
==== Front
BMJ Open Diabetes Res Care
BMJ Open Diabetes Res Care
bmjdrc
bmjdrc
BMJ Open Diabetes Research & Care
2052-4897
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39214626
10.1136/bmjdrc-2024-004291
bmjdrc-2024-004291
Review
Emerging Technologies, Pharmacology and Therapeutics
Glucokinase activators and imeglimin: new weaponry in the armamentarium against type 2 diabetes
http://orcid.org/0000-0002-5274-9748
Sjöholm Åke 12ake.sjoholm@regiongavleborg.se

1 University of Gävle, Gavle, Sweden
2 Department of Internal Medicine, Region Gävleborg, Gavle, Sweden
Professor; ake.sjoholm@regiongavleborg.se
ÅS has received lecture and consultancy fees from Boehringer-Ingelheim, Novo Nordisk, Novartis, Amarin, MSD, Lilly, Amgen, Bayer, Astrazeneca, Sanofi, Abbott Diabetes Care, Grünenthal Nordic, and Pfizer.

2024
30 8 2024
12 4 e00429125 4 2024
10 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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.

Diabetes Mellitus, Type 2
Glucokinase
Diabetes Complications
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pmcIntroduction

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 >1.3 billion people globally suffering from diabetes.1 T2D was previously called elderly-onset diabetes because the prevalence increases with increasing age. However, this designation is now obsolete as the disease is striking ever-younger individuals. Recent reports have shown alarmingly rapid β-cell dysfunction and the rapid onset of aggressive angiopathic complications among patients with childhood-onset T2D,24 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 hyperglycemia 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 production6), 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.

Table 1 Currently approved antidiabetic agents

Class	Drugs	MoA	Glucose lowering	Body weight	CVD effects	Side effects	Hypoglycemia risk*	References	
Sulfonylureas and meglitinides	Glimepiride, glipizide, gliclazide, glibenclamide, repaglinide, nateglinide, mitiglinide	Stimulation of insulin secretion	+++	Increase	No	Weight gain	Yes	8 11	
Biguanides	Metformin	Inhibition of hepatic glucose production	+++	Neutral	Weak	Gastrointestinal, lactic acidosis	No	12 16	
α-Glucosidase inhibitors	Acarbose, miglitol, voglibose	Inhibition of intestinal carbohydrate uptake	+	Decrease	Unclear	Gastrointestinal	No	9 17 18	
Thiazolidinediones	Pioglitazone, rosiglitazone lobeglitazone, janagliflozin	Stimulation of glucose uptake	+++	Increase	Yes	Edema, fractures	No	19 22	
GLP-1 receptor agonists	Liraglutide, exenatide, dulaglutide, semaglutide, lixisenatide, tirzepatide†	Multiple, see text	++++	Decrease	Yes	Gastrointestinal	No	23 30	
DPP-4 inhibitors	Sitagliptin, linagliptin, vildagliptin, saxagliptin, alogliptin, anagliptin, evogliptin, gemigliptin, gosogliptin,	Elevation of endogenous GLP-1 levels	+	Neutral	No	Uncommon	No	23 24	
SGLT-2 inhibitors	Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, sotagliflozin, bexagliflozin, ipragliflozin,	Increased urinary glucose excretion	++++	Decrease	Yes	Genitourinary infections	No	31 35	
Insulin		Stimulation of glucose uptake	+++++	Increase	No	Weight gain	Yes	5 9	
Amylin receptor agonists	Pramlintide	Slowing of gastric emptying, increase in satiety	++	Decrease	No	Nausea	No	81	
Dopamine receptor agonists	Bromocriptine	Activation of dopamine receptors	+	Neutral	No	Nausea	No	82	
Bile acid sequestrants	Colesevelam	Increase in GLP-1 secretion	+	Neutral	No	Bloating, constipation, heartburn, abdominal pain	No	83	
The Table lists the different classes of antidiabetic drugs and examples within each class of specific agents approved at any market are listed. The mechanism of action (MoA) and side effects of each class are described summarily.

Glucose-lowering potency: +, weak/modest; ++, marked; +++, strong; ++++, very strong; +++++, extremely strong. See text for details.

* In monotherapy.

† Also activates the GIP receptor.

CVDcardiovascular diseaseDPP-4dipeptidyl peptidase-4GLP-1glucagon-like peptide-1SGLT-2sodium-glucose cotransporter 2

The traditional oral antidiabetic drugs (sulfonylureas and meglitinides,811 biguanides,1216 α-glucosidase inhibitors,9 17 18 and thiazolidinediones1922) have been the subject of excellent reviews. Below, I briefly describe three classes of antidiabetic agents that are frequently and increasingly used against T2D and which hold great promise in terms of vascular protection.

