Peripheral Neuropathy in Diabetes: Burden, Lifestyle and Pharmacological Interventions for Prevention and Treatment

Diabetes mellitus (DM) is a very common comorbidity worldwide, and it is associated with a wide variety of complications. Diabetic peripheral neuropathy (DPN) is one of these complications that increases the morbidity and mortality of these patients. Multiple studies indicated that lifestyle modifications are very beneficial for these patients in terms of decreasing the symptoms or preventing the progression of the disease. Therefore, a thorough search was conducted to study and shed light on the effects of lifestyle interventions, such as physical exercise, and Systematic Review Fairag et al.; JPRI, 33(49B): 349-355, 2021; Article no.JPRI.77108 350 pharmacological treatment on DPN. A total of 100 studies were found and 32 were selected based on whether or not they support the aim of the study. It was concluded that lifestyle interventions such as regular exercise, healthy diet and weight loss, which will all in turn improve the patient’s glycemic control, play a major role in controlling the disease and preventing its complications. Moreover, the aim of pharmacological interventions is a 30% reduction in pain intensity, however pharmacological interventions are limited in DPN, up till now the FDA approved only three medications that help in the reduction of the pain intensity. These medications are antidepressant duloxetine, anticonvulsant pregabalin, and the opioid-like analgesic tapentadol.

pharmacological treatment on DPN. A total of 100 studies were found and 32 were selected based on whether or not they support the aim of the study. It was concluded that lifestyle interventions such as regular exercise, healthy diet and weight loss, which will all in turn improve the patient's glycemic control, play a major role in controlling the disease and preventing its complications. Moreover, the aim of pharmacological interventions is a 30% reduction in pain intensity, however pharmacological interventions are limited in DPN, up till now the FDA approved only three medications that help in the reduction of the pain intensity. These medications are antidepressant duloxetine, anticonvulsant pregabalin, and the opioid-like analgesic tapentadol.  [1,2]. Diabetic peripheral neuropathy (DPN) is the commonest complication of diabetes and it affects almost 50% of all patients with both types of DM [3]. Moreover, the prevalence of DPN among adults in the United States (US) is approximately 28% [4,5]. DPN is defined as "the presence of signs and/or symptoms of peripheral nerve dysfunction in diabetic patients after exclusion of other causes" [4]. Symptoms of this disease include neuropathic pain and reduced sensation which in turn will lead to a lot of complications that would eventually impair and restrict the daily life of the patients [6,7]. Symmetrical DPN is the most common form of the disease, and the lower limbs are most commonly affected [8,9]. DPN, especially the aforementioned type, has a major impact on morbidity and mortality since it hugely increases the risk of developing ulcers, amputation, and disability [8,9]. In fact, DM is considered the most common cause of non-traumatic lower limb amputation in the United Kingdom (UK) [10]. Besides, it also poses a tremendous financial burden on hospitals and healthcare systems, since the total annual cost required to manage DPN symptoms and its complications such as amputation in the US is approximately between $4.6 and $13.7 billion [11].
It has been proven in multiple studies that nerve function in DM patients is improved with better glycemic control [8,12]. Additionally, strict glycemic control was shown to be effective in reducing the risk of acquiring DPN in type 1 diabetes patients, and it may decrease the risk in type 2 DM [13]. In fact, in type 1 DM the risk is dramatically decreased with improved glycemic control (78% relative risk reduction), while slight risk reduction is achieved through better glycemic control in type 2 DM (5%-9% relative risk reduction) [14,15]. Lifestyle modifications are extremely important for the treatment and control of DPN such as physical activity, healthy diet, and weight loss [16]. Regular physical exercise has been shown to be effective in relieving the pain associated with DPN as well as improving the neural function [16,17]. Moreover, multiple studies concluded that combined resistance and aerobic exercise training drastically decreases neuropathic pain, improves walking and balance, and strengthens the muscular fibers [17,18]. As for diet and weight loss, a long-term intensive program about lifestyle modifications and interventions targeted to achieve and maintain weight loss led to a significant reduction in questionnaire based DPN in overweight as well as obese patients with DM [19,20].
Knowing how huge the burden of DPN is, shows just how important the prevention of such issue is as well as the importance of controlling the disease and preventing its complications. The main aim of this study is to determine the effects and impact of lifestyle interventions such as better glycemic control, physical exercise, healthy diet, and weight loss on diabetic peripheral neuropathy and the importance of these changes in controlling the disease and preventing its complications.

MATERIALS AND METHODS
A comprehensive search was carried out by five co-authors independently on Pubmed using the following MeSH terms: "Diabetes mellitus", "Diabetic peripheral neuropathy", "DM", "DPN", "Lifestyle interventions". Then, search results were filtered based on the title, abstract, study included humans only, and availability in English language as well as availability of full texts. A total of 100 articles were found and based on the previously mentioned criteria and whether or not they provide benefit towards achieving the aim of the study, 32 were selected.

Prevalence of Diabetic Peripheral Neuropathy
The most common complication of diabetes is DPN as it affects about half of all cases with diabetes mellitus [3]. Furthermore, diabetes is the most common cause of neuropathy all over the world [21]. In fact, 66% of insulin dependent diabetes mellitus patients had some form of neuropathy as per a population-based cohort study done by Dyck PJ et al. [3]. According to Patricia Kluding et al. in their study about DPN, it is present in about one third of diabetic patients aged 40 or older in the US [17]. Moreover, the primary symptom in one third of DPN patients is pain [17]. Furthermore, according to a study done by Rayan Sendi et al. regarding DPN among Saudi diabetic patients, the prevalence of DPN among type 2 diabetic patients was 30.1%, while the prevalence among type 1 diabetic patients was 25.9% [22]. As per the aforementioned study, the overall prevalence of DPN is estimated to be 29.1% [22]. Moreover, the most common signs and symptoms were tingling (26.7%), hypoesthesia to touch (23.3%), and pins and needles (23%) [22]. This shows how prevalent the condition is among diabetic patients which is considered the most common cause of neuropathy worldwide.

