Glucokinase activators and imeglimin: new weaponry in the armamentarium against type 2 diabetes

Åke Sjöholm
1University of Gävle, Gavle, Sweden
2Department of Internal Medicine, Region Gävleborg, Gavle, Sweden

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BMJ Open Diab Res Care 2024;12:e004291. doi:10.1136/bmjdrc-2024-004291 1

From the article
SUMMARY
The prevalence of type 2 diabetes (T2D) is increasing relentlessly all over the world, in parallel with a similar increase in obesity, and is striking ever younger patients. Only a minority of patients with T2D attain glycemic targets, indicating a clear need for novel antidiabetic drugs that not only control glycemia but also halt or slow the progressive loss of β-cells.

Two entirely novel classes of antidiabetic agents—glucokinase activators and imeglimin—have recently been approved and will be the subject of this review.

• Allosteric activators of glucokinase, an enzyme stimulating insulin secretion in β-cells and suppressing hepatic glucose production, are oral low-molecular-weight drugs. One of these, dorzagliatin, is approved in China for use
in adult patients with T2D, either as monotherapy or as an add-on to metformin. It remains to be seen whether the drug will produce sustained antidiabetic effects over many years and whether the side effects that led to the discontinuation of early drug candidates will limit the usefulness of dorzagliatin.

• Imeglimin—which shares structural similarities with metformin—targets mitochondrial dysfunction and was approved in Japan against T2D. In preclinical studies, the drug has also shown promising β-cell protective and preservative effects that may translate into disease- modifying effects.

Hopefully, these two newcomers will contribute to filling the great medical need for new treatment modalities, preferably with disease-modifying potential. It remains
to be seen where they will fit in contemporary treatment algorithms, which combinations of drugs are effective and which should be avoided.

Time will tell to what extent these new antidiabetic agents will add value to
the current treatment options against T2D in terms of sustained antidiabetic effect, acceptable safety, utility in combination therapy, and impact on hard end-points such as cardiovascular disease.

INTRODUCTION
The diabetes epidemic
The prevalence of type 2 diabetes (T2D) is increasing relentlessly all over the world, in parallel with a similar increase in obesity. Recent estimates hold that, by the year 2050, there will be >1.3billion people glob- ally suffering from diabetes.1 T2D was previ- ously called elderly-onset diabetes because
the prevalence increases with increasing age. However, this designation is now obsolete as the disease is striking ever-younger individ- uals. Recent reports have shown alarmingly rapid β-cell dysfunction and the rapid onset of aggressive angiopathic complications among patients with childhood-onset T2D,2–4 calling for early and multifactorial treatment of these patients.

Current classes of antidiabetic drugs
There are currently nearly 60 FDA-approved antidiabetic agents and some 100 more in various stages of clinical trials.5 This quest reflects a great unmet medical need for drugs that ideally provide sustained antidiabetic effects with good tolerance and a minimum of side effects (and thereby high treatment compliance), efficaciously curb hyper- glycemia without causing hypoglycemia, promote weight loss instead of weight gain, stop or slow the relentless loss of β-cells (ie, disease-modifying agents), and afford robust protection against microangiopathic and macroangiopathic diabetes complications.

Since T2D is a multifactorial disease with several disparate and concurrent pathogenic mechanisms (eg, insulin resistance, β-cell failure, disproportionate glucagon excess, and unrestrained hepatic glucose produc- tion6), along with its progressive natural course,7 treatment with a combination of several antidiabetic drugs is usually required sooner or later. Despite this, a substantial proportion of patients with T2D fail to attain glycemic targets.
See table 1 for an overview of currently approved antidiabetic drug classes.

The traditional oral antidiabetic drugs (sulfonylureas and meglitinides,8–11 biguanides,12–16 α-glucosidase inhibitors,9 17 18 and thiazolidinediones19–22) have been the subject of excellent reviews. Below, I briefly describe three classes of antidiabetic agents that are frequently and increasingly used against

CONCLUSIONS
As more than 10 years have passed since the introduction of the latest class of antidiabetic drugs, the approval of two entirely novel drug classes is very welcome, especially since many of the current drugs are less than perfect in terms of efficacy and side effects, leaving many patients far above their glycemic targets. Hopefully, these newcomers will contribute to filling the great medical need for new treatment modalities, preferably with disease-modifying potential (ie, with protective and/or trophic effects on the β-cells).

It remains to be seen where they will fit in contemporary treatment algorithms and which combina- tions of drugs are effective and which should be avoided. Time will tell to what extent these new antidiabetic agents will add value to the current treatment options against T2D in terms of sustained antidiabetic effect, acceptable safety, utility in combination therapy, and impact on hard end-points such as cardiovascular disease.

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