Glucagon-like peptide-1-based agents

Glucagon-like peptide-1 (GLP-1)-based drugs offer a novel approach to T2D management by enhancing insulin secretion, suppressing glucagon release, slowing gastric emptying, and promoting satiety without causing hypoglycemia.23 24

GLP-1-based therapy, including GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, targets the incretin system to regulate glucose homeostasis. GLP-1RAs mimic the effects of endogenous GLP-1 by activating GLP-1 receptors, while DPP-4 inhibitors prolong the half-life of GLP-1.23 24

Numerous clinical trials have demonstrated the efficacy of GLP-1RAs in reducing HbA1c levels, promoting weight loss, and lowering the risk of hypoglycemia in patients with T2D.23 24 Studies such as the LEADER and SUSTAIN trials have highlighted the cardiovascular benefits of GLP-1RAs, including reductions in major adverse cardiovascular events.2528

GLP-1-based agents are generally well tolerated, with gastrointestinal side effects such as nausea, vomiting, and diarrhea being the most common adverse reactions, particularly with GLP-1RAs, but these usually disappear after a few weeks. Rare but serious complications, including pancreatitis, have been reported, necessitating careful patient monitoring.23 24

Tirzepatide is a once weekly injectable medication that acts as a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, addressing basically the same pathogenic factors of diabetes as GLP-1 (see above), but with a higher potency.29

Clinical trials have demonstrated the efficacy of tirzepatide in reducing HbA1c levels, promoting weight loss, and improving cardiovascular risk factors in patients with T2D.29 30

Sodium-glucose cotransporter 2 inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors act by inhibiting SGLT2 in the proximal renal tubules, thereby increasing urinary glucose excretion. This results in a net loss of glucose and calories, leading to improved glycemic control and weight loss.31

Clinical trials have demonstrated the efficacy of SGLT2 inhibitors in reducing HbA1c levels, promoting weight loss, and lowering blood pressure in patients with T2D. Large cardiovascular outcome trials such as EMPA-REG OUTCOME and CANVAS have shown significant reductions in cardiovascular events and renal outcomes.3234

SGLT2 inhibitors are generally well tolerated, with common side effects including genital mycotic infections and urinary tract infections. Rare but serious complications such as euglycemic diabetic ketoacidosis and acute kidney injury have been reported with SGLT2 inhibitor use, necessitating careful patient selection.35

Insulin

Due to the progressive loss of insulin-producing β-cells in T2D,7 21 many patients with long-standing diabetes ultimately require supplemental insulin therapy to control their glycemia. While necessary, this comes with the price of increased risk for hypoglycemia (particularly in elderly, frail, and lean patients) and weight gain.

Traditionally, insulin therapy in T2D has been in the form of adding bedtime NPH-(Neutral Protamine Hagedorn) insulin or long-acting insulin analogs. If the patient has become severely insulin deficient (as reflected by low C-peptide levels), thus resembling type 1 diabetes, the addition of short-acting meal-time insulin analogs may be required.

Notwithstanding the unlimited hypoglycemic potential of insulin, with no maximum doses, in contemporary clinical practice, addition of insulin has become the last resort to control glycemia in T2D when other drugs have failed. Nonetheless, temporarily switching to insulin can be very useful in transient situations in patients with T2D, such as severe hyperglycemia with/without ketosis, pregnancy, glucocorticoid therapy, and during/after surgery.

Newly approved novel classes of antidiabetic agents

The latest class of antidiabetic drugs, SGLT2 inhibitors, was launched >10 years ago. However, there remains a very great medical need for new treatment modalities, preferably with disease-modifying potential. Recently, two novel classes have been approved for clinical use, glucokinase activators (GKAs) and imeglimin, which will be described in detail below.

Glucokinase activators

Glucokinase (aka, hexokinase 4) is a glycolytic enzyme of critical importance in controlling glucose flux in both islet β-cells and hepatocytes for maintenance of normoglycemia by catalyzing the phosphorylation of glucose to glucose-6-phosphate necessary for energy production and cellular homeostasis. Glucokinase is considered the primary glucose “sensor” in β-cells and is thus crucial in rapidly transducing the metabolic signals into finely tuned rates of insulin secretion.36 In contrast to the other three hexokinases, glucokinase reaches half-maximal enzymatic activity at a plasma concentration of glucose ~8 mmol/L. This is of pathophysiological significance as it will promote insulin secretion preferably during hyperglycemia and reduce the risk of hypoglycemia, a therapeutically desirable effect resembling that of GLP-1RAs. In islet α-cells, activation of glucokinase by glucose results in reduced glucagon secretion, another beneficial treatment effect in T2D.37 Interestingly, decreased glucokinase expression has been found in islets and liver in T2D.38 In pancreatic β-cells, not only glucose but also GLP-1 promotes insulin secretion in part by activating glucokinase.39 Glucokinase is also expressed in GLP-1-producing enteroendocrine L-cells; however, the enzyme seems not to be required for glucose-stimulated GLP-1 release.40

