Article Text
Abstract
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
Data availability statement
Data sharing not applicable as no datasets generated and/or analyzed for this study. No data are available. This is a review paper.
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/.
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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 >1.3 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,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 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.
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 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.25–28
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.32–34
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.44–51 Among the new-generation GKAs are dorzagliatin, a full dual-acting agent that targets both pancreatic and hepatic glucokinase52–56 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.
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.65–69 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.73–75 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.73–75 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,70–72 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. This is a review paper.
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Not applicable.
References
Footnotes
Contributors The author (ÅS) wrote and revised the manuscript and is the guarantor of this work.
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.
Competing interests 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.
Provenance and peer review Not commissioned; externally peer reviewed.