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New Strategies to Tackle Diabetic Kidney Disease
Duygu Batu Demir; Mark E. Cooper
Curr Opin Nephrol Hypertens. 2016;25(4):348-354.
Abstract and Introduction
Abstract
Purpose of review The purpose of this review is to provide an overview of recent preclinical and clinical studies, which demonstrate new insights for the treatment of diabetic kidney disease (DKD) and to outline future directions with respect to novel therapies.
Recent findings Positive findings with respect to new glucose-lowering agents such as sodium-dependent glucose transporter 2 inhibitors may lead to a change in the way we treat diabetic individuals with or at risk of DKD. Additional positive phase 2 clinical studies with drugs that have hemodynamic actions such as endothelin antagonists and mineralocorticoid receptor antagonists have led to larger phase 3 trials with atrasentan and finerenone, respectively, in order to address if these drugs indeed delay the development of end-stage renal disease. A number of other pathways are currently under active preclinical investigation and hopefully over the next decade will lead to promising drug candidates for subsequent clinical trials.
Summary DKD remains an area of active preclinical and clinical investigation. Positive results with some of the more promising agents should lead to strategies to reverse, attenuate or prevent DKD.
Introduction
Among diabetic complications, kidney disease remains one of the most devastating as it is closely associated with early mortality in both type 1[1,2] and type 2 diabetes.[3] As has been seen not only in clinical epidemiological studies but also in many clinical trials, the presence of any stage of diabetic kidney disease (DKD) is strongly associated with the development of cardiovascular disease. Currently, strict glycemic control and blockade of the reninangiotensinaldosterone system are considered fundamental to the treatment of DKD.[4,5] Even though these interventions are effective at postponing the development of kidney disease, many patients ultimately develop end-stage renal disease (ESRD). Indeed, the annual incidence and prevalence of diabetic kidney disease as well as ESRD continues to increase probably because of the increasing number of individuals developing not only type 2 but also type 1 diabetes.[6]
Intensive Glycemic Control
The role of glycemic control in altering the outlook of DKD in type 1 and type 2 diabetes mellitus was demonstrated in The Diabetes Control and Complications Trial[7] and the United Kingdom Prospective Diabetes Study.[8] A recent meta-analysis looking into the renal outcomes of type 2 diabetes mellitus patients reported a significant reduction in the cumulative risk of both microalbuminuria and macroalbuminuria but no benefit on macrovascular disease with intensification of glycemic control.[9] These findings are strengthened by the results of the renal outcomes of the Action in Diabetes and Vascular Disease (ADVANCE) study of over 11 000 type 2 diabetic individuals, wherein the risk of ESRD, microalbuminuria and macroalbuminuria was significantly reduced with intensive glycemic control.[10] The follow-up study, Action in Diabetes and Vascular Disease: PreterAx and Diamicron MR controlled evaluation post-trial observational study (ADVANCE-ON), confirmed a sustained benefit on renal outcomes with intensive glycemic control.[11]
Although glucose-lowering per se may confer renal benefits in diabetes, there is increased interest as to whether certain classes of glucose-lowering drugs may afford advantages independent of their glucose-lowering actions. This includes sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors, which appear to have promising renoprotective effects.
Furthermore, it is well known that the major determinant of the degree of glucose lowering relates not to the specific drug but to the baseline glucose level. In brief, the higher the baseline HbA1c, the greater the decrease in glucose with the various agents.[12]
Sodium-Dependent Glucose Transporter 2 Inhibitors
SGLT-2 inhibitors are one of the most recently introduced classes of oral glucose-lowering drugs and may represent the most exciting breakthrough since the advent of reninangiotensin system blockade, with respect to their impact on cardiovascular and renal outcomes in diabetic patients. This is best reflected by the exciting results from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) study with the SGLT-2 inhibitor empagliflozin.[13] These drugs act on the SGLT2 in the proximal tubule of the kidney, inhibiting 90% of renal glucose reabsorption.[14] In addition to their beneficial effects on improving glycemic control, to a similar level to most other agents (a decrease in HbA1c of <1%), SGLT-2 inhibitors are associated with weight loss of approximately 4%[15] and blood pressure (BP) reduction of 4/1.6 mmHg[16,17] partly as a result of enhancing urinary glucose and sodium excretion.
The EMPA-REG study[13] not only demonstrated cardiovascular benefits including decreased mortality, reduced cardiovascular mortality and heart failure, but was also associated with impressive effects on various renal endpoints. This included the preservation of renal function, as reflected by calculated estimated glomerular filtration rate (eGFR), reduced albuminuria and a decrease in doubling of serum creatinine. Furthermore, despite only a small number of individuals with advanced renal disease in that study, a reduction in ESRD was seen in the empagliflozin-treated group.[18] As yet, the underlying mechanisms responsible for both cardiovascular and renal protection have not been defined. If this relates specifically to glucose lowering or to the natriuretic effects of these agents has not been elucidated but the rapid onset of cardiovascular benefit including heart failure would suggest that promoting sodium excretion with a concomitant decrease in heart failure may be a key factor in explaining end organ protection with this class of glucose-lowering drugs.
Interestingly, despite an attenuated effect on reducing serum glucose in chronic kidney disease (CKD) patients, BP reduction and weight loss is still observed. Ongoing studies with other SGLT-2 inhibitors including dapagliflozin and canagliflozin are in progress and include detailed evaluation of renal endpoints. Furthermore, as the mechanism of action of SGLT-2 inhibitors is independent of insulin, these agents may also play a role in the treatment of type 1 diabetes patients. Indeed, SGLT-2 inhibitors are being tested in type 1 diabetic individuals, and effects of SGLT-2 inhibition on intrarenal hemodynamics in type 1 diabetic individuals have been observed including a decrease in renal hyperfiltration.[19]
It is important to appreciate that SGLT-2 inhibition is associated with side-effects, in particular genital mycotic infections and possibly an increase in urinary tract infections. In general, these complications appear to be manageable and rarely lead to discontinuation of the drug. Recent studies reported that the SGLT-2 inhibitor canagliflozin is associated with significant decreases in bone mineral density at the total hip, and there was an increase in the fracture rate in distal extremities within the first 3 months of use of this agent.[20]
Dipeptidyl Peptidase-4 Inhibitors
DPP-4 inhibitors are another relatively recently introduced group of glucose-lowering drugs, which act by inhibiting the degradation of numerous substrates including certain incretins such as glucagon-like peptide-1. In addition to their glucose-lowering effects, various DPP-4 inhibitors have been shown to have antialbuminuric effects in small preclinical[21] and clinical trials.[22]
For example, in a recent pooled analysis of four phase III clinical trials of the DPP-4 inhibitor, linagliptin,[23] it was shown that this drug had a significant albuminuria-lowering effect and this effect on albuminuria appeared to be independent of BP or HbA1c changes. However, this retrospective pooled analysis has limitations and thus well-designed randomized clinical trials are currently in progress in order to confirm the antialbuminuric effects of DPP-4 inhibitors as well as determining if this translates to preservation of GFR. This class of drugs may be particularly relevant clinically as some of these DPP-4 inhibitors have been shown to be safe and efficacious in diabetic individuals with reduced renal function.
The underlying mechanism to explain the renoprotective effects of this group of drugs is unknown. However, in recent animal studies, the DPP-4 inhibitor linagliptin was shown to have antifibrotic effects in diabetic kidney disease models through the inhibition of endothelial-to-mesenchymal transition, a process that is considered to play a role in promoting tubular fibrosis.[24] In addition, several studies have reported interactions between DPP-4 and well-described pathways implicated in renal damage such as advanced glycation and oxidative stress.[25,26]
Intensive Blood Pressure Control
Independent of the antihypertensive agent used, BP lowering results in beneficial effects on renal outcomes of diabetic patients, as reviewed in a recent meta-analysis.[27]
Despite the ongoing debate as to the target BP level that should be achieved in diabetic individuals as recently outlined in the 8th Joint National Committee guidelines.[28] there is general agreement regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first-line BP-lowering drugs in the presence of DKD. Blockade of the RAS is still considered one of the most effective strategies to combat with DKD, because it is not only effective at decreasing BP, but also appears to have independent renoprotective actions. Nevertheless, even though RAS blockade confers significant renoprotection, a large residual risk for DKD persists. Furthermore, combination therapies using ACEIs and ARBs or ARBs and renin inhibitors have demonstrated disappointing results in clinical trials with serious side-effects such as hyperkalemia and occasional exacerbation of renal impairment.[29]
Renal Denervation
Renal denervation is an approach that is currently undergoing investigation as an approach to treat resistant hypertension by targeting the sympathetic nervous system through the destruction of renal nerves using radiofrequency ablation. Preclinical research including renal denervation of diabetic rats was shown to reduce glomerular hyperfiltration and prevent structural changes such as glomerular enlargement. Initially, nonplacebo-controlled clinical studies suggested efficacy of this method in the treatment of resistant hypertension including in diabetic patients. However, this area of clinical research has been influenced by the more recent negative findings in a larger placebo-controlled study performed in the USA.[30] Thus, enthusiasm for this approach has decreased and awaits results from ongoing trials including in diabetic individuals with and without nephropathy.
Mineralocorticoid Receptor Antagonists
In DKD patients treated with RAS blockers, a phenomenon known as 'aldosterone breakthrough' is often observed. This led to consideration of the mineralocorticoid receptor antagonists (MRAs) in DKD with small studies having reported reductions in albuminuria with older MRAs such as spironolactone and eplerenone. Unfortunately, in individuals with diabetes and/or impaired renal function, despite decreasing albuminuria, life-threatening side-effects such as hyperkalemia were commonly seen with these agents.
Recently, several novel MRAs, with potentially less risk of hyperkalemia, are in clinical development. Specifically, a new and highly selective nonsteroidal MRA, finerenone, has already proven its efficacy, safety and tolerability in two major clinical trials including one in DKD.[31] In that study, type 2 diabetes mellitus with CKD and proteinuria, already using an ACEI or ARB, were randomized to finerenone or placebo for 90 days. Finerenone showed a dose-dependent reduction in albuminuria. Even though this trial provided promising results, larger and longer duration studies investigating other renal outcomes such as reduction in GFR and progression to ESRD are still needed and are indeed being considered.
Endothelin Antagonists
Endothelin (ET) is a potent vasoconstrictor peptide, which by acting through its cognate receptors, the ETA and ETB receptor subtypes, may contribute to renal injury by promoting renal vasoconstriction, increasing BP and by direct cellular effects including promoting inflammation,[32] fibrosis and podocyte injury.[33] These effects occur at least in part independent of their effect on BP via the renal ETA receptor.[34]
Initial studies with avosentan, although promising in DKD, had to be terminated early because of fluid retention. Subsequently, a more selective ETA receptor antagonist than avosentan, atrasentan, was investigated. In a recent analysis of the pooled data from two trials RADAR (NCT01356849) and RADAR/JAPAN (NCT01424319), atrasentan treatment led to a more than 35% reduction in albuminuria without an increase in adverse events such as peripheral edema and heart failure.[35]
These positive findings have led to further development of the atrasentan clinical program with a new trial known as Study of Diabetic Nephropathy with Atrasentan having been commenced, which will assess effects on cardiovascular morbidity and mortality, albuminuria and changes in eGFR.
Compound 21
The angiotensin type II receptor, subtype 1 (AT1 receptor), is the best characterized angiotensin receptor, with vasopressor effects thereby influencing BP. Another identified receptor of angiotensin II is the angiotensin 2 receptor type 2 subtype, which is considered in general to counterbalance the deleterious effects of Ang II mediated via the AT1 receptor. Compound 21 (C21) is an AT2R agonist, which has been shown experimentally by several groups to attenuate experimental DKD.[36,37] Our own group recently showed that C21 treatment attenuates albuminuria and glomerulosclerosis in experimental diabetes, presumably by inhibiting oxidative stress and inflammation.[37]
Targeting the Metabolic Pathways Responsible for Diabetic Kidney Disease
In the diabetic milieu, prolonged exposure of complication-prone renal cells such as vascular endothelia, mesangial cells, proximal tubular cells and podocytes, to chronic hyperglycemia activates a series of metabolic pathways which are considered to play a central role in DKD.[38]
Advanced Glycation End Products/Receptor for Advanced Glycation End Products Pathway
Advanced glycation end products (AGEs), which accumulate in complication-prone tissues including in the kidney, are formed as a result of chronic hyperglycemia and the associated generation of key carbonyl intermediates including methylglyoxal. AGEs exert their detrimental effects directly by influencing the structure of proteins and indirectly by interacting with a number of cellular receptors including the best characterized, the receptor for AGE (RAGE).[38]
Targeting the AGE-RAGE axis to slow down or reverse the progression of DKD has been a major focus of experimental and clinical research. Most studies have been disappointing, but one AGE inhibitor, pyridoxamine, continues to be actively investigated clinically. A recently published post-hoc analysis of one of these clinical trials showed that the renoprotective effect of pyridoxamine was more evident in individuals with serum creatinine less than 2.0 mg/dl.[39] Furthermore, the results from the post-hoc analysis of this trial have been used to design a phase 3 trial, called Pyridorin in Diabetic Nephropathy (PIONEER), evaluating the safety and efficacy of oral pyridoxamine in reducing the rate of progression of DKD.
Another way of targeting this pathway may be via the enzyme glyoxalase-1 (Glo1), which is responsible for the degradation of the AGE precursor, methylglyoxal. Recently, induction of diabetes in Glo-1 knockdown and Glo-1 overexpressing mice led to enhanced or reduced renal injury, respectively.[40] This study demonstrated the important role of Glo-1 in the development of DKD and has attracted attention to this pathway as a new target for novel renoprotective interventions. However, as yet, there is no clinical strategy or lead compound to target this specific pathway.
NADPH Oxidase
Although oxidative stress appears to be pivotal in the development of DKD, most recent interest has focused on a particular source of reactive oxygen species, the NADPH oxidase enzyme family.[41] There are various isoforms of this enzyme with Nox4, also known as Renox, the most abundantly found isoform in the kidney.[42] In a recently published study, our group investigated the effects of deletion of either Nox1 or Nox4, using a gene deletion approach as well as pharmacologically by assessing a specific Nox1/4 inhibitor GKT137831, on renal functional and structural parameters.[42] Indeed, albuminuria was attenuated in diabetic Nox4 knockout mice, an effect not seen in Nox1 knockout mice. Furthermore, inhibition with GKT137831 retarded the development of albuminuria. Both Nox4 deletion and GKT137831 treatment also attenuated structural changes in the kidney such as glomerulosclerosis and mesangial area expansion.[42] Consistent with these findings in another experiment, in a model of insulin-deficient mice with DKD, GKT137831 for 4 weeks led to significant reduction in macrophage infiltration of glomeruli, glomerular hypertrophy, mesangial expansion, podocyte loss and albuminuria.[43]
To further define the importance of certain glomerular cell populations in influencing Nox4-related renal injury, podocyte-specific Nox4-deleted mice were generated. It was shown that these diabetic mice had less albuminuria and reduced glomerular basement membrane thickness, glomerulosclerosis and mesangial expansion.[44] However, these beneficial results have not yet been validated in human clinical trials.
Xanthine Oxidase
Xanthine oxidase, the enzyme that leads to the formation of uric acid, may have a role in kidney injury via a number of pathogenic mechanisms including increasing oxidative stress. In a recent preclinical study, the pathogenic effect of uric acid in promoting DKD by activating a range of proinflammatory pathways including the inflammasome was demonstrated.[45]
Building on these fundamental research findings and epidemiological data linking uric acid to decline in renal function in both type 1 and type 2 diabetes, a multicenter randomized clinical trial, Preventing Early Renal Function Loss in Diabetes[46] is currently being conducted to assess the effects of allopurinol treatment on eGFR in type 1 diabetes patients.
Nuclear 1 Factor (Erythroid-Derived 2)-Related Factor 2
Recent interest has focused on the nuclear 1 factor (erythroid-derived 2)-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (Keap1) pathway, an important antioxidant defense pathway. The most extensively studied pharmacological NRF2 activator is bardoxolone. Two clinical trials have been published, exploring the effects of bardoxolone in type 2 diabetes mellitus patients with relatively advanced kidney disease. Even though the results of the Bardoxolone Methyl and Diabetic Nephropathy trial[47] were promising, the subsequent Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes trial[48] was terminated prematurely because of the unacceptedly high rates of morbidity and mortality, particularly regarding cardiovascular events. This disappointing result has reduced enthusiasm for this class of agents in DKD.
Nevertheless, our group has recently investigated the effects of another NRF2 agonist, a bardoxolone methyl derivative, dh404, on atherosclerosis and DKD.[49] In that study, streptozotocin-induced diabetic APO-E knockout mice were randomized to receive either placebo or three different doses of the study drug (3, 10 and 20 mg/kg dh404) for 18 weeks. Dh404 was shown to attenuate glomerular and tubular injury, as reflected by a reduction in albuminuria, a decrease in profibrotic and proinflammatory markers such as tumor necrosis factor-α, monocyte chemoattractant protein (MCP)-1 and interleukin-6 and attenuation of glomerular mesangial and tubulointerstitial expansion. Unfortunately, higher doses of this drug appeared to be less effective and rather than being antiinflammatory, promoted expression of chemokines such as MCP-1. Thus, there appears to be a narrow doseresponse curve with this class of drugs.
Inflammatory Chemokines
Inflammation is considered an important pathological process in DKD, particularly when the disease is rather advanced. One of the key targets is the MCP-1 chemokine ligand 2/C chemokine receptor type 2 pathway, which plays a central role in macrophage recruitment.[50] CCX140-B is a selective antagonist of the MCP-1 receptor CCR2, and has been shown to improve renal markers of injury in diabetic mice.[51] In order to translate the results of the animal studies to the clinic, a multinational, randomized clinical trial recently assessed the efficacy of oral CCX140-B on renal outcomes in DKD patients.[52] Modest effects on albuminuria were reported with this drug, albeit not in a dose-dependent manner. The long-term renal benefit of this approach remains to be confirmed with several other strategies to target this pathway under active clinical investigation.
Profibrotic Growth Factors (Transforming Growth Factor-β1) and Micro-RNAs
Fibrosis, a prominent structural hallmark of DKD is regulated by the prosclerotic cytokine, transforming growth factor-β1 (TGF-β1). A range of stimuli such as AGEs, hyperglycemia and oxidative stress trigger the production of this potent profibrotic molecule. How TGF-β1 mediates these effects remains an active area of fundamental investigation with identification of signaling molecules factors such as connective tissue growth factor (CTGF) and microRNAs all playing a role in modulating the action of this growth factor.[53] Targeting TGF-β has proven difficult with generally disappointing results with approaches such as a humanized TGF-β antibody. As certain microRNAs can modulate TGF-β expression and action,[54] this could theoretically be an alternative approach, but no such treatments have as yet reached the clinic. Our own group has identified another molecule, CDA1, which appears to modulate TGF-β action and signaling with positive preclinical results in CDA1 knockout mice.[55]
Phosphodiesterase Inhibitors
As outlined earlier, minimizing inflammation with the use of certain antiinflammatory drugs could potentially be renoprotective in diabetes. A phosphodiesterase inhibitor, pentoxyfilline, with both anti-inflammatory and antifibrotic actions has been shown to be antiproteinuric in DKD in several small clinical studies as summarized in a recent meta-analysis.[56] Therefore, the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial[57] was instituted in patients with type 2 diabetes mellitus and stages 34 CKD and was reported to be renoprotective. However, as the patients included in that study had relatively advanced kidney disease and there was no placebo group, one must be cautious in overinterpreting the findings of that study.[58]
Conclusion
As the epidemic of DKD continues unabated, new treatments are desperately needed to reduce the progression of this disorder. Although many fundamental discoveries have increased our understanding of the factors and pathways involved in DKD, there are few positive clinical studies to change the way we manage this condition. The disappointment of the bardoxolone trial[48] and the limited benefits of conventional glucose and BP-lowering agents mean that DKD continues to be a major burden in both type 1 and type 2 diabetes. Hopefully, the new studies with endothelin antagonists and mineralocorticoid receptor antagonists and the promising findings with some of the new glucose-lowering agents including SGLT-2 inhibitors will lead to major improvements over the next decade in the way we manage diabetes and its complications.
Sidebar
Key Points
Targeting hemodynamic pathways remains a major focus of renoprotective treatments in diabetes with increasing interest in new drugs such as endothelin antagonists and MRAs.
Intensification of glycemic control has been shown in recent clinical trials to reduce progression of DKD even in individuals with relatively advanced disease.
Exciting results with SGLT-2 inhibitors on both cardiovascular and renal endpoints could lead to this class of glucose-lowering agents being particularly useful in reducing the progression of DKD.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
* of special interest
** of outstanding interest
Acknowledgements
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Curr Opin Nephrol Hypertens. 2016;25(4):348-354. © 2016 Lippincott Williams & Wilkins
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Thank you for posting this. It's heartening to see that there may be some potential breakthroughs in how DKD is approached in the next decade and what additional benefits these new medications may provide.
Our insurance company stopped paying for Januvia about 2 years ago. Along with Metformin and Actos, it treated G very well for many years, but it became a higher tier drug and required him to "fail" on at least three other glucose lowering meds before they would consider it a necessary treatment. After two strikes with two alternative meds (A1c rising to 10.5 during all of this), he was finally put on Invokana almost 6 months ago. A1c is down to 7.5, so I guess we can say that third time was the charm? I'm anticipating additional adjustments in order to stuff that number back down under 7.0 :urcrazy;
It concerns me that the SGLT-2 inhibitors are so darn new, and the long-term side effects are unknown. Among other things, the Invokana acts as a very strong diuretic, at least with G, and he tries to drink at least 3 liters of water a day to offset this. I'm constantly worrying about dehydration and "volume depletion." He says he's taking the internet away from me, so I stop reading all the negative stuff. ;D
Thanks again for sharing!
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You might also want to check into this. http://www.medscape.com/viewarticle/864857 : Empagliflozin Slows Progression of Renal Disease in Diabetes
I don't know what your husband's kidney function is, and whether he's still eligible for this med. I know I'm not.
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Thank you! I will ask at his next appointment if empagliflozin and canagliflozin (Invokana) are similar enough to perhaps provide the same secondary benefits. I believe they're both SGLT2 inhibitors, and right now, neither is contraindicated according to his levels.
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Thank you so much for this article, K&S. Wow, what a great one!
With regards to the novel drug, what stood out for me was:
"It is important to appreciate that SGLT-2 inhibition is associated with side-effects, in particular genital mycotic infections and possibly an increase in urinary tract infections. In general, these complications appear to be manageable and rarely lead to discontinuation of the drug. Recent studies reported that the SGLT-2 inhibitor canagliflozin is associated with significant decreases in bone mineral density at the total hip, and there was an increase in the fracture rate in distal extremities within the first 3 months of use of this agent"
I would love the renal protective benefits but sure would love to protect my bones as well! And UTIs need to be treated with antibiotics - something that definitely can harm kidneys.
But one thing that also stood out for me is that little wonder supplement called pyrixidone, that has cropped up in discussions for the last few years that I have been reading. It seems to be something that is always being investigated further. Does anyone know anything more about this one? Or has taken it in the past?
For those of us who are in moderate to advanced stage of CKD, the picture doesn't look too promising, unfortunately.
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Don't you mean pyridoxone and not pyrixidone? AKA pyridoxine or Vitamin B6. Pyridoxine is a treatment for pyridpoxone deficiency. I used to take it.
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The article mentions pyridoxamine, a form of B6, as a studied agent.