Heterozygous loss-of-function mutations in the glucokinase gene are also known to be the cause of a monogenic form of diabetes, GCK-MODY (previously called MODY241). Conversely, gain-of-function mutations in the glucokinase gene result in insulin hypersecretion and hypoglycemia.41

From the above, it may be inferred that glucokinase would constitute an enticing antidiabetic target for drugs aimed at activating the enzyme. Indeed, such efforts have been under way since the 1990s and met with mixed, but overall disappointing, results for the early drug candidates.38 42

GKAs are oral low-molecular-weight drugs that allosterically activate glucokinase.38 42 In doing so, insulin secretion from the pancreas is increased and hepatic glucose production is reduced through enhanced glycogen synthesis. Thus, these two mechanisms contribute to improving glycemia by GKA treatment.

The results of clinical trials with first-generation GKAs were generally not encouraging and characterized by significant setbacks such as hypoglycemia, loss of sustained antidiabetic effects, hepatic steatosis, hypertriglyceridemia, hypertension, and other harmful side effects.36 38 Consequently, many of these early drug candidates (eg, piragliatin, ASD1656, ARRY403, and PSN010) were discontinued from further development as they did not pass muster in clinical trials.36 38 43

However, recent years have witnessed a renewed interest in improved and organ-selective GKAs, which are either full or partial activators of the enzyme.4451 Among the new-generation GKAs are dorzagliatin, a full dual-acting agent that targets both pancreatic and hepatic glucokinase5256 and TTP399 (aka, cadisegliatin), which is hepatoselective and also in clinical trials as an adjunct to insulin in type 1 diabetes.57

The first, and as of yet the only, GKA to be approved for clinical use is dorzagliatin, which in 2022 received approval in China for use in adult patients with T2D, either as monotherapy or as an add-on to metformin.58 Dorzagliatin was produced by Roche from which Hua Medicine in China licensed it in 2011.

In early-phase clinical studies, dorzagliatin was found to improve early-phase insulin secretion, stimulate GLP-1 secretion, and act in synergy with sitagliptin and empagliflozin in lowering HbA1c levels.54 55

Two pivotal prospective clinical trials formed the basis for regulatory approval of dorzagliatin: the Study for Early Evaluation of Dorzagliatin (SEED) study with dorzagliatin as monotherapy59 and the Dorzagliatin, A New Treatment Option for People with Type 2 Diabetes (DAWN) study in which dorzagliatin was used in combination with metformin.60

The SEED study was a randomized, double-blind, placebo-controlled phase III trial in which a total of 463 adult drug-naive newly diagnosed T2D patients with a BMI of 18.5–35 kg/m2 and an HbA1c of 7.5–10% (DCCT [Diabetes Control and Complications Trial] standard) were randomized to a 24-week double-blind treatment with either placebo or dorzagliatin (75 mg two times per day) followed by 28 weeks of open-label treatment with dorzagliatin for all patients.59 At 24 weeks, the SEED trial met its primary endpoint, a change from baseline HbA1c (−1.07% for dorzagliatin vs −0.5% for placebo). While the estimated treatment difference in HbA1c (0.57 %) between the groups was statistically significant (p<0.001), it was numerically modest and—in comparison to other antidiabetic drugs—clinically less than impressive. The effect of dorzagliatin on HbA1c was paralleled by corresponding changes in fasting and postprandial glycemia. Dorzagliatin was well tolerated and, in contrast to early GKAs, no increase in hypoglycemic events by dorzagliatin was noted and no major changes in body weight were reported.59

The DAWN study was a randomized, double-blind, placebo-controlled phase III trial in which a total of 767 adult patients with T2D with a BMI of 18.5–35 kg/m2 who had inadequate glycemic control (HbA1c levels between 7.5% and 10%) despite treatment with metformin were randomized to a 24-week treatment with either placebo or dorzagliatin (75 mg two times per day) as an add-on to metformin.60 At 24 weeks, the DAWN trial met its primary endpoint, a change from baseline HbA1c (−1.02% for dorzagliatin vs −0.36% for placebo), thus an estimated treatment difference in HbA1c of 0.66% between the groups. Again, while statistically significant, this effect is rather modest. As in the SEED study, dorzagliatin was well tolerated, no increase in severe hypoglycemia was noted, and body weight was not affected by dorzagliatin.60

