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Review
.2022 Jan 19:12:807548.
doi: 10.3389/fphar.2021.807548. eCollection 2021.

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

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Review

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

Amelia D Dahlén et al. Front Pharmacol..

Abstract

Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

Keywords: FDA approved; antihyperglycemics; clinical developments; diabetes mellitus; efficacy and safety; global trends.

Copyright © 2022 Dahlén, Dashi, Maslov, Attwood, Jonsson, Trukhan and Schiöth.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
FDA-approved monotherapies and combination regimens.(A) The current 59 FDA-approved anti-diabetic agents. The data includes the year of first approval for new molecular entities and unique combinations. Single agents are indicated in green while combination regimens are in yellow.(B) FDA-approved unique combinations. Data compiled and verified using the United States Drugs@FDA resource. DPP4i, Dipeptidyl peptidase 4 (DPP4) inhibitor; GLP-1Ra, Glucagon-like peptide-1 (GLP-1) receptor agonist; SGLT2i, Sodium-glucose co-transporter-2 (SGLT2) inhibitor; SU, Sulfonylureas; TZD, Thiazolinediones.
FIGURE 2
FIGURE 2
Agents in clinical development.(A) The ∼100 antihypertensive agents in clinical development include both biological agents and small molecule therapies. A high number of novel targets (i.e., targets that have not been validated through the approval an FDA-approval antidiabetic agent) are being investigated in clinical development. Novel targets include both single targets and unique combination regimens in trials.(B) ∼375 clinical studies associated with the investigative agents have been registered. A surprising number of agents are in phase 3 trials, indicating that more approvals may occur in the near future. Ten studies were not included as they did not have a phase identified.(C) The 121 active trials include registrations that have these statuses:active, not recruiting; enrolling by invitation; not yet recruiting; andrecruiting as all of these are soon-to-be active. The 44 not active trials include studies withsuspended, terminated, unknown, and withdrawn status.
FIGURE 3
FIGURE 3
FDA-approved drug classes per year.(A) Timeline of the major classes of antihypertensive drugs that have approved including monotherapies (mono) and combinations (comb). DPP4, Dipeptidyl peptidase 4; GLP-1R, Glucagon-like peptide-1 (GLP-1) receptor; SGLT2, Sodium-glucose co-transporter-2; SU, Sulfonylureas; TZD, Thiazolinediones.(B) The proportion of combination regimens in comparison to monotherapies that have been approved each year. The use of agents in two and three combination regimens is increasing as treatment options expand to target multiple facets of diabetes pathophysiology.
FIGURE 4
FIGURE 4
The molecular targets of the 99 anti-diabetic agents in clinical trials. The phase status is the highest clinical phase each agent has achieved. A surprising number clinical agents–nearly half–target novel molecular targets or combination regimens. Novel targets or pathways are those that have not yet been validated through approval of an FDA-approved drug for treatment of diabetes. Approximately half of the agents target already established pathways, i.e., molecular targets that have been validated through the FDA-approval of an agent targeting that pathway for the treatment of diabetes. Six of the agents had an undisclosed mechanism of action. DPP4, Dipeptidyl peptidase 4; GLP-1R, Glucagon-like peptide-1 (GLP-1) receptor; SGLT2, Sodium-glucose co-transporter-2; TZD, Thiazolinediones; GCGR, Glucagon receptor; GPR119, Glucose-dependent insulinotropic receptor (G-Protein coupled receptor 119); GR, Glucocorticoid receptor; GIPR, Gastric Inhibitory Polypeptide Receptor; GCK, glucokinase; AMPK, 5′-AMP-activated protein kinase.
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