Imeglimin – Current Development and Future Potential in Type 2 Diabetes

Abstract

Imeglimin is the first of a new class of drugs, “glimins,” developed for the treatment of type 2 diabetes (T2D). This review highlights its mechanism of action, and its context in the field of T2D treatment. Preclinical data in multiple rodent models detail significant effects on mitochondria, particularly improved mitochondrial bioenergetics. This includes changes favoring complex II and complex III metabolism, a mechanism potentially promoting increased fatty acid oxidation, leading to the decrease in hepatic lipid accumulation observed in these mice. Imeglimin was also shown to increase muscle glucose uptake and decrease hepatic glucose production both in vitro and in vivo. Though studies have also shown imeglimin to significantly improve insulin secretion and decrease beta cell death, the question of whether its physiologic effects are purely insulin-dependent is still unclear. Early preclinical studies have shown evidence for improvements in cardiac and renal function in rats with metabolic syndrome, effects not conferred by most currently available T2D drugs. Clinical studies of imeglimin in humans have shown increased insulin secretion, along with decreased fasting plasma glucose and hemoglobin A1c. Its observed efficacy was comparable to currently available agents metformin and sitagliptin, and was increased when given in combination with either agent. When considered alongside its benign safety profile reported in patients with chronic kidney disease, imeglimin shows true promise to provide a novel mechanism for T2D treatment with potential application in a larger, more comprehensive patient population.

1. Introduction

Type 2 diabetes (T2D) is a disease which has continued to grow in prevalence, with an estimated 463 million people ages 20-79 living with diabetes worldwide in 2019, expected to grow to up to 700 million by 2045[1]. As a metabolic disorder highlighted by poor glycemic control, secondary to a complex interplay between both insulin resistance in peripheral organs, and decreased beta cell function, effective management and treatment of the condition can be a challenging task. As the progression of T2D can be linked to associated pathology in multiple organ systems, including increased beta-cell apoptosis, increased hepatic glucose production, and decreased uptake of glucose into peripheral tissues, specifically addressing these different aspects of disease would be quite meaningful for therapy.

Throughout the years, there has been a growing number of available therapies for the treatment of T2D. However, as is its nature as a progressive disease, management later in its course requires a combination of pharmacological agents to maintain treatment efficacy, and with that comes a growing side effect profile which ultimately becomes a limiting factor in treatment. In addition to the side effects of this diverse group of therapies, there is the risk to those with pre-existing conditions or T2D sequelae which may dose-limit, or prevent use at all, such as with the use of insulin, metformin, sulfonylureas, and SGLT2 inhibitors in chronic kidney disease (CKD), and with the use of thiazolidinediones (TZDs) in heart failure. Given the inextricable link between T2D and metabolic syndrome, which shows significant deleterious effects on cardiac health, in addition to diabetic nephropathy being the leading cause of CKD in the US, it is clear that having therapies appropriate for use in these conditions is important for making true progress in the treatment of T2D throughout the duration of this progressive disease.

Imeglimin, the first drug of a new class of glycemic control drugs “glimins”, seems to have the potential of being a solution to a number of these problems present with our current therapies for T2D. In decreasing beta-cell apoptosis and hepatic gluconeogenesis, while improving skeletal muscle glucose uptake, it targets pathology in three of the primary organ systems affected by T2D pathology. With the potential for use as monotherapy or combination therapy with agents on the market, it shows promise in significantly improving the treatment course for many for whom previous therapies have failed or have been contraindicated.