In a small pilot trial with GCK-MODY patients,61 dorzagliatin was given as a single oral dose (75 mg) and was found to improve β-cell glucose sensitivity and enhance insulin secretion, thus demonstrating proof-of-concept for its mechanism of action in these patients. It remains to be determined whether these effects translate into long-term and sustained improvements in glycemia after chronic treatment in GCK-MODY patients. Thus, dorzagliatin may prove valuable in the treatment of patients with GCK-MODY, which would align logically with its mechanism of action. However, it should be recognized that GCK-MODY, while constituting a significant proportion of monogenic diabetes, unlike T2D, has a benign and asymptomatic phenotype characterized by mild fasting hyperglycemia, a nonprogressive course, usually does not cause angiopathic complications, and rarely if ever requires pharmacological treatment.41 Also, homozygous loss-of-function mutations in the glucokinase gene, causing severe neonatal diabetes (GCK-PNDM), are exceedingly rare.62

All of the above relies on the premise that glucokinase activation confers long-term benefits to the β-cell in diabetes. This rationale was recently conceptually challenged63 based on the hypothesis that activation of glucose metabolism by GKAs might evoke detrimental effects on the β-cell by chronic overstimulation. Such an effect would be akin to the known deleterious effects of chronic hyperglycemia (glucose toxicity)64 and long-term sulfonylurea treatment21 on the β-cell. Mechanistically, based on experimental findings, the increase in glucose-6-phosphate—a known allosteric activator of glycogen synthase and inhibitor of glycogen phosphorylase—would serve to promote β-cell accumulation of glycogen that would induce apoptotic death of the β-cell.63

Irrespective of whether the above concern will play out in clinical reality as accelerated loss of β-cell function, several other outstanding issues need to be addressed. Glucokinase is not only expressed in pancreatic β-cells and hepatocytes but also in other tissues such as glucose-sensitive neurons in the CNS.50 The long-term effects of GKAs remain unknown but will require scrutiny. Additionally, the clinical trials referred to above were done in a relatively short time (24 weeks) in patients with newly diagnosed diabetes and it remains to be studied how effective GKAs are in improving glycemia in patients with long-standing T2D and whether they will modify the disease progression (ie, loss of insulin production) positively or negatively in the long-term (>10 years).

As these are new drugs, only time will tell to what extent clinically approved GKAs 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. The latter is especially important in view of the disconcerting atherogenic side effects (hypertriglyceridemia, hypertension, and hepatic steatosis) of certain GKAs that have led to their discontinuation.38 43 It is worth noting that the increase in blood triglycerides by dorzagliatin was similar to that by earlier GKAs that were discontinued (eg, AZD165647). Loss of sustained effect on HbA1c appears to be the main distinguishing feature between dorzagliatin and the GKAs that were discontinued. However, whether this is due to the properties of the GKA or the substantially lower BMI of the dorzagliatin trials is unknown.

The main features of GKAs are summarized in table 2.

Table 2 Newly approved antidiabetic agents

Class	Drugs	MoA	Glucose lowering	Body weight	CVD effects	Side effects	Hypoglycemia risk*	References	
Glucokinase activators	Dorzagliatin	Stimulation of insulin secretion, inhibition of hepatic glucose production	+	Neutral	No	Hepatic steatosis, hypertriglyceridemia, hypertension	No?	44 51	
Imeglimin	Imeglimin	Inhibition of hepatic glucose production, stimulation of insulin secretion	+	Neutral	No	Gastrointestinal	No	65 69	
The Table lists the different classes of antidiabetic drugs and examples within each class of specific agents approved at any market are listed. The mechanism of action (MoA) and side effects of each class are described summarily.

Glucose-lowering potency: +, weak/modest. See text for details.

* In monotherapy.

CVDcardiovascular disease

Imeglimin

Imeglimin, a first-in-class oral antidiabetic agent, has garnered significant attention for its attractive mechanisms of action and potential clinical benefits in T2D.6569 Imeglimin—which shares structural similarities with metformin—targets mitochondrial dysfunction, a hallmark of T2D pathophysiology, with the potential to address multiple facets of the disease process. Imeglimin modulates mitochondrial bioenergetics by inhibiting mitochondrial complex I (similar to metformin70 71), thereby activating AMPK through changes in the ATP/AMP ratio, and exerting pleiotropic effects on cellular metabolism.72 Its mechanism involves inhibition of mitochondrial permeability transition pore opening and enhancement of mitochondrial function, collectively contributing to enhanced insulin secretion, reduced hepatic gluconeogenesis, and improved glucose utilization and insulin sensitivity in skeletal muscle.68 69 72 By restoring mitochondrial function and reducing cellular stress, imeglimin enhances glucose metabolism and augments pancreatic β-cell function.7375 Preclinical studies have suggested that imeglimin may exert protective effects on β-cells, preventing their dysfunction and apoptosis in conditions of glucotoxicity and lipotoxicity commonly observed in T2D.7375 If this also proves to be the case in humans on long-term imeglimin treatment, the drug may help to maintain long-term glycemic control and delay the progression of T2D.

