Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice

Abstract

Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.

Keywords: Type 2 diabetes mellitus; novel agents; treatment for type 2 diabetes mellitus.

Figure 1.

A graphical description of the IDF-estimated number of adults living with diabetes globally since the year 2000 which is projected to rise to 700 million by 2045.^,

Figure 2.

A brief illustrative explanation of molecular mechanisms responsible for insulin resistance in T2DM followed by a discussion on organ-specific contributions. Insulin resistance in the muscles; defective insulin signalling, glucose transport, glucose phosphorylation, glycogen synthesis, pyruvate dehydrogenase complex activity, and mitochondrial oxidative activity.^,, Events in the liver; insulin resistance/deficiency, hyperglucagonaemia, enhanced glucagon sensitivity, and increased substrate (fatty acids, lactate, glycerol, and amino acids) delivery, leads to increased gluconeogenesis, which is responsible for the increased basal rate of glucose production and fasting hyperglycaemia.^– Renal contribution; renal insulin resistance and augmented renal gluconeogenesis contribute to fasting hyperglycaemia. Vascular endothelium; impaired vasodilation due to insulin resistance resulting in reduced insulin and glucose delivery. Finally, post-prandial hyperglycaemia ensues due to increased hepatic glucose output, muscle insulin resistance, reduced non-insulin-mediated glucose uptake, and excessive renal glucose re-absorption.^,

Figure 3.

Potential mechanisms via which glucose homeostasis is improved by imeglimin therapy.

Figure 4.

The Medtronic 670G with a guardian 3 sensor; an example of a hybrid closed-loop pump system.