Clinical Impact of Combination Therapy in Diabetic Neuropathy and Nephropathy

 

Harmeet Kaur, Arvinder Kaur, Pankaj Kumar Prashar, Anamika Gautam, Ankita Sood, Sachin Kumar Singh, Monica Gulati, Narendra Kumar Pandey, Bimlesh Kumar*

School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.

 

ABSTRACT:

Diabetes is a complex metabolic disorder. At chronic condition it causes severe damage to the multiple organs like heart, eyes, blood vessels, kidneys, and nerves which further brings about macrovascular and microvascular complications. In present situation sufficient drugs are available for the treatment of diabetes but risk and rate of mortality of a patient suffering from diabetes is very high. Reported partial relief and regular suffering of patient is a leading challenge of medical as well as health care professionals. Available drugs given in the form of monotherapy restricted to certain conditions only and it is not able to provide inadequate relief. Hence, timely diagnosis with combination therapy adopted at right time can improve the hyperglycaemic condition and worst condition of diabetic complications. It is evident that insulin with metformin provides beneficial effect in avoiding weight gain and hypoglycaemia. Herbal, poly-herbal and synthetic drug administration in combination form is a novel therapeutic approach for treatment diabetes and its complications. Hence this review will focus to justify the dual therapy can be a potentially good therapeutic approach to solve the problems of diabetic complications with special impact to diabetic neuropathy and nephropathy over monotherapy using preclinical and clinical evidences.

 

 

 

INTRODUCTION:

An abnormal insulin secretion, insulin action or both leads to a disease state to an individual called as Diabetes mellitus (DM). It is metabolic defect which in turn leads to chronic condition of hyperglycemia and certain microvascular and macrovascular complications. It is a progressive and ongoing condition in which activity of pancreas gets worsen^1,2. The insulin is secreted by the beta cells of the pancreatic islets and any defect in pancreas affect the insulin production^1,3. In most of the cases decrease/interruption in secretion of insulin and insulin resistance shows a major role in the growth of DM⁴. It is well known that glucose the primary source of energy for the body and its entry in the blood stream allows secretion of insulin from β cells which further results in decrease in the blood glucose level (BGL).

 

So, unprecedented rise in the level of glucose can be also due to abrupt functioning of pancreas. Hence, this abnormal rise in BGL is known as DM^5,6. DM alters the quality as well life span of individual⁷.  Diabetes can be categorized into three major types which include type 1 diabetes also known as juvenile diabetes or insulin dependent diabetes mellitus, type 2 diabetes or non-insulin dependent diabetes mellitus and gestational diabetes as type 3. Type 1 diabetes occurs when the body is unable to produce insulin whereas in type 2 diabetes though the insulin secretion is normal but the body cells stop responding effectively to it. Gestational diabetes occurs in some of the women during pregnancy which disappears after delivery⁸. This manuscript presents an extensive review on monotherapy and combination therapy for effective management of diabetic neuropathy and nephropathy. 

 

Clinical overview of DM:

Earlier it was considered as a disease of western disease but now  a days it has spread as global burden⁹. In 2017 its  prevalence  was estimated  around the world was about 451 million and is projected to increase to 693 million by 2045¹⁰.  The extensiveness of its severity has become a matter of concern since it is not only affecting the BGL but also leads to various chronic and acute complications which include macrovascular complications such as coronary heart disease (CAD), peripheral artery disease and stroke while in microvascular complications it includes retinopathy, neuropathy, end-stage renal disease (ESRD) and lower extremity amputations¹¹. It has become an issue of concern as 12% ($727 Billion) of the health expenditure  around the world is spent on it and yet around 5 million people die because of this disease¹². Hence these statistics clearly indicates that DM is serious threat to mankind.

 

Classification of DM:

DM is clinically recognized by hyperglycemia (increased BGL) because of relative insulin insufficiency¹³. DM is broadly classified as Type I and II but it is also manifested in pregnancy, or due to chemical/drug induction, sometimes genetic defects etc¹⁴.

 

Type I DM:

It is also known as Disease of wealth.  In this case hyperglycemia occurs due to due to autoimmune response which may be mediated by genetic and environmental factors¹⁵.  In this state destruction of islets of Langerhans takes place consequently patients relying completely on exogenously administrated insulin^16,17. Major histocompatibility locus (HLA) at the HLA-DRB1 and DQB1 loci (421) and HLA-B*39 locus (259) account for about approximately 50% of the familial clustering of type I DM^18,19. Any change in lifestyle may lead to an imbalance in gut microbial status which contributing to increased gut permeability and hence causing T1DM²⁰. Since, in this type of DM exogenous supply of insulin is required to provide relief, so that insulin resistance exacerbated due to higher doses of insulin²¹.

 

Type II DM:

It accounts for major part of DM (85%). In this type of DM decrease in secretory function of insulin occur due to peripheral insulin resistance and increased insulin elease from pancreatic islets²¹. The tissue involve to show the reduced sensitivity towards insulin at this moment include liver, skeletal muscles and adipose tissues as they are the prime location for glucose regulation and metabolism²². The increase occurrence of type II DM is because of western lifestyle adaptation occurs mostly in developing countries associated with obesity.