2. Mitochondrial Mechanism

Imeglimin has been shown to have positive benefits on three of the primary organ systems negatively impacted by T2D - the pancreas, the liver, and skeletal muscle. A number of the effects of the drug, at least in liver tissue, have been shown to be a result of improved mitochondrial bioenergetics, and potentially biogenesis[2]. A significant increase in mtDNA content was observed with imeglimin treatment in high fat-high sucrose diet (HFHSD)-fed mice, beyond the increase that was already produced with HFHSD. However, while a correlated increase in PGC1-alpha levels was observed with HFHSD, a similar increase was not observed with imeglimin treatment. Imeglimin was shown to increase succinate-dependent respiration, but decrease both glutamate/malate (GM)-dependent respiration and complex I (CI) activity. Further, it also resulted in a decrease in hyperglycemia-induced oxidative stress only when undergoing complex II (CII), but not CI-dependent respiration. Imeglimin also increased CIII subunit expression, and completely recovered CIII activity. This increase in CII and CIII-dependent respiration, along with the inhibition of CI, likely allows for the utilization of more CII substrates, and ultimately more fatty acid oxidation. This also seemed to be correlated with an increase in the expression of fatty acid oxidation enzymes, as well as normalized carnitine levels. This is likely one of the mechanisms leading to the decreased accumulation of hepatic fatty acids in imeglimin-treated mice. In addition to its apparent effects in decreasing hepatic lipid accumulation, observed decreases in diacylglycerol (DAG) and oxidative stress levels could also be potential contributors to improvements in insulin resistance in HFHSD mice treated with imeglimin.

Further studies have illustrated a role for imeglimin in improving mitochondrial health without any effects on mitochondrial bioenergetics[3]. In oxidative stress models of endothelial cell injury from both tert-butyl hydroperoxide and hyperglycemia, imeglimin prevented cell death to a degree comparable or even greater than that of cyclosporine A (CsA) and N-acetylcysteine (NAC), agents known to prevent oxidative stress-induced cell death[4, 5]. Imeglimin was further shown to inhibit both the formation of the mitochondrial permeability transition pore (MPTP) and cytochrome C release, mechanisms likely responsible for its effect on endothelial cell viability. In line with preventing cell death in multiple models of oxidative stress, imeglimin showed significantly decreased production of reactive oxygen species, notably via the prevention of reverse electron transport through CI. Of note, a comparison of CI activity (via NADH consumption), oxygen consumption, and other measures of energy metabolism between imeglimin and metformin showed a stark contrast in their metabolic effects. While imeglimin showed virtually no difference in metabolic activity compared to control in all measures, metformin showed signs of decreased metabolic activity, including decreased ATP production and increased lactate production, a known potential side effect of metformin usage. These function as positive signs for imeglimin, as they signal low potential for adverse side effects as a result of altered energy metabolism.

Interestingly, imeglimin showing no alterations in mitochondrial bioenergetics in endothelial cells is in stark contrast from what was observed in liver tissue, where significant alterations were observed in the activity of multiple electron transport chain complexes, as well as changes in gene expression and carnitine levels pointing to increased fatty acid oxidation (Figure 1). It is worth noting, however, that HFHSD mice showed significant mitochondrial dysfunction due to increased intracellular lipids. It is possible that the effect of imeglimin on respiratory chain and fatty acid metabolism could potentially be greater on dysfunctional mitochondria than on healthy mitochondria. Furthermore, measurements of both mitochondrial respiration and oxygen consumption were performed on liver samples from HFHSD mice in the presence of insulin, a potential explanation for the observed mitochondrial effects given that the experiments in endothelial cells lacked insulin. ROS production, however, both generated via CI reverse electron transport in endothelial cells, and via CI from mitochondria of HFHSD mice energized with succinate, was decreased with imeglimin treatment. This could potentially point to a role for imeglimin in correcting mitochondrial defects, with little impact directly on energetics without functional impairment. However, the difference in both cell type and experimental model could also be responsible for differences in mitochondrial effects, which may require deeper study to determine imeglimin effects on different tissues.

Figure 1. Proposed mechanisms by which imeglimin improves mitochondrial bioenergetics.

Red arrows indicate changes in levels/activity observed in experimental models. Experimental models showed an increase in enzymes involved in fatty acid metabolism, such as CD36/fatty acid translocase (FAT) and 3-hydroxyacyl-CoA dehydrogenase (HAD), pointing to increased fatty acid oxidation. Increased fatty acid oxidation leads to the production of acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle and increases flux through complex II (CII) and complex III (CIII). Reverse electron transfer (RET) from CII to CI is decreased, which results in a decrease in ROS production. Figure created with BioRender.com.

