes mellitus management has progressed significantly, driven by an evolving understanding of its mechanism, and the persistent pervasive impact of the disease, not only on the individual patient but also on their family and society. Efficacious solutions already exist, among them is vildagliptin, with its benefits extending beyond just glycemic control, supported by evidence from clinical trials and real-world data.