Clinical trials have demonstrated the efficacy and safety of imeglimin as monotherapy and combination therapy in reducing HbA1c levels, fasting plasma glucose concentrations, and postprandial glucose excursions.76 Studies such as the Trials of Imeglimin for Efficacy and Safety (TIMES) trials have shown consistent improvements in glycemic control with imeglimin compared with placebo or active comparators. The TIMES program consists of several phase 2 and phase 3 clinical trials evaluating imeglimin in patients with T2D. These trials investigate the efficacy and safety of imeglimin as monotherapy or in combination with other antidiabetic agents, such as metformin or insulin.

TIMES 1, TIMES 2, and TIMES 3 were phase 3 clinical trials that assessed the efficacy and safety of imeglimin as monotherapy or in combination with other antidiabetic agents in patients with T2D. The trials evaluated different doses and treatment regimens of imeglimin and compared them with placebo or active comparators.

TIMES 1 was a randomized, double-blind trial conducted on 213 adult (mean age 62 years) Japanese subjects with T2D and an HbA1c between 7.0% and 10.0%. In TIMES 1, imeglimin (1000 mg two times per day) was superior to placebo in lowering HbA1c after 24 weeks of treatment, with an estimated treatment difference in HbA1c of 0.87% between the groups.77

In TIMES 2, which was a 52-week, open-label, parallel-group trial, imeglimin (1000 mg two times per day) was given to 714 adult Japanese subjects with T2D, either as monotherapy or on top of oral or injectable antidiabetic agents. The decreases in HbA1c levels from baseline at 52 weeks of combination treatment with imeglimin and the other drugs were: 0.67% (metformin), 0.56% (SUs), 0.70% (meglitinides), 0.85% (AGIs), 0.88% (TZDs), 0.57% (SGLT2 inhibitors), 0.92% (DPP4 inhibitors), 0.12% (GLP-1R agonists), and 0.46% (imeglimin in monotherapy).78 Thus, while the HbA1c-lowering effect of imeglimin was modest, there were additive effects by certain combinations of the drugs.

In TIMES 3, the effects of imeglimin (1000 mg two times per day) as an add-on to insulin monotherapy were studied in 215 adult Japanese subjects with inadequately controlled T2D. TIMES 3 consisted of a 16-week, double-blind, placebo-controlled randomized clinical trial, followed by a 36-week open-label extension phase (without placebo). Treatment with imeglimin was superior to placebo in lowering HbA1c from baseline after 16 weeks of treatment with an estimated treatment difference in HbA1c of 0.60% between the groups.79 In the subsequent 36-week open-label phase, the decrease in HbA1c by imeglimin observed at week 16 was maintained at week 52.79

Common side effects of imeglimin include gastrointestinal symptoms such as nausea and diarrhea, which tend to be transient and diminish over time. Notably, imeglimin has demonstrated minimal risk of hypoglycemia or weight gain, enhancing its appeal as a therapeutic option for T2D.76 Given that imeglimin shares with metformin inhibition of mitochondrial complex I,7072 which enhances lactate production, it is possible that lactic acidosis may become a serious, although rare, side effect also of imeglimin.

Imeglimin (brand name Twymeeg) was approved by Japanese regulatory agencies in 2021 for clinical use in T2D.80 Imeglimin represents a promising addition to the therapeutic armamentarium for T2D, offering an attractive approach to addressing mitochondrial dysfunction and metabolic abnormalities underlying the disease. Its favorable efficacy, safety profile, and potential for synergistic effects with existing therapies thus position it as a promising candidate for improving outcomes in patients with T2D.66 72 The preservative and protective effects of imeglimin on β-cells noted in preclinical models are very appealing as it may have the potential to modify the progressive natural course of T2D with its relentless loss of functional β-cell mass. As with all new drugs, however, the final judgment must await long-term data on efficacy, safety, disease modification potential, and organ protection.

The main features of imeglimin are summarized in table 2.

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 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.

Data availability statement

Data sharing not applicable as no datasets generated and/or analyzed for this study. No data are available.

Funding: The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Data availability free text: This is a review paper.

Patient consent for publication: Not applicable.

Ethics approval: Not applicable.