Morbidity and Prognosis of DPN
Symmetrical distal degeneration of peripheral nerves is the most common form of DPN associated with pain and sensory loss due to both large and small nerve fibers being affected [17]. This eventually leads to gait and balance abnormalities which can precipitate lower limb injuries and potentially amputations [17]. Furthermore, this balance impairment can easily lead to falls in diabetic patients especially if it was associated with diabetic retinopathy [15]. In fact, patients with diabetic distal symmetrical polyneuropathy have 2-3 times higher risk of falls compared to those with diabetes without neuropathy [15]. Additionally, falls leading to fractures occur in approximately 25% of diabetics above 65 years of age [23]. Amputations are one of the most deleterious complications of this disease since it affects the patient's quality of life tremendously with a 15-fold increase in amputation risk in diabetic patients [15]. Additionally, neuropathic pain associated with this condition is quite troublesome and it approximately develops in 10%-20% of all diabetic patients and in 40%-60% of those with neuropathy [15]. However, these numbers are thought to be underestimated since it was found that 12% of patients with DPN did not tell their doctors about it [24].

Management and Prevention of DPN
DPN management is centered around various principles that aim to slow or prevent the progression of the disease and its complications [6]. As per Brian Callaghan et al. in their study about prevention and treatment of DPN, glycemic control is not an effective way of reducing the symptoms of DPN [15]. However, according to two other studies regarding the same topic, better glycemic control is associated with improved nerve function in diabetic patients leading eventually to less symptoms [8,12]. Generally, the first step in the management and prevention of DPN is glycemic control [26]. Regular physical activity has an impactful role in the prevention of DPN in diabetic patients by significantly improving the most important three risk factors which are glucose control, obesity, and dyslipidemia [1]. A clinical trial done by Patricia Kluding et al. involving 17 subjects with diabetic neuropathy concluded after 10 weeks of aerobic and strengthening exercise program that there is significant improvement in terms of pain and neuropathic symptoms [17]. Moreover, intraepidermal nerve fiber branching was found to be increased and HbA1c significantly improved [17]. On the other hand, no significant changes in nerve conduction studies and quantitative sensory testing were found [17]. Exercise as well as diet counseling can reduce the incidence of type 2 diabetes according to The Diabetes Prevention Program [27]. A significant randomized controlled pilot study conducted in May 2015 about dietary intervention for chronic diabetic neuropathy pain concluded that a low fat-based diet had potential improvement in regard to some clinical and pain measures [28]. Additionally, alpha-lipoic acid (ALA) is a type of dietary supplementation that has characteristic antioxidant properties [29]. It has been proven according to a study trial known as SYDNEY 1 trial that ALA reduces neuropathic pain [29]. However, further studies are required to test the effectiveness of ALA in reducing the symptoms of DPN and preventing its progression, since SYDNEY 1 was a short-term study [29]. Although vitamin B12 deficiency is implemented to be one of the main causes of peripheral neuropathy, there is no evidence supporting the use of vitamin B12 supplementation in DPN [19]. There is emerging evidence that dietary and physical modifications prevent the development of diabetic neuropathy in type 2 diabetes mellitus subjects by the effect on biochemical pathways that improve muscle function and affect other organ systems like peripheral nerves, however, data from randomized controlled trials are needed [1]. Therefore, as per these different studies and more, lifestyle interventions including physical activity and diet as well as improved glycemic control are very important aspects in the management of DPN.
Furthermore, pain management is a very important aspect in the management of this disease. A 30% reduction in pain intensity, regardless of the baseline pain score, is considered a purposeful and considerable reduction in patients with DPN [30]. Only three pain-relieving medications have secured FDA approval regarding their usage in DPN patients which are; the antidepressant duloxetine, the anticonvulsant pregabalin, and the opioid-like analgesic tapentadol [30]. Pregabalin and duloxetine are considered the initial and most appropriate choices for the management of neuropathic pain in diabetic patients [4].
Pregabalin is an effective medication for neuropathic pain in DPN and has a rapid onset of action [31]. According to the American Academy of Neurology (AAN) guidelines, pregabalin is the preferred treatment for patients with DPN (Level A) [30]. Duloxetine is also effective and has been found to improve neuropathy-related quality of life [32]. Venlafaxine, amitriptyline, gabapentin, valproate, opioids (i.e., morphine sulfate, tramadol, and oxycodone), and topical capsaicin are "probably effective" and should be considered for these patients (Level B) [30].

CONCLUSION
In conclusion, diabetic peripheral neuropathy is the most common complication of diabetes mellitus and is a major factor in increasing morbidity and mortality in these patients. Quality of life is majorly affected by DPN and its complications that can eventually lead to amputation. Furthermore, this condition exerts a huge economic burden to the whole healthcare system. Lifestyle modifications such as regular physical activity and healthy diet are major factors in managing the disease as well as preventing its complications. Pain and glycemic control are essential aspects that should not be overlooked during the management. All in all, DPN is a very common complication of DM that should be managed thoroughly in order to control the disease and prevent its debilitating complications.