3. Physiological Effects

Metabolic

Imeglimin is a drug with unique potential due to its ability to target the pathophysiology of multiple organ systems affected in T2D - the pancreas, liver, and skeletal muscle. It has been shown to increase insulin secretion in a glucose-dependent manner. Studies in a rat model of T2D compared the insulinogenic response of imeglimin with repaglinide (meglintide) and sitagliptin (DPP-4 inhibitor) at two stages of hyperglycemia, for which imeglimin showed the greatest increase[6]. It is interesting to note that the significant increase in insulinemia in diabetic mice treated with imeglimin, compared to that of repaglinide or sitagliptin, may also point to the role of imeglimin in improving both beta cell function and survival, a property not held by these drugs. The improvement in the insulinemic response to glucose also points to the question of whether beta cell survival is improved, particularly under conditions of T2D pathology. In line with this possibility, imeglimin also decreased beta cell apoptosis in rat pancreatic islet cells with and without treatment with cytokines, with a 37% decrease in apoptosis with imeglimin treatment with cytokines, compared to control. Interestingly, it was noted that the protective effect of imeglimin was 49% greater than that of exenatide (GLP-1 agonist), which showed a decrease of 29% compared to control. The effect of imeglimin on beta cell health was also studied in rat INS-1 insulinoma cells under hyperglycemic conditions (30 mM), where it provided significant protection in cell survival. Given the deleterious effect that both hyperglycemic and inflammatory conditions have been shown to have on beta cell survival in the context of T2D[7, 8], the protective effect of imeglimin points to the potential benefits of this therapy.

One of the primary mechanisms yet to be resolved for imeglimin, however, is the extent to which its function is dependent on insulin, as it has been shown to have varied effects on both hepatic gluconeogenesis and muscle glucose uptake. While some in vivo studies have shown an amplifying effect of imeglimin on insulin release, with no effect of imeglimin in decreasing hepatic glucose production or increasing muscle glucose uptake[9], suppression of glucose production was observed in both cultured hepatocytes and liver slices of non-diabetic mice, with muscle effects also observed in both in vitro and in vivo rodent models[6]. Interestingly, the positive effects of imeglimin in both reducing hepatocyte glucose production and increasing in vitro muscle glucose uptake appeared to be insulin independent, as these experiments were performed in the absence of insulin. Evidence has also been shown, however, for an insulin-sensitizing effect of imeglimin on both liver and muscle beyond that caused by increased insulin secretion, with imeglimin treatment in HFHSD mice resulting in increased phosphorylation of protein kinase B (PKB), a marker for insulin signaling, compared to untreated HFHSD mice[2].

It is important to note that the study observing no change in hepatic gluconeogenesis or muscle glucose uptake was performed under conditions of a hyperinsulinemic-euglycemic clamp, while that showing a change was performed in an STZ mouse model of T2D, with significantly reduced beta cell function mimicking that of late-stage T2D. This model showed significantly decreased insulin levels compared to normal mice, and imeglimin action in this context would likely not be the same as in healthy animals undergoing a hyperinsulinemic-euglycemic clamp. This is an interesting concept with implications for T2D treatment, as late-stage T2D presents with extensive beta-cell deterioration which leads to decreased insulin secretion, a pathological mechanism shown to be improved by imeglimin.

These data, taken together, seem to point to a joint insulin-dependent and independent mechanism of action. However, given the seemingly contradictory nature of these results, further studies must be performed to truly understand the physiologic action of imeglimin, particularly in terms of both its effects on the utilization of glucose by peripheral organs, and the dependence of its physiologic effects on insulin.

Cardiovascular & Renal

One of the primary causes of morbidity and mortality in T2D is heart disease, and improvements in cardiovascular outcomes is becoming a more important characteristic of newer T2D therapies, as it is with certain SGLT2 inhibitors and GLP-1 receptor agonists (RA), for example[10, 11]. This benefit of these therapies has made them increasingly popular options in T2D treatment. In a recent study, however, imeglimin was also shown to improve multiple indications of cardiac pathology in a rat model of metabolic syndrome[12]. It was shown to decrease age-associated dilation of left ventricular (LV) diastolic and systolic diameter in Zucker rats at 30 and 90 days of treatment, respectively, and increased LV fractional shortening in these rats as well, reaching significance at 90 days. A similar trend was observed in LV end diastolic pressure, the relaxation constant, and the LV end diastolic pressure-volume relationship. Furthermore, imeglimin was shown to increase LV myocardial perfusion, decrease LV ROS production, and improve coronary relaxation in response to acetylcholine. These improvements in cardiac function were likely observed, at least in part, due to both increased plasma nitrites (used as a marker for NO levels), and decreased LV collagen deposition observed after imeglimin treatment. In line with the benefits observed with imeglimin treatment on cardiac-specific pathology associated with metabolic syndrome, it was also shown to significantly prevent impairment of flow-induced dilation of mesenteric arteries in Zucker rats, reaching control levels at 90 days of treatment. Interestingly, improvement in LV function and decreased LV ROS production were observed prior to any change in plasma glucose level, showing potential for the drug to provide cardiovascular benefit in a glucose-independent manner. These observations seem to correlate with the findings on the effect of imeglimin on mitochondrial function, showing decreased ROS production and cell death of cultured endothelial cells under high-stress conditions[3]. This is a particularly important observation given the endothelium-dependent nature of these cardiovascular defects, lending confidence to the fact that the effects of imeglimin on improvements in endothelial survival and function play a significant role.

The negative sequelae of T2D on the kidney are also well known, given that diabetic nephropathy is the leading cause of kidney disease in the US. In addition to data showing potential for benefit in metabolic syndrome-associated cardiovascular impairment, preliminary pre-clinical data has shown potential for imeglimin to improve metabolic syndrome-associated renal impairment as well. In a rat model of metabolic syndrome, long-term (90 day) imeglimin treatment resulted in a reduction in kidney damage and improved kidney function, assessed through decreased glomerular injury, albuminuria, and both interstitial inflammation and fibrosis[12]. It is important to emphasize that these effects have not yet been shown in humans with T2D. However, the positive effects observed in both cardiac and renal endpoints in this rat model of metabolic syndrome show potential for systemic benefit from imeglimin in those with T2D beyond simply glycemic control, endpoints which have become more important as properties of effective T2D therapies.

4. Clinical Findings

Imeglimin is currently in development for use either as a monotherapy, or in combination with other T2D treatments which may have failed, particularly metformin, GLP-1 RA, or DPP-4 inhibitors like sitagliptin. Initial studies comparing imeglimin efficacy to metformin showed that a twice-daily (bid) regimen was favored over the once-daily regimen, with 1000-2000 mg bid regimens showing results comparable to metformin in lowering area under the curve (AUC) glucose, fasting plasma glucose (FPG), and hemoglobin A1c (HbA1c) from baseline[13]. When studied in phase 2 trials in patients inadequately controlled with metformin, metformin in combination with imeglimin decreased HbA1c levels from a baseline of 8.5% by 0.65%, compared to a 0.21% decrease for the placebo combination, resulting in a mean change from baseline versus placebo of −0.44%[14]. The study also showed more subjects experiencing a decrease in HbA1c >0.5 (63.6%) with the imeglimin combination than placebo (36.4%) (p =0.001).

One of the strongest findings of this study was a decrease in the proinsulin/insulin ratio in metformin-imeglimin compared to metformin-placebo, signaling improved beta-cell function. In addition, metformin-imeglimin showed, while not significant, trends toward decreased body weight (p = 0.08) and waist circumference (p = 0.053) compared to metformin-placebo. This is an interesting and welcome observation, as weight loss can reduce T2D severity.

In patients inadequately controlled with sitagliptin, sitagliptin in combination with imeglimin decreased HbA1c levels from a baseline of 8.5% by 0.6% at 12 weeks, compared to showing no significant change in combination with placebo, ultimately resulting in a mean change from baseline versus placebo of −0.72%, regardless of the baseline starting point[15]. The combination of imeglimin and sitagliptin was also shown to decrease FPG to a greater degree than the placebo combination (−0.93 vs. −0.11 mmol/L, p < 0.014). Interestingly, no significant changes were observed in fasting insulin concentration, C-peptide concentration, or HOMA-IR in the imeglimin combination compared with placebo. In both the metformin and sitagliptin studies, reductions in HbA1c were found to be similar in individuals with baseline BMI ≤30 kg/m² compared those with baseline BMI >30 kg/m².

In phase 3 trials, imeglimin reached statistical significance (p<0.0001) in achieving its primary endpoint of change in HbA1c, with a placebo-corrected mean change from baseline of −0.87%. Its main secondary endpoint of a decrease from baseline of FPG also reached statistical significance (p<0.0001) versus placebo at 24 weeks, with a placebo-corrected mean change from baseline of −19 mg/dL[16, 17].

In concordance with the endpoints observed in these trials related to both HbA1c, FPG, and proinsulin/insulin ratio, another study in drug naïve/metformin-withdrawn patients showed imeglimin significant increased the insulin secretory response to glucose (112%), as well as first and second phase insulin secretion rates (110% and 29%, respectively), effects observed with other anti-hyperglycemic agents like DPP-4 inhibitors and sulfonylureas shown to increase insulin secretion[18]. It was also shown to increase beta-cell glucose sensitivity by 36%, though, unlike DPP-4 inhibitors, it did not show any effect on glucagon levels. These results largely parallel those observed in pre-clinical studies, and point to strong potential for improving treatment options for T2D patients, particularly those for whom previous therapies have failed.

Safety

In addition to the significant cardiovascular sequelae of T2D, it is also the leading cause of end-stage renal disease in the US. With the significant burden of renal disease on T2D progression, one of the primary gaps in treatment lies in those with moderate to severe renal impairment, with drug classes like insulin, metformin, DPP-4 inhibitors, and some sulfonylureas having restricted use in those with severe renal dysfunction[19, 20]. In clinical trials, however, imeglimin has been shown to have a good safety profile, both on its own, as well as in combination with a number of commonly used T2D therapies[14, 15]. It has also been shown to be safe in populations with pre-existing conditions such as CKD, a critically important population for T2D therapies[16]. Pre-clinical data in rats which shows evidence for improved renal function with imeglimin treatment also brings to light the possibility that imeglimin could not just be an option for those who would have renal limitations preventing them from taking other diabetes medications, but also for individuals who could benefit from its potentially reno-protective properties. With this being a very preliminary pre-clinical finding, however, much more investigation must be done in order to confirm any sort of protective effect this may have on the kidneys of diabetic patients, a property which could revolutionize the treatment of T2D.

5. Conclusion

With the burden of T2D on the health of a growing subset of the world’s population, developing more effective therapies targeting the key pathophysiology of the disease is becoming more and more important. Imeglimin has been shown to target three of the key pathophysiologic mechanisms at play in T2D (Figure 2), a property held by few drug classes used in its treatment. Its true effect on peripheral organ glucose utilization and its insulin dependence should be further studied, and the cardiorenal benefit shown in animal models must be investigated in humans as well. Though effective in individuals having failed other T2D therapies, the extent of its glucose lowering effects have been shown to be comparable to that of these medications. However, given its unique mechanism, and its seemingly benign safety profile compared to therapies currently on the market, imeglimin, representing glimins as a new group of anti-diabetic drugs, has the potential to fill important gaps present in the current treatment of T2D.

Figure 2. Proposed mechanisms by which imeglimin may improve glycemic control in T2D.

Figure created with BioRender.com.

Key Points.

• Glimins are robust glucose-lowering agents, likely with a multifactorial mechanism for glucose-lowering.

• The glimin furthest along in preclinical and clinical studies is imeglimin, which has been suggested to lower glucose by increasing insulin secretion, enhancing mitochondrial bioenergetics, increasing muscle glucose uptake, and decreasing hepatic glucose production.

• In contrast to commonly used hypoglycemic agents, the adverse effect profile of imeglimin is generally benign, particularly in those with diabetic kidney disease.