Provenance and peer review: Not commissioned; externally peer reviewed.
==== Refs
References

1 GBD 2021 Diabetes Collaborators Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021 Lancet 2023 402 203 34 10.1016/S0140-6736(23)01301-6 37356446
2 Dabelea D Mayer-Davis EJ Saydah S et al Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009 JAMA 2014 311 1778 86 10.1001/jama.2014.3201 24794371
3 Temple KA Tjaden AH Atkinson KM et al Association of Habitual Daily Physical Activity With Glucose Tolerance and β-Cell Function in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes From the Restoring Insulin Secretion (RISE) Study Diabetes Care 2019 42 1521 9 10.2337/dc19-0538 31177181
4 Magliano DJ Sacre JW Harding JL et al Young-onset type 2 diabetes mellitus - implications for morbidity and mortality Nat Rev Endocrinol 2020 16 321 31 10.1038/s41574-020-0334-z 32203408
5 Dahlén AD Dashi G Maslov I et al Trends in Antidiabetic Drug Discovery: FDA Approved Drugs New Drugs Clin Trials Glob Sales Front Pharmacol 2022 12 807548 10.3389/fphar.2021.807548
6 Roden M Shulman GI The integrative biology of type 2 diabetes Nature New Biol 2019 576 51 60 10.1038/s41586-019-1797-8
7 U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group Diabetes 1995 44 1249 58 10.2337/diabetes.44.11.1249 7589820
8 Davies MJ D’Alessio DA Fradkin J et al Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care 2018 41 2669 701 10.2337/dci18-0033 30291106
9 DeFronzo RA Pharmacologic therapy for type 2 diabetes mellitus Ann Intern Med 1999 131 281 303 10.7326/0003-4819-131-4-199908170-00008 10454950
10 Ashcroft FM Rorsman P K(ATP) channels and islet hormone secretion: new insights and controversies Nat Rev Endocrinol 2013 9 660 9 10.1038/nrendo.2013.166 24042324
11 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998 352 837 53 10.1016/S0140-6736(98)07019-6 9742976
12 Bailey CJ Turner RC Metformin N Engl J Med 1996 334 574 9 10.1056/NEJM199602293340906 8569826
13 Zhou G Myers R Li Y et al Role of AMP-activated protein kinase in mechanism of metformin action J Clin Invest 2001 108 1167 74 10.1172/JCI13505 11602624
14 Rena G Hardie DG Pearson ER The mechanisms of action of metformin Diabetologia 2017 60 1577 85 10.1007/s00125-017-4342-z 28776086
15 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) The Lancet 1998 352 854 65 10.1016/S0140-6736(98)07037-8
16 Triggle CR Mohammed I Bshesh K et al Metformin: Is it a drug for all reasons and diseases? Metab Clin Exp 2022 133 155223 10.1016/j.metabol.2022.155223 35640743
17 Holman RR Cull CA Turner RC A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44) Diabetes Care 1999 22 960 4 10.2337/diacare.22.6.960 10372249
18 Chiasson J-L Josse RG Gomis R et al Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial Lancet 2002 359 2072 7 10.1016/S0140-6736(02)08905-5 12086760
19 DeFronzo RA Inzucchi S Abdul-Ghani M et al Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes Diab Vasc Dis Res 2019 16 133 43 10.1177/1479164118825376 30706731
20 Di Pino A DeFronzo RA Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents Endocr Rev 2019 40 1447 67 10.1210/er.2018-00141 31050706
21 Kahn SE Haffner SM Heise MA et al Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy N Engl J Med 2006 355 2427 43 10.1056/NEJMoa066224 17145742
22 Dormandy JA Charbonnel B Eckland DJA et al Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Lancet 2005 366 1279 89 10.1016/S0140-6736(05)67528-9 16214598
23 Tschöp M Nogueiras R Ahrén B Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy Diabetologia 2023 66 1796 808 10.1007/s00125-023-05929-0 37209227
24 Drucker DJ Holst JJ The expanding incretin universe: from basic biology to clinical translation Diabetologia 2023 66 1765 79 10.1007/s00125-023-05906-7 36976349
25 Ussher JR Drucker DJ Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action Nat Rev Cardiol 2023 20 463 74 10.1038/s41569-023-00849-3 36977782
26 Drucker DJ Prevention of cardiorenal complications in people with type 2 diabetes and obesity Cell Metab 2024 36 338 53 10.1016/j.cmet.2023.12.018 38198966
27 Marso SP Daniels GH Brown-Frandsen K et al Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med 2016 375 311 22 10.1056/NEJMoa1603827 27295427
28 Marso SP Bain SC Consoli A et al Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes N Engl J Med 2016 375 1834 44 10.1056/NEJMoa1607141 27633186
29 Karagiannis T Avgerinos I Liakos A et al Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis Diabetologia 2022 65 1251 61 10.1007/s00125-022-05715-4 35579691