 

Drugs involve in treatment of DM:

There are various drugs available for the treatment of diabetes but they are not providing sufficient relief as the DM is multifactorial in nature like Sulfonylurea, it provides a greater risk of heart failure when given in high‐dose as monotherapy with a patients suffering from type 2 diabetes. It is a class of drug which are the most commonly prescribed as antidiabetic drugs given by oral route to patients of type 2 DM²³. Principles of treatment DM involve 1. Metformin is the most suitable oral hypoglycemic agent. 2.  In case of non-toleration an alternative class of antihdiabetic agent can be given. 3. In monotherapy fails, combination therapy with a second agent can be adopted as they have different mechanism of action²⁴. Metformin like drugs are contraindicated in like dysfunction of hepatic system, chronic kidney disease, infection, and heart failure. Hence suggestion was given to use with care^25,26. Recently, a study suggesting that metformin use cause deficiency of vitamin B12 and anemia²⁷.

 

Side effects of monotherapy:

Although diabetes treatment using monotherapy of antidiabetic drugs can decrease the hyperglycaemia but they cannot provide safe outcomes in terms of their adverse reactions and might complicate the other bodily functions²⁸. Like sulfonylurea therapy alone can increase the risk of mortality, major adverse cardiovascular event (MACE), stroke and heart failure^29-31, metformin enhances the risk of gastrointestinal related side effects which are usually overcome by administering it as a combination to other antihyperglycemic drugs³². It can also cause vitamin B12 deficiency and lactic acidosis in rare cases^24,33. Dipeptidyl peptidase 4 (DPP4) inhibitors monotherapy may cause serious adverse effects like urticaria, angioedema, acute pancreatitis and even risk for heart failure³³, Sodium glucose cotransporter 2 (SGLT2) Inhibitors monotherapy can cause polyuria, mycotic genital infections, dehydration and to some extent it might cause benign urinary tract infections (UTIs^33,34 etc.

 

Need of combination therapy in DM:

As no single drug has been shown to provide complete pain relief^35,36, combination therapy with agents that act at different sites and by different mechanisms may be necessary for some patients. Rational multimodal polypharmacy may be beneficial in patients that do not respond to monotherapy and in those who are unable to receive the maximal dose of a particular treatment due to adverse effects³⁷. The diabetic neuropathic pain is usually difficult to treat because of its multiple aetiology and complexity in pathophysiology. Now a day, various available drugs have limited therapeutic potential for the management of NP. Hence, NP continues to pose challenges to medical system and scientific research^38-42. Current strategies use to of treat NP have provided symptomatic relief to the patients to some extent only, but complete cure is still a dream. Despite of huge synthetic diversity, natural products and its related structural analogues continued to be extremely important⁴³ as they present fewer and less side effects^{38, 44,45}. In the future, it is expected that a combination of new and improved pharmaceutical developments may lead to satisfy effective pain management to improve quality of life⁴⁶. There is dire need for improved treatment of NP⁴⁷ caused by diabetes. There are much evidence that monotherapy or combination therapy provides less percentage substantial pain relief and most of the time they have their own kinetic as well as pharmacological challenges. Sometimes they are needed for longer duration of time at higher doses too which brings about several complications and side effects. Combination of duloxetine (DXH) which is selective serotonin-norepinephrine reuptake inhibitor (SSNRI) and pregabalin has only been approved for the treatment of diabetic NP. However, their treatment as monotherapy at 60 and 300 mg/day, respectively exhibited partial kind of pain relief. It showed its effects to only 40% of patients^48,49. Curcumin (CRM), a drug having multiple targets is extensively reported for the treatment of various types of NP^38,50-54. It has been reported to possess antioxidant, anti-inflammatory, immunomodulatory, cancer chemo-preventive and neuro-protective activities^54-62. Apart from that, single treatment can’t works in all conditions of neuropathy⁶³. In table 1 and 2 benefits of combination therapy in treatment of diabetes in clinical evaluation are represented. This table also gives evidence for therapeutic benefit of combination therapy in preclinical evaluation.  Evidences for combination therapy in case of clinical study also documented here in table.2. 

Diabetic Complications:

Diabetes is not only limited to hyperglycemia but it also shows direct and indirect effects on the vascular structure of the body. Both Type 1 and Type 2 DM cause various microvascular and macrovascular complications which results in morbidity and mortality⁶⁴ in patients. Whenever microvascular complications arise it represents damage of small blood vessels and in case of macrovascular diseases, damage to the arteries takes place. Eye diseases, retinopathy, nephropathy and neuropathy come under the class of microvascular diseases of DM²¹, in present review actually we have discussed detailed preclinical and clinical available drugs given in combination form and how they are superior over monotherapy. Macrovascular complications include cardiovascular diseases associated with DM.

 

Diabetic Nephropathy (DNP):

It is well established that the person suffering from diabetes may face the challenges/complications of DNP. It is the most serious concern as it is the prime most cause for the failure of renal system. Basically it is indicated or recognized by albuminuria and enlargement of glomerulus due to alteration in the level of magnesium. Preclinical as well as clinical evidences suggest that hyperglycaemia is in close connection with vascular complications^65,66. DNP has been considered as the major cause of chronic kidney disease (CKD) and end stage renal disease (ESRD)⁶⁷. In DN there is occurrence of proteinuria or albuminuria or drop off in glomerular filtration rate (GFR) or both for extended period of time without interruption⁶⁸.

 

Table 1. Clinical evidences of potential therapeutic benefits of combination therapy in DM

 

Table.2. Clinical studies for the efficacy and safety of combination therapy over monotherapy in the treatment of DNP

CKD, chronic kidney disease; SGLT2, sodium-glucose cotransporter 2; DKA, diabetic ketoacidosis

 

Table 3 Clinical studies for combination therapy in DN

 

Risk factors for DNP:

1.     Hypertension: Hypertensive patients show more risk of microvascular complications as patients with high blood pressure that is <180/105mmHg has shown 37% higher risk of complication as compared to patients with <150/85mmHg of BP.

2.     Hyperglycaemia: A poor glycaemic control can affect the kidney function but if at early stage the hyperglycaemia is controlled in patients who are at early stage with either type 1 or type 2 DM then the risk of diabetic kidney disease is decreased.¹⁰⁹

3.     Dyslipidaemia: High level of triglycerides and low level of high density lipoproteins (HDL) leads to dyslipidaemia and this in turn increases the progression of diabetic retinopathy in type 2 diabetic patients as HDL provide renal protective action by reducing inflammation oxidative stress¹¹⁰.

 

Adverse effects in the treatment of diabtes and its complications using monotherapy

For the treatment of diabetes lifestyle modification (LSM) and monotherapy of antihyperglycemic drugs, preferably metformin is given as the first-line treatment but if glycaemic control is not reached then combination therapy of drugs with different mechanisms is specified²⁴. However, there are various types of drugs available for the treatment diabetes like biguanide, thiazolidinediones and sulfonylurea but the monotherapy of these drugs has certain limitations which can be overcome by combination therapy¹¹¹. It is already reported that development of albuminuria in type 2 DM is not only creating a concern for renal disease but also increasing the risk of cardio vascular disease. It is responsible to cause mortality by 4 fold. It is also very important to note that antihypertensive agents showed insufficient relief or non significant results in deceasing the level of albuminuria in type 2 diabetes. Clinical trial conducted indicates that metformin is ineffective in reducing albuminuria in short term as well as in long term treatment^112-114. Rosiglitazone class of drugs retarded albumin/creatinine ratio (ACR) with very slow rate. The rate of change of ACR over time was slowest with rosiglitazone (1.8% per year) versus metformin (5.2% per year), and glyburide (4.6% per year)¹¹⁴. Hence to avoid creation of multiple abnormalities and treatment of complications combination therapy is required to follow. Here in table 3  clinical study  indicates therapeutic benefits of combination of drugs in DNP.

 

Diabetic neuropathy (DN):

Diabetic neuropathy is the set of heterogenous disorders which is the result of long standing hyperglycemia and it affects the sensory and motor nerves of the body which leads to large fiber neuropathy (LFN) which further leads to impairment or absence of sensation, paraesthesia and poor balance or small fiber neuropathy (SFN) which involves burning pain or electric shocks¹¹⁵. The diabetic neuropathy is the result of nerve fiber degeneration and microangiopathy¹¹⁶. About 25% of diabetic patients with sensory loss in the limbs are inclined to develop diabetic foot ulcers with a 70% recurrence that ultimately results in lower limpamputation¹¹⁷.  DN occurrence is higher in case of type 2 diabetic patients as compared to type 1 diabetic patients¹¹⁸. In DN, neuropathic pain (NP) is one of the major concerns recognizing worldwide. Neuropathic pain (NP) is a terrible kind of tortures which causes infliction to the nerve. Despite various knowledge like sign, symptoms and causes behind this syndrome, its mechanistic details poorly understood^{36, 119}. NP results from damage to components of the nervous system such as primary afferent nerves, spinal cord, and central nervous system (CNS) regions¹²⁰. It is characterized by dysesthesia (unpleasant and abnormal sensation), hyperalgesia (exaggerated pain sensations due to exposure of mild noxious stimuli) as well as allodynia (pain in response to a non-painful stimulus)^{52, 119,121-125}. Spinal cord neurons exhibit changes in their response but it depends on size of the receptive fields when the peripheral tissue is activated in presence of noxious stimuli, electrical stimulation of nerve thin fibers, or damage of nerve fibers. Drugs tested in preclinical and clinical evaluations are mentioned in table 3.

 

Risk factors for DN:

DN is the most persistent complication of diabetes with high risk of treatment failure so its prevention should be taken by taking precaution against certain risk factors.¹²⁶

1.     BMI: Numerous researches has been done to find the interrelation between the body mass index (BMI) values and diabetic neuropathy among which some studies show that people with BMI >30 have higher risk of peripheral neuropathy¹²⁷

2.     Hypertension: The cardiovascular risk factors like baseline hypertension is found to be allied with the risk of neuropathy¹²⁸. Preclinical study in type II diabetes shows that HTN can aggravate the diabetic neuropathy due to myelin loss in nerves¹²⁹

3.     Age: The risk of polyneuropathy increases with the advancing age and the prevalence is more pronounced in elderly diabetic patients whereas it has also been proven that with older age neuronal damage might occur and that can be more influential in causing neuropathy even at prediabetic stage as compared to known diabetes^130-133

4.     Smoking and drinking: It has been proven that patients with smoking history has high risk of diabetic neuropathy and neuropathic pain^.134 Furthermore, according to analytical studies the risk of diabetic foot amputation also increases due to cigarette smoking¹³⁵ Frequent alcoholism causes nutritional deficiencies mainly that of vitamins and PNS toxicity due to accumulation of harmful metabolite of ethanol that  is acetaldehyde which ends up in neuropathy¹³⁶

5.     Others: Factors like increased total cholesterol, microalbuminuria, history of cardiovascular disease etc play a major role in producing the risk of diabetic neuropathy¹²⁸

 

CONCLUSION:

Although combination therapy provides better therapeutic results than monotherapy in the treatment of diabetes and its complications but it has some disadvantages also. Most of the combination therapies are well tolerated, providing influential impact, additive effect and synergistic effects. Hence, before administrating combination therapy one should know the physiological state and sensitivity of patients.

Authors are thankful to second International Conference of Pharmacy, held by School of Pharmaceutical Sciences, Lovely Professional University on September 13-14, 2019 to fund the publication of this manuscript.

 

REFERENCES:

1.   Cahn, A. and W.T. Cefalu, Clinical considerations for use of initial combination therapy in type 2 diabetes. Diabetes Care, 2016. 39(Supplement 2): p. S137-S145.

2.   Jameshorani, M., et al., Comparative study on adding pioglitazone or sitagliptin to patients with type 2 diabetes mellitus insufficiently controlled with metformin. Open access Macedonian journal of medical sciences, 2017. 5(7): p. 955.

3.   Kharroubi, A.T. and H.M. Darwish, Diabetes mellitus: The epidemic of the century. World J Diabetes, 2015. 6(6): p. 850-67.

4.   Ren, J., et al., Hearing impairment in type 2 diabetics and patients with early diabetic nephropathy. Journal of diabetes and its complications, 2018. 32(6): p. 575-579.

5.   Egan, A.M. and S.F. Dinneen, What is diabetes? Medicine, 2014. 42(12): p. 679-681.

6.   Guillausseau, P.-J., et al., Abnormalities in insulin secretion in type 2 diabetes mellitus. Diabetes and metabolism, 2008. 34: p. S43-S48.

7.   Holland-Carter, L., et al., Impact on psychosocial outcomes of a nationally available weight management program tailored for individuals with type 2 diabetes: results of a randomized controlled trial. Journal of Diabetes and its Complications, 2017. 31(5): p. 891-897.

8.   Md Rashedul Islam Rashed1, A.S., Md Al Sabah3, and M.M. Momin4, Review of diabetes types and Care. International Journal of Current Research in Medical Sciences, 2018. 4(11).

9.   Lam, D.W. and D. LeRoith, The worldwide diabetes epidemic. Curr Opin Endocrinol Diabetes Obes, 2012. 19(2): p. 93-6.

10. Sotoudeh, R., Zahra Gholamnezhad Mousa-Al-Reza Hadjzadeh, and Azita Aghaei, "The anti-diabetic and antioxidant effects of a combination of Commiphora mukul, Commiphora myrrha and Terminalia chebula in diabetic rats.". Avicenna journal of phytomedicine, 2019. 9.5: p. 454.

11. Harding, J.L., et al., Global trends in diabetes complications: a review of current evidence. Diabetologia, 2019. 62(1): p. 3-16.

12. Ghosh, K., P. Dhillon, and G. Agrawal, Prevalence and detecting spatial clustering of diabetes at the district level in India. Journal of Public Health, 2019.

13. Mathis, D., L. Vence, and C. Benoist, β-Cell death during progression to diabetes. Nature, 2001. 414(6865): p. 792.

14. Scheen, A.J., Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Drugs, 1997. 54(3): p. 355-368.

15. Harjutsalo, V., L. Sjöberg, and J. Tuomilehto, Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. The Lancet, 2008. 371(9626): p. 1777-1782.

16. Davies, J.L., et al., A genome-wide search for human type 1 diabetes susceptibility genes. Nature, 1994. 371(6493): p. 130.

17. Keenan, H.A., et al., Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes, 2010. 59(11): p. 2846-2853.

18. Nejentsev, S., et al., Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature, 2007. 450(7171): p. 887.

19. Hyttinen, V., et al., Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes, 2003. 52(4): p. 1052-1055.

20. Davis-Richardson, A.G. and E.W. Triplett, A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia, 2015. 58(7): p. 1386-1393.

21. Forbes, J.M. and M.E. Cooper, Mechanisms of diabetic complications. Physiological reviews, 2013. 93(1): p. 137-188.

22. Kahn, S.E., et al., Quantification of the relationship between insulin sensitivity and β-cell function in human subjects: evidence for a hyperbolic function. Diabetes, 1993. 42(11): p. 1663-1672.

23. McAlister, F.A., et al., The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. European journal of heart failure, 2008. 10(7): p. 703-708.

24. Rhee, S.Y., et al., Monotherapy in Patients with Type 2 Diabetes Mellitus. Diabetes Metab J, 2017. 41(5): p. 349-356.

25. Association, A.D., 8. Pharmacologic approaches to glycemic treatment. Diabetes Care, 2017. 40(Supplement 1): p. S64-S74.

26. Harper, W., et al., Pharmacologic management of type 2 diabetes. Canadian Journal of Diabetes, 2013. 37: p. S61-S68.

27. Aroda, V.R., et al., Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. The Journal of Clinical Endocrinology and Metabolism, 2016. 101(4): p. 1754-1761.

28. Maruthur, N.M., et al., Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med, 2016. 164(11): p. 740-51.

29. Sola, D., et al., Sulfonylureas and their use in clinical practice. Arch Med Sci, 2015. 11(4): p. 840-8.

30. Morgan, C.L., et al., What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes. J Clin Endocrinol Metab, 2012. 97(12): p. 4605-12.

31. Kasznicki, J. and J. Drzewoski, Heart failure in the diabetic population - pathophysiology, diagnosis and management. Arch Med Sci, 2014. 10(3): p. 546-56.

32. Blonde, L., S. Dipp, and D. Cadena, Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations. Adv Ther, 2018. 35(7): p. 939-965.

33. Ko, S.H., et al., Antihyperglycemic Agent Therapy for Adult Patients with Type 2 Diabetes Mellitus 2017: A Position Statement of the Korean Diabetes Association. Diabetes Metab J, 2017. 41(5): p. 337-348.

34. Scheen, A.J., SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf, 2015. 14(12): p. 1879-904.

35. Kaur, G., et al., Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats. Anais da Academia Brasileira de Ciências, 2015. 87(1): p. 417-429.

36. Kaur, G., A.S. Jaggi, and N. Singh, Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats. Journal of brachial plexus and peripheral nerve injury, 2010. 5(1): p. 3.

37. Tölle, T.R., Challenges with current treatment of neuropathic pain. European journal of pain Supplements, 2010. 4(2): p. 161-165.

38. Quintans, J.S., et al., Natural Products Evaluated in Neuropathic Pain Models‐A Systematic Review. Basic and clinical pharmacology and toxicology, 2014. 114(6): p. 442-450.

39. Woolf, C.J. and R.J. Mannion, Neuropathic pain: aetiology, symptoms, mechanisms, and management. The lancet, 1999. 353(9168): p. 1959-1964.

40. Dworkin, R.H., et al., Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain, 2007. 132(3): p. 237-251.

41. Dworkin, R.H., et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. in Mayo Clinic Proceedings. 2010. Elsevier.

42. Vo, T., A.S. Rice, and R.H. Dworkin, Non‐steroidal anti‐inflammatory drugs for neuropathic pain: How do we explain continued widespread use? Pain, 2009. 143(3): p. 169-171.

43. Ngo, L.T., J.I. Okogun, and W.R. Folk, 21st century natural product research and drug development and traditional medicines. Natural product reports, 2013. 30(4): p. 584-592.

44. Butler, M.S., Natural products to drugs: natural product-derived compounds in clinical trials. Natural product reports, 2008. 25(3): p. 475-516.

45. Li, J.W.-H. and J.C. Vederas, Drug discovery and natural products: end of an era or an endless frontier? Science, 2009. 325(5937): p. 161-165.

46. Gangadhar, M., et al., Future directions in the treatment of neuropathic pain: A review on various therapeutic targets. CNS and Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS and Neurological Disorders), 2014. 13(1): p. 63-81.

47. Dworkin, R.H. and D.C. Turk, Accelerating the development of improved analgesic treatments: the ACTION public–private partnership. Pain Medicine, 2011. 12(s3).

48. Tesfaye, S., et al., Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”–a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. PAIN®, 2013. 154(12): p. 2616-2625.

49. Ye, W., et al., Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder. BMC psychiatry, 2011. 11(1): p. 19.

50. Díaz-Triste, N.E., et al., Pharmacological evidence for the participation of NO–c GMP–K ATP pathway in the gastric protective effect of curcumin against indomethacin-induced gastric injury in the rat. European journal of pharmacology, 2014. 730: p. 102-106.

51. Li, Y., et al., Curcumin attenuates diabetic neuropathic pain by downregulating TNF-α in a rat model. International journal of medical sciences, 2013. 10(4): p. 377.

52. Kaur, M., et al., Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats. European journal of pharmacology, 2017. 805: p. 58-66.

53. Jeon, Y., et al., Curcumin could prevent the development of chronic neuropathic pain in rats with peripheral nerve injury. Current Therapeutic Research, 2013. 74: p. 1-4.

54. Anand, P., et al., Bioavailability of curcumin: problems and promises. Molecular pharmaceutics, 2007. 4(6): p. 807-818.

55. Vyas, A., et al., Perspectives on new synthetic curcumin analogs and their potential anticancer properties. Current pharmaceutical design, 2013. 19(11): p. 2047-2069.

56. Argyriou, A.A., et al., Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature. Cancer Manag Res, 2014. 6: p. 135-47.

57. Moorthi, C. and K. Kathiresan, Curcumin–Piperine/Curcumin–Quercetin/Curcumin–Silibinin dual drug-loaded nanoparticulate combination therapy: A novel approach to target and treat multidrug-resistant cancers. Journal of Medical Hypotheses and Ideas, 2013. 7(1): p. 15-20.

58. Aggarwal, B.B. and K.B. Harikumar, Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The international journal of biochemistry and cell biology, 2009. 41(1): p. 40-59.

59. Ahmad, M., Protective effects of curcumin against lithium-pilocarpine induced status epilepticus, cognitive dysfunction and oxidative stress in young rats. Saudi J Biol Sci, 2013. 20(2): p. 155-62.

60. Zhao, X., et al., Curcumin exerts antinociceptive effects in a mouse model of neuropathic pain: descending monoamine system and opioid receptors are differentially involved. Neuropharmacology, 2012. 62(2): p. 843-854.

61. Jain, K., S. Sood, and K. Gowthamarajan, Modulation of cerebral malaria by curcumin as an adjunctive therapy. The Brazilian Journal of Infectious Diseases, 2013. 17(5): p. 579-591.

62. Mendonça, L.M., et al., Curcumin reduces cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. Neurotoxicology, 2013. 34: p. 205-211.

63. Muthuraman, A. and N. Singh, Attenuating effect of Acorus calamus extract in chronic constriction injury induced neuropathic pain in rats: an evidence of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory effects. BMC complementary and alternative medicine, 2011. 11(1): p. 24.

64. Ndisang, J.F., A. Vannacci, and S. Rastogi, Insulin Resistance, Type 1 and Type 2 Diabetes, and Related Complications 2017. Journal of Diabetes Research, 2017. 2017: p. 1-3.

65. Xu, X.-X., et al., Superior renoprotective effects of the combination of breviscapine with enalapril and its mechanism in diabetic rats. Phytomedicine, 2013. 20(10): p. 820-827.

66. Najafian, B., C.E. Alpers, and A.B. Fogo, Pathology of human diabetic nephropathy, in Diabetes and the Kidney. 2011, Karger Publishers. p. 36-47.

67. Ameh, O.I., et al., Global, Regional, and Ethnic Differences in Diabetic Nephropathy, in Diabetic Nephropathy. 2019. p. 33-44.

68. JORGE L. GROSS, M.M.J.D.A., MD SANDRA P. SILVEIRO, MD and M.M.L.C. LU ́IS HENRIQUE CANANI, MD THEMIS ZELMANOVITZ, MD, Diabetic Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes care, 2005. 28: p. 164-176.

69. Widjajakusuma, E.C., et al., Phytochemical screening and preliminary clinical trials of the aqueous extract mixture of Andrographis paniculata (Burm. f.) Wall. ex Nees and Syzygium polyanthum (Wight.) Walp leaves in metformin treated patients with type 2 diabetes. Phytomedicine, 2019. 55: p. 137-147.

70. Sankar, D., et al., Sesame oil exhibits synergistic effect with anti-diabetic medication in patients with type 2 diabetes mellitus. Clin Nutr, 2011. 30(3): p. 351-8.

71. P. Berhanu, A.P.a.S.Y., Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy. Diabetes, Obesity and Metabolism, 2007: p. 512-520.

72. Matthews, D.R., et al., Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. The Lancet, 2019. 394(10208): p. 1519-1529.

73. Yu, H.M., et al., A comparison study on efficacy, insulin sensitivity and safety of Glimepiride/Metformin fixed dose combination versus glimepiride single therapy on type 2 diabetes mellitus patients with basal insulin therapy. Diabetes Res Clin Pract, 2019. 155: p. 107796.

74. Bernard Zinman, S.B.H., Jan Neuman, Hertzel C Gerstein, Ravi R Retnakaran, Janet Raboud, Ying Qi, Anthony J G Hanley, Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. 2010. 376.

75. Tatsumi, F., et al., Concomitant use of miglitol and mitiglinide as initial combination therapy in type 2 diabetes mellitus. Diabetes Res Clin Pract, 2013. 101(1): p. 35-44.

76. Fonseca, V., et al., Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications, 2013. 27(2): p. 177-83.

77. Bellido, D., et al., Intensification of Basal Insulin Therapy with Lixisenatide in Patients with Type 2 Diabetes in a Real-World Setting: The BASAL-LIXI Study. Curr Ther Res Clin Exp, 2018. 89: p. 37-42.

78. White, W.B., et al., Alogliptin in Patients with Type 2 Diabetes Receiving Metformin and Sulfonylurea Therapies in the EXAMINE Trial. Am J Med, 2018. 131(7): p. 813-819 e5.

79. Kanazawa, I., et al., Long-term efficacy and safety of vildagliptin add-on therapy in type 2 diabetes mellitus with insulin treatment. Diabetes Res Clin Pract, 2017. 123: p. 9-17.

80. Wang, J.S., et al., Acarbose plus metformin fixed-dose combination outperforms acarbose monotherapy for type 2 diabetes. Diabetes Res Clin Pract, 2013. 102(1): p. 16-24.

81. R. Gomis1, R.-M.E., R. Jones3, H. J. Woerle4 and K. A. Dugi5, Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. DIABETES, OBESITY AND METABOLISM, 2011. 13: p. 653-661.

82. Julio Rosenstock, L.C., 2, et al., Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Na ̈ıve Type 2 Diabetes. Diabetes Care, 2016.

83. Ralph A. DeFronzo, A.L., 2, D. 344 SanjayPatel, ReneeKaste,, and a.U.C.B. Hans J. Woerle, Combination of Empagliflozin and Linagliptin as Second-Line Therapy in Subjects With Type 2 Diabetes Inadequately Controlled on Metformin. Diabetes Care, 2015. 38: p. 384-393.

84. K. H. Yoon1, H.S., R. Teng2, G. T. Golm2, M. Lee2, E. A. O’Neill2, K. D. Kaufman2 and B. J. Goldstein2, Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study. Diabetes, Obesity and Metabolism, 2012.

85. Konya, H., et al., Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes, 2013. 6: p. 317-25.

86. Ishii, H., et al., Efficacy of combination therapy with sitagliptin and low-dose glimepiride in Japanese patients with type 2 diabetes. J Clin Med Res, 2014. 6(2): p. 127-32.

87. Chen, Y., et al., Effects of Different Doses of Irbesartan Combined With Spironolactone on Urinary Albumin Excretion Rate in Elderly Patients With Early Type 2 Diabetic Nephropathy. Am J Med Sci, 2018. 355(5): p. 418-424.

88. Roozbeh, J., et al., Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. Ren Fail, 2010. 32(2): p. 172-8.

89. Persson, F., et al., Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol, 2011. 6(5): p. 1025-31.

90. Momeni, A., et al., Evaluation of spironolactone plus hydrochlorothiazide in reducing proteinuria in type 2 diabetic nephropathy. J Renin Angiotensin Aldosterone Syst, 2015. 16(1): p. 113-8.

91. Lukashevich, V., et al., Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment. Vasc Health Risk Manag, 2013. 9: p. 21-8.

92. Fallahzadeh, M.K., et al., Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial. Am J Kidney Dis, 2012. 60(6): p. 896-903.

93. Esteghamati, A., et al., Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol Dial Transplant, 2013. 28(11): p. 2823-33.

94. Heerspink, H.J., et al., Effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes and chronic kidney disease. Eur Heart J, 2010. 31(23): p. 2888-96.

95. Morikawa, A., et al., Pioglitazone reduces urinary albumin excretion in renin-angiotensin system inhibitor-treated type 2 diabetic patients with hypertension and microalbuminuria: the APRIME study. Clin Exp Nephrol, 2011. 15(6): p. 848-53.

96. Zhu, H., et al., Telmisartan combined with probucol effectively reduces urinary protein in patients with type 2 diabetes: A randomized double-blind placebo-controlled multicenter clinical study. J Diabetes, 2016. 8(5): p. 677-85.

97. Bakris, G.L., et al., Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int, 1998. 54(4): p. 1283-9.

98. Jacobsen, P., et al., Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol, 2003. 14(4): p. 992-9.

99. Hamed, A.T., M.M. Taha, and L.M. Nasser, Renoprotective effect of aliskiren monotherapy and aliskiren−pentoxifylline combination in hypertensive-diabetic type 2 patients with diabetic nephropathy. Bulletin of Faculty of Pharmacy, Cairo University, 2013. 51(2): p. 221-227.

100. Luo, Y., et al., Use of Ophiocordyceps sinensis (syn. Cordyceps sinensis) combined with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus ACEI/ARB alone in the treatment of diabetic kidney disease: a meta-analysis. Ren Fail, 2015. 37(4): p. 614-34.

101. Massone, F.B.a.A., Combination of Alpha Lipoic Acid and Superoxide Dismutase Leads to Physiological and Symptomatic Improvements in Diabetic Neuropathy. 2012. 12(1): p. 29-34.

102. Xu, Q., et al., Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Res Clin Pract, 2013. 101(2): p. 99-105.

103. Hanna, M., C. O'Brien, and M.C. Wilson, Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain, 2008. 12(6): p. 804-13.

104. Vasudevan, D., M.M. Naik, and Q.I. Mukaddam, Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol, 2014. 17(1): p. 19-24.

105. Gilron, I., et al., Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. The Lancet, 2009. 374(9697): p. 1252-1261.

106. Tesfaye, S., et al., Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain, 2013. 154(12): p. 2616-25.

107. Jiang, D.Q., et al., Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy. J Clin Neurosci, 2016. 27: p. 8-16.

108. Mimenza Alvarado, A. and S. Aguilar Navarro, Clinical Trial Assessing the Efficacy of Gabapentin Plus B Complex (B1/B12) versus Pregabalin for Treating Painful Diabetic Neuropathy. J Diabetes Res, 2016. 2016: p. 4078695.

109. Radica Z. Alicic, M.T.R., * and Katherine R. Tuttle*, Diabetic Kidney Disease Challenges, Progress, and Possibilities. Clinical Journal of the American Society of Nephrology. 12(12).

110. Song, K.H., et al., Discordance in risk factors for the progression of diabetic retinopathy and diabetic nephropathy in patients with type 2 diabetes mellitus. J Diabetes Investig, 2019. 10(3): p. 745-752.

111. Rashid, M., et al., Fenofibrate Potentiates the Antihyperglycemic, Antidyslipidemic and Hepatoprotective Activity of Pioglitazone on Alloxan-Induced Diabetic Rats. Pharmacologia, 2016. 7(1): p. 53-59.

112. Miyazaki, Y., et al., Rosiglitazone decreases albuminuria in type 2 diabetic patients. Kidney international, 2007. 72(11): p. 1367-1373.

113. Holman, R.R., et al., 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine, 2008. 359(15): p. 1577-1589.

114. Lachin, J.M., et al., Renal function in type 2 diabetes with rosiglitazone, metformin, and glyburide monotherapy. Clinical Journal of the American Society of Nephrology, 2011. 6(5): p. 1032-1040.

115. Iqbal, Z., et al., Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clin Ther, 2018. 40(6): p. 828-849.

116. Yagihashi, S. and H. Mizukami, Diabetic Neuropathy, in Diabetes and Aging-related Complications. 2018. p. 31-43.

117. Catherine N. Tchanque-Fossuo, M., MS; Andrew M. Wishy, DO; Kaitlyn I. M. West; David L. Dawson, MD; Sara E. Dahle, DPM, MPH; and John G. Carson, MD, Reclaiming Autologous Amputated Tissue for Limb Salvage of a Diabetic Foot Burn with Underlying Critical Limb Ischemia. Advances in skin and wound, 2018. 31(1): p. 596-600.

118. Mixcoatl-Zecuatl, T. and N.A. Calcutt, Biology and Pathophysiology of Painful Diabetic Neuropathy, in Painful Diabetic Polyneuropathy. 2013. p. 13-26.

119. Jaggi, A.S., V. Jain, and N. Singh, Animal models of neuropathic pain. Fundamental and clinical pharmacology, 2011. 25(1): p. 1-28.

120. Ueda, H., Molecular mechanisms of neuropathic pain–phenotypic switch and initiation mechanisms. Pharmacology and therapeutics, 2006. 109(1): p. 57-77.

121. Bansode, V.J., et al., Ameliorative effect of ethyl pyruvate in neuropathic pain induced by chronic constriction injury of sciatic nerve. Indian Journal of Pain, 2014. 28(2): p. 82.

122. Bridges, D., S. Thompson, and A. Rice, Mechanisms of neuropathic pain. British journal of anaesthesia, 2001. 87(1): p. 12-26.

123. Chaplan, S.R., et al., Quantitative assessment of tactile allodynia in the rat paw. Journal of neuroscience methods, 1994. 53(1): p. 55-63.

124. Yoon, C., et al., Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain, 1994. 59(3): p. 369-376.

125. Cohen, S.P. and J. Mao, Neuropathic pain: mechanisms and their clinical implications. Bmj, 2014. 348(f7656): p. 1-12.

126. Liu, X., et al., The risk factors for diabetic peripheral neuropathy: A meta-analysis. PLoS One, 2019. 14(2): p. e0212574.

127. Smith, A.G. and J.R. Singleton, Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications, 2013. 27(5): p. 436-42.

128. Solomon Tesfaye, M.D., Nish Chaturvedi, M.D., Simon E.M. Eaton, D.M., John D. Ward, M.D., Christos Manes, M.D., Constantin Ionescu-Tirgoviste, M.D., Daniel R. Witte, Ph.D., and John H. Fuller, M.A.,, Vascular Risk Factors and Diabetic Neuropathy. The new england journal of medicine, 2005. 352(4).

129. De Visser, A., et al., The adjuvant effect of hypertension upon diabetic peripheral neuropathy in experimental type 2 diabetes. Neurobiol Dis, 2014. 62: p. 18-30.

130. Battula, P., et al., Prevalence of sensory peripheral neuropathy in diabetic patients at diabetes care centre: a cross sectional study. International Journal of Research in Medical Sciences, 2017. 5(9).

131. Ziegler, D., et al., Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with pre-diabetes and diabetes. The KORA Myocardial Infarction Registry. Eur J Pain, 2009. 13(6): p. 582-7.

132. Ziegler, D., et al., Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol, 2014. 126: p. 3-22.

133. Papanas, N. and D. Ziegler, Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015. Rev Diabet Stud, 2015. 12(1-2): p. 48-62.

134. Win, M., et al., Prevalence of peripheral neuropathy and its impact on activities of daily living in people with type 2 diabetes mellitus. Nurs Health Sci, 2019.

135. Liu, M., et al., Smoking increases the risk of diabetic foot amputation: A meta-analysis. Exp Ther Med, 2018. 15(2): p. 1680-1685.

136. Koike, H., Myelopathy and Neