Evidence Scant on Nutraceuticals for Neuropathy in Diabetes
There is currently no specific treatment approved for diabetic neuropathy, a huge unmet clinical need since up to half of all patients with diabetes will eventually develop neuropathy.
Part of the problem is that there is no clear path to successful approval of any such agents, with ongoing arguments about which clinical end points would be most relevant in trials. The only therapeutic strategy shown to prevent development or curtail progression of neuropathy is tight glucose control.
There are, however, numerous therapeutics for the pain associated with this complication, which is said to affect up to a quarter of all patients with diabetic neuropathy to the extent that it "produces considerable disability and is challenging to assess and manage," according to a recent review of neuropathy in diabetes, led by Solomon Tesfaye, MD, professor of diabetic medicine at University of Sheffield, United Kingdom (Medicine. 2015;43:26-32).
But even the approved treatments for diabetic neuropathy pain are not ideal.
"None affords complete relief, even when used in combination," according to the latest American Diabetes Association Standards of Care, published at the beginning of this year.
As a result, there is growing interest in nonpharmaceutical approaches to the treatment of both diabetic neuropathy itself and the associated pain, with a plethora of vitamins, vitamin complex combinations, and other agents emerging that purport to affect this debilitating complication of diabetes.
But what is the scientific evidence that these "nutraceuticals" can actually help? Medscape Medical News surveyed several experts in the field to garner their views.
"The problem is there is no unequivocal evidence based on randomized controlled trials that [nutraceuticals] slow or reverse nerve damage in diabetes," Dr Tesfaye told Medscape Medical News.
But he says there may be a rationale for the use of certain vitamins in patients with diabetic neuropathy who are actually deficient — such as vitamin D or vitamin B12 — and such people may benefit from injections of these vitamins.
Dr Brian C Callaghan, MD, from the University of Michigan, Ann Arbor, echoes these thoughts: "Vitamins can be effective in treating neuropathies that are due to vitamin deficiencies; unfortunately, most neuropathies are not caused by a vitamin deficiency."
No nutraceuticals are approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA), for the treatment of diabetic neuropathy or associated pain, but several such products are available over the counter.
Treating Vitamin D or B12 Deficiencies
Dr Tesfaye says there is "a clear rationale for replacing vitamin D and B12 if there is a deficiency," which is common in colder countries such as the United Kingdom, which has limited sunshine in the winter (and which therefore has an effect on vitamin D levels) and where patients with diabetes commonly receive metformin (which can lower levels of vitamin B12).
"There is, however, no evidence that these are helpful if individuals have normal levels of these vitamins," he cautioned.
Recent research conducted in Pakistan by Abdu Basit, MD, at the Baqai Institute of Diabetology & Endocrinology in Karachi, and colleagues showed that a single, high dose of intramuscular vitamin D was safe and effective for patients with painful diabetic neuropathy (BMJ Open Diabetes Res Care. 2016;4:e000148).
In that study, 143 patients with predominantly type 2 diabetes and diabetic neuropathy pain received a single intramuscular injection of 600,000 IU vitamin D. At baseline, 40% of patients had vitamin D deficiency (25 OH vitamin D < 20 ng/mL).
Pain scores improved the most at 10 weeks and remained lower than baseline levels until the study end at 20 weeks. Significant effects were seen on the Douleur Neuropathique 4 score, the McGill pain score, and the McGill Pain Questionnaire Score (all P < .0001).
However, the researchers admit that the lack of a placebo group is a major study limitation, and they call for a longer, placebo-controlled study to assess the optimal dose and safety and efficiency of vitamin D in painful diabetic neuropathy. It would also be useful to assess the administration of vitamin D in diabetic neuropathy per se, they add.
Divided Opinion on α-Lipoic Acid and the NATHAN 1 Study
Another nutraceutical claimed to be of some benefit in diabetic neuropathy is the antioxidant α-lipoic acid (ALA, also known as thioctic acid), which is approved for use in Germany for neuropathic pain.
In a large study called NATHAN 1, Dan Ziegler, MD, from the Leibniz Center for Diabetes Research, in Düsseldorf, Germany, and colleagues randomized 460 patients with mild to moderate diabetic distal symmetric sensorimotor polyneuropathy to receive 600 mg/day of α-lipoic acid (Thioctacid HR, MEDA Pharma) or placebo for 4 years (Diabetes Care. 2011;34:2054-2060).
The study failed to meet its primary efficacy end point (a composite of pain scores) or improve nerve conduction.
But the patients treated with α-lipoic acid did have improvements in some symptoms and less progression of impairment, compared with patients who received placebo, and the agent was well tolerated.
In a post hoc analysis published earlier this year (J Diabetes Complications. 2016;30:350-356), Dr Ziegler and colleagues show that patients with normal baseline blood pressure and weight, but older age, longer duration of diabetes and neuropathy, and a history of CVD were less likely to have progression of neuropathic impairment after 4 years of treatment with α-lipoic acid than those on placebo.
And patients who also received ACE inhibitors were more likely to have improved heart rate during deep breathing (a measure of cardiac autonomic function).
"Thus, the drug may be particularly suitable for the elderly patient with a history of CVD and ACE-inhibitor treatment and both more severe diabetes and neuropathy who cannot meet individualized glycemic targets," the researchers say.
In other words, the worse a patient was, the better they responded to treatment with ALA.
Dr Ziegler told Medscape Medical News that this α-lipoic acid is warranted for "all diabetic patients with neuropathy, [and patients] can expect symptom relief, slowing of neuropathy progression, or even improvement at a dose of 600 mg/day."
However, Drs Tesfaye and Callaghan beg to differ and stress that the evidence to support use of the oral version of α-lipoic acid is weak.
"The NATHAN 1 trial results showed that the primary end point of [improvement in] composite neuropathy score was not achieved," Dr Tesfaye cautioned.
However, there is some clinical trial evidence for efficacy of the intravenous version of α-lipoic acid (Diabetes Care. 2010;33:2285-2293), he said.
Dr Callaghan agreed that "α-lipoic acid has some evidence for the treatment of painful diabetic neuropathy, but the evidence is not strong."
Vitamin Combinations: Metanx and NutriNerve
There are also products that combine different B vitamins and purport to be effective in diabetic neuropathy and its associated pain, but clinical-trial evidence for efficacy of any of these is currently sparse.
In a recent trial of patients with type 2 diabetes and neuropathy, Metanx (Nestle Health Science-Pamlab), which consists of capsules that contain a cocktail of B vitamins — 2.8-mg L-methylfolate (vitamin B9), 35-mg pyridoxal 5'-phosphate (vitamin B6), and 2-mg methylcobalamin (vitamin B12) — did not meet its primary end point of improved vibration-perception threshold, although patients reported symptom improvement, and adverse events were infrequent (Am J Med. 2013;126:141-149).
In the study — published by Vivian A Fonseca, MD, professor of medicine and pharmacology, Tulane University Health Sciences Center, in New Orleans, Louisiana, and colleagues — the 214 patients were randomized at centers in Alabama, Louisiana, Nebraska, and Texas to receive this B vitamin combination or placebo daily for 24 weeks.
Metanx did show a clinically significant improvement in Neuropathy Total Symptom Score (NTSS-6), a secondary end point, among those taking Metanx compared with those on placebo.
"Metanx appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term," Dr Fonseca and colleagues conclude, noting that the trial may have been too short to show an effect on vibration-perception threshold. "Further longer studies are needed," they said.
In an email to Medscape Medical News, Dr Fonseca said nutraceuticals such as vitamin D, B vitamins, alpha-lipoic acid, or combinations of vitamins such as Metanx may "help some patients [with diabetic neuropathy], but there is no clear indication" for them.
"There are very few good studies…[but] not enough for FDA approval," he stressed.
However, in an editorial accompanying Dr Fonseca's 2013 paper, Aaron Vinik, MD, director of research and the neuroendocrine unit at Eastern Virginia Medical School and Strelitz Diabetes Research Center, in Norfolk, suggested that vibration-perception threshold was not a suitable end point for the study (Am J Med. 2013;126:95-96).
"Currently…the only agents approved for the treatment of symptomatic diabetic peripheral neuropathy in the US are duloxetine and pregabalin, which do not affect nerve conduction, have mechanisms of action unrelated to the pathophysiology of diabetic neuropathy, and only address pain relief," Dr Vinik wrote. (There is a third medication approved in the United States for diabetic neuropathy pain, an opioid called tapentadol.)
Dr Vinik stressed that patients who received Metanx did report improvements in NTSS-6 (based on numbness, tingling, and aching, burning, or lancinating pain; P = .013) and allodynia (P = .033 at week 24), and in components of an SF-36 mental health survey.
Dr Vinik has himself developed a nutraceutical, NutriNerve , which consists of capsules that contain 150-mg α-lipoic acid, 130-mg gamma-linoleic acid, 75-mg vitamin B1 (benfotiamine), 85-mg vitamin C, 1-mg vitamin B12 (methylcobalamin), and 500-IU vitamin D (cholecalciferol).
Indicating that NATHAN 1 showed that α-lipoic acid "improves many of the symptoms of neuropathy if you treat for long enough, usually 4 years," he told Medscape Medical News that NutriNerve "is very effective for patients [with painful diabetic neuropathy and] symptoms of numbness, tingling, and burning."
Patients also comment that their skin is less dry, their nails are less brittle, and their hair grows more, he noted.
But according to Dr Callaghan, Metanx and NutriNerve "each have different vitamin cocktails that are purported to help nerves, [but] there is no strong evidence to support the use of either….I do not think that there is a good scientific rationale for their use," he asserted.
"Upcoming guidelines [are unlikely to] recommend nutraceuticals because of the lack of strong evidence to support their use," Dr Callaghan concluded.
Recommendations for Drugs for Painful Diabetic Neuropathy
The most recent American Diabetes Association (ADA) Standards of Care recommend optimizing glucose control to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in patients with type 2 diabetes. Patients with type 1 diabetes for 5 years and all patients with type 2 diabetes should be assessed annually for diabetic peripheral neuropathy, it adds.
However, specific treatment for the underlying nerve damage is currently not available, it notes.
Yet "several medications have been demonstrated to be effective for the treatment of pain associated with [diabetic peripheral neuropathy], but there is limited clinical evidence regarding which medication is most effective for an individual patient," the ADA notes.
Various international guidelines recommend slightly different therapeutic approaches for treating patients with painful diabetic neuropathy.
In 2010, the European Federation of Neurological Societies recommended using tricyclic antidepressants (TCAs, such as amitriptyline or imipramine), antiepileptic medications (such as gabapentin or pregabalin) and serotonin-norepinephrine reuptake inhibitors (SNRIs, such as duloxetine and venlafaxine) as first-line agents to treat painful diabetic neuropathy. Tramadol or stronger opioids are recommended as second- or third-line medications.
In 2011, the International Toronto Expert Panel on Diabetic Neuropathy issued similar guidance.
Meanwhile, the American Academy of Neurology recommends offering pregabalin as a first-line option and then considering offering venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and controlled-release oxycodone), and capsaicin.
The FDA has approved three medications for the treatment of pain associated with diabetic peripheral neuropathy (pregabalin, duloxetine, and tapentadol), "but none affords complete relief, even when used in combination," according to the ADA Standards of Care.
The EMA has also approved pregabalin and duloxetine and, more recently, capsaicin patches (Qutenza, Astellas Pharma) for diabetic neuropathy pain.
Although tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, and tramadol are not officially approved for treating painful diabetic neuropathy, they may be effective, and clinicians may consider using them to treat patients with this condition, the Standards of Care continues.
"Comparative efficacy studies and trials that include quality-of-life outcomes are rare, so treatment decisions must consider each patient's presentation and comorbidities and often follow a trial-and-error approach," it advises.
"Given the range of partially effective treatment options, a tailored and stepwise pharmacological strategy with careful attention to relative symptom improvement, medication adherence, and medication side effects is recommended to achieve pain reduction and improve quality of life."