30 Frías JP Davies MJ Rosenstock J et al Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes N Engl J Med 2021 385 503 15 10.1056/NEJMoa2107519 34170647
31 Marilly E Cottin J Cabrera N et al SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits Diabetologia 2022 65 2000 10 10.1007/s00125-022-05773-8 35925319
32 Zinman B Wanner C Lachin JM et al Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes N Engl J Med 2015 373 2117 28 10.1056/NEJMoa1504720 26378978
33 Neal B Perkovic V Mahaffey KW et al Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes N Engl J Med 2017 377 644 57 10.1056/NEJMoa1611925 28605608
34 Wiviott SD Raz I Bonaca MP et al DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med 2019 380 347 57 10.1056/NEJMoa1812389 30415602
35 Rosenstock J Ferrannini E Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors Diabetes Care 2015 38 1638 42 10.2337/dc15-1380 26294774
36 Matschinsky FM Assessing the potential of glucokinase activators in diabetes therapy Nat Rev Drug Discov 2009 8 399 416 10.1038/nrd2850 19373249
37 Basco D Zhang Q Salehi A et al α-cell glucokinase suppresses glucose-regulated glucagon secretion Nat Commun 2018 9 546 10.1038/s41467-018-03034-0 29416045
38 Matschinsky FM GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci 2013 34 90 9 10.1016/j.tips.2012.11.007 23305809
39 Ding SY Nkobena A Kraft CA et al Glucagon-like peptide 1 stimulates post-translational activation of glucokinase in pancreatic beta cells J Biol Chem 2011 286 16768 74 10.1074/jbc.M110.192799 21454584
40 Murphy R Tura A Clark PM et al Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor Diabetologia 2009 52 154 9 10.1007/s00125-008-1183-9 18974968
41 Bonnefond A Unnikrishnan R Doria A et al Monogenic diabetes Nat Rev Dis Primers 2023 9 12 10.1038/s41572-023-00421-w 36894549
42 Thilagavathi R Hosseini-Zare MS Malini M et al A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes Chem Biol Drug Des 2022 99 247 63 10.1111/cbdd.13979 34714587
43 Meininger GE Scott R Alba M et al Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes Diabetes Care 2011 34 2560 6 10.2337/dc11-1200 21994424
44 Haddad D Dsouza VS Al-Mulla F et al New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment Int J Mol Sci 2024 25 571 10.3390/ijms25010571 38203742
45 Ren Y Li L Wan L et al Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists J Enzyme Inhib Med Chem 2022 37 606 15 10.1080/14756366.2021.2025362 35067153
46 Sharma P Singh S Sharma N et al Targeting human Glucokinase for the treatment of type 2 diabetes: an overview of allosteric Glucokinase activators J Diabetes Metab Disord 2022 21 1129 37 10.1007/s40200-022-01019-x 35673438
47 Gao Q Zhang W Li T et al The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus: A meta-analysis Medicine (Baltimore) 2021 100 e27476 10.1097/MD.0000000000027476 34622877
48 Yang W Wu H Cai X et al Evaluation of efficacy and safety of glucokinase activators—a systematic review and meta-analysis Front Endocrinol 2023 14 1175198 10.3389/fendo.2023.1175198
49 Kaur U Pathak BK Meerashahib TJ et al Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far Clin Drug Investig 2024 44 223 50 10.1007/s40261-024-01351-5
50 Li W Zhang X Sun Y et al Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2 Pharmazie 2020 75 230 5 10.1691/ph.2020.0409 32539915
51 Li P Zhu D Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes J Diabetes 2024 16 e13544 10.1111/1753-0407.13544 38664885
52 Dutta D Khandelwal D Kumar M et al Efficacy and safety of novel dual glucokinase activator dorzagliatin in type-2 diabetes a meta-analysis Diabetes Metab Syndr Clin Res Rev 2023 17 102695 10.1016/j.dsx.2022.102695
53 Wu Y Wang K Su J et al Efficacy and safety of dorzagliatin, a novel glucokinase activators, in the treatment of T2DM: A meta-analysis of randomized controlled trials Medicine (Abingdon) 2024 103 e36916 10.1097/MD.0000000000036916
54 Zhu X Zhu D Li X et al Dorzagliatin (HMS5552), a novel dual‐acting glucokinase activator, improves glycaemic control and pancreatic β‐cell function in patients with type 2 diabetes: A 28‐day treatment study using biomarker‐guided patient selection Diabetes Obesity Metabolism 2018 20 2113 20 10.1111/dom.13338 29707866
55 Wang Y Su X Zhang W et al Effects of a Novel Glucokinase Activator, Dorzagliatin, on Glycemic Control and Glucose Fluctuation in Drug-Naïve Patients with Type 2 Diabetes Mellitus Int J Endocrinol 2023 2023 4996057 10.1155/2023/4996057 38179187
56 Lin F He R Ling B et al Dorzagliatin for Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Phase II/III Trials Clin Ther 2023 45 1277 83 10.1016/j.clinthera.2023.09.011 37777375
57 Egan A Vella A TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes Expert Opin Investig Drugs 2019 28 741 7 10.1080/13543784.2019.1654993
58 Syed YY Dorzagliatin: First Approval Drugs (Abingdon Engl) 2022 82 1745 50 10.1007/s40265-022-01813-0
59 Zhu D Li X Ma J et al Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial N Med 2022 28 965 73 10.1038/s41591-022-01802-6
60 Yang W Zhu D Gan S et al Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial Nat Med 2022 28 974 81 10.1038/s41591-022-01803-5 35551292
61 Chow E Wang K Lim CKP et al Dorzagliatin, a Dual-Acting Glucokinase Activator Diabetes 2023 72 299 308 10.2337/db22-0708 36342518
62 Njølstad PR Søvik O Cuesta-Muñoz A et al Neonatal diabetes mellitus due to complete glucokinase deficiency N Engl J Med 2001 344 1588 92 10.1056/NEJM200105243442104 11372010
63 Ashcroft FM Lloyd M Haythorne EA Glucokinase activity in diabetes: too much of a good thing? Trends Endocrinol Metab 2023 34 119 30 10.1016/j.tem.2022.12.007 36586779
64 Weir GC Glucolipotoxicity, β-Cells, and Diabetes: The Emperor Has No Clothes Diabetes 2020 69 273 8 10.2337/db19-0138 31519699
65 Konkwo C Perry RJ Imeglimin: Current Development and Future Potential in Type 2 Diabetes Drugs (Abingdon Engl) 2021 81 185 90 10.1007/s40265-020-01434-5
66 Huston J Schaffner H Langley L et al Imeglimin in type 2 diabetes Drugs Today (Barc) 2022 58 437 49 10.1358/dot.2022.58.9.3419555 36102904
67 Shrestha SC Gupta S Imeglimin: the New Kid on the Block Curr Diab Rep 2024 24 13 8 10.1007/s11892-023-01531-1 38051432
68 Doupis J Baris N Avramidis K Imeglimin: A New Promising and Effective Weapon in the Treatment of Type 2 Diabetes touchREV Endocrinol 2021 17 88 91 10.17925/EE.2021.17.2.88 35118453
69 Vuylsteke V Chastain LM Maggu GA et al Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes Drugs R D 2015 15 227 32 10.1007/s40268-015-0099-3 26254210
70 El-Mir MY Nogueira V Fontaine E et al Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I J Biol Chem 2000 275 223 8 10.1074/jbc.275.1.223 10617608
71 Owen MR Doran E Halestrap AP Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain Biochem J 2000 348 Pt 3 607 14 10839993
72 Hallakou-Bozec S Vial G Kergoat M et al Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes Diabetes Obes Metab 2021 23 664 73 10.1111/dom.14277 33269554
73 Li J Inoue R Togashi Y et al Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway Diabetes 2022 71 424 39 10.2337/db21-0123 34588186
74 Pacini G Mari A Fouqueray P et al Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes Diabetes Obes Metab 2015 17 541 5 10.1111/dom.12452 25694060
75 Fauzi M Murakami T Yabe D et al Current understanding of imeglimin action on pancreatic β-cells: Involvement of mitochondria and endoplasmic reticulum homeostasis J Diabetes Investig 2023 14 186 8 10.1111/jdi.13951
76 Singh AK Singh A Singh R et al Efficacy and safety of imeglimin in type 2 diabetes: A systematic review and meta-analysis of randomized placebo-controlled trials Diabetes Metab Syndr 2023 17 102710 10.1016/j.dsx.2023.102710 36702046
77 Dubourg J Fouqueray P Thang C et al Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial Diabetes Care 2021 44 952 9 10.2337/dc20-0763 33574125
78 Dubourg J Fouqueray P Quinslot D et al Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial Diabetes Obes Metab 2022 24 609 19 10.1111/dom.14613 34866306
79 Reilhac C Dubourg J Thang C et al Efficacy and safety of imeglimin add-on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): A randomized, double-blind, placebo-controlled phase 3 trial with a 36-week open-label extension period Diabetes Obes Metab 2022 24 838 48 10.1111/dom.14642 34984815
80 Lamb YN Imeglimin Hydrochloride: First Approval Drugs (Abingdon Engl) 2021 81 1683 90 10.1007/s40265-021-01589-9
81 Eržen S Tonin G Jurišić Eržen D et al Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity Int J Mol Sci 2024 25 1517 10.3390/ijms25031517 38338796
82 Dereje B Nardos A Dopamine 2 agonists for the management of type 2 diabetes: a systematic review and meta-analysis J Diabetes Metab Disord 2023 22 931 43 10.1007/s40200-023-01230-4 37975084
83 Nerild HH Christensen MB Knop FK et al Preclinical discovery and development of colesevelam for the treatment of type 2 diabetes Expert Opin Drug Discov 2018 13 1161 7 10.1080/17460441.2018.1538206 30336707
