Diabetic neuropathy is by no means a "late complication" of diabetes, as was assumed over decades: according to current data, nerve damage begins at a very early stage of the metabolic disorder and frequently occurs in pre-diabetes. The insidious damage to the nerve fibres usually goes unnoticed at the beginning. However, Prof. Karlheinz Reiners, Head of the Neuromuscular Outpatient Department at the Neurological Clinic of Hermann-Josef Hospital in Erkelenz, called for measures to prevent the progression of neuropathy at this early stage. The reason for this is that progressive nerve damage increasingly restricts the quality of life of patients and raises the risk of mortality: many of those affected suffer from sometimes agonising pain and discomfort such as a tingling or burning sensation in their feet, others from painless foot ulcers, which often result in amputations. Cardiovascular morbidity and mortality also increase.
Foot problems not taken seriously
In spite of the severe consequences, the symptoms in the feet are obviously often underestimated, as the currently published data of the PROTECT study (2), which was presented by study director Prof. Dan Ziegler, Deputy Director at the Institute for Clinical Diabetology of the German Diabetes Centre at Heinrich-Heine University in Düsseldorf, show. The study involved 1,850 people with and without known diabetes who had their nerve function in their feet examined as part of the National Educational Initiative on Diabetic Neuropathy. The alarming result: almost 70% of patients with proven neuropathy were previously unaware that they were suffering from this nerve disease. Even in the case of pain or burning in their feet, two thirds of those affected were unaware that neuropathy was the cause of the symptoms. The number of unreported cases of painless neuropathy, which is asymptomatic or manifests itself in the form of numbness or paraesthesias in the feet, was even higher: this had not been diagnosed in the patient’s history in 81% of cases.
Intensive training and monitoring required
The fact that diabetic neuropathy is underestimated and often not recognised could have a negative influence on the development of diabetic foot ulcers as well as amputations, Ziegler warned. He therefore considers it necessary not to rely on the – often overly optimistic – self-assessment of patients when it comes to the subject of foot health, but instead to carry out checks. For high-risk patients, regular foot examinations and intensive training should be carried out. Ziegler also believes it is important to promote the early detection of diabetes, as almost 40 per cent of the study participants who had stated that they did not have diabetes had long-term blood glucose values within the pre-diabetes or diabetes range. "Unidentified diabetes can be a major cause of neuropathy," warned the diabetologist.
The PROTECT study was also able to identify important risk factors:
• In patients with type 2 diabetes, painful neuropathy was associated with a higher body mass index (BMI) and the painless form with a lower BMI. Ziegler concludes that the connection between neuropathy and obesity seems to be specific to the painful form.
• Another new finding is the connection between painless neuropathy and the male sex, both in type 2 and non-diabetics. Only recently, another study (3) demonstrated an association between the female sex and painful neuropathy.
• In agreement with the study referred to above, Ziegler and his scientific team showed that in cases of painful neuropathy a more severe nerve damage is present than in the painless form.
The basis of the success of the therapy: early diagnosis
In order to be able to successfully treat neuropathy, early diagnosis is required. As neurologist Prof. Reiners explained, the detection of diabetic neuropathy is an exclusion diagnosis: it should be noted that even if its origin is very likely to be diabetogenic, other – often easier-to-treat – causes of distal-symmetric polyneuropathy may also exist at the same time. "In addition to the medical history, the clinical pattern and appropriate laboratory parameters are aids in the differential diagnosis," said Reiners. In cases of doubt and if the course of the disease is untypical, he advises consulting a neurologist to help clarify the situation with the help of electrodiagnostics.
Stopping nerve damage and alleviating symptoms
The therapy is a challenge: on the one hand it is necessary to stop the progression of the nerve damage, and on the other to alleviate the symptoms of the patients. For this reason, the main focus is on the treatment of the nerve-damaging factors. As PD Dr. med. Ovidiu Alin Stirban, Chief Physician in the Department of Internal Medicine, Diabetology and Endocrinology at the Schön Clinic in Nuremberg Fürth, explained, hyperglycaemia triggers various cell-damaging processes such as oxidative stress and the formation of aggressive advanced glycation end products (AGEs) that cause secondary diseases. At the same time, diabetes is often accompanied by the increased excretion of vitamin B1 (thiamine) via the kidneys, which can lead to serious vitamin B1 deficiency. In a British study, thiamine plasma levels in type 1 and type 2 diabetics were found to be 75% lower than in healthy people on average (4). Since the vitamin plays key roles in the nerve and glucose metabolism, a deficit promotes nerve damage and disturbances in the glucose metabolism, which in turn promote the formation of vascular-damaging degradation products such as AGEs.
Treatment according to the 3-pillar approach
In view of the complex pathogenesis of nerve damage, multi-factorial intervention is required according to Stirban. Treatment according to the 3-pillar approach was suitable for this:
The first pillar is the optimisation of diabetes management, which represents the most important measure.
The second pillar aims at intervening in the pathogenesis of neuropathy, stopping nerve damage and alleviating symptoms. Well-tolerated substances are available for this, such as benfotiamine and the anti-oxidative alpha-lipoic acid. Benfotiamine is a vitamin B1 precursor with approximately 5 times higher bio-availability than conventional thiamine (5). It can therefore compensate for vitamin B1 deficiency and inhibit nerve-damaging processes. Clinical studies have shown that long-term treatment with benfotiamine can relieve the symptoms of diabetic neuropathy such as tingling, burning and numbness in the feet (6 - 8).
The third pillar is the symptomatic therapy of neuropathic pain. However, Stirban pointed out that although treatment with serotonin noradrenaline re-uptake inhibitors, anticonvulsants or opioids was symptomatically effective, it was also the pillar of the therapy with the most side effects and did not influence the underlying disease. Since long-term clinical data was not available for most of these substances, he considers long-term therapy to be problematic. In Stirban’s opinion, alternative symptomatic therapies such as local treatment with capsaicin or electrostimulation using high tone therapy were also interesting.
1. Symposium "Diabetic Neuropathy: Earlier Detection – Better Treatment" on May 9, 2018 in Berlin, organised by WÖRWAG Pharma.
2. Ziegler D et. al: Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT-Study). Diabetes Res Clin Pract. 2018;139:147-154
3. Raputova J, Srotova I, Vlckova E et al. Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain 2017; 158: 2340-2353
4. Thornalley PJ et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 2007; 50: 2164-2170
5. Schreeb KH et al. Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. Eur J Clin Pharmacol 1997; 52: 319-320
6. Stracke H et al. Benfotiamine in diabetic polyneuropathy (BENDIP): Results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diab 2008; 116: 600-605
7. Haupt E et al. Benfotiamine in the treatment of diabetic polyneuropathy - a three-week randomized, controlled pilot study (BEDIP Study). Int J Clin Pharmacol Ther 2005; 43: 71-77
8. Stirban et. al. Neurodiab 2016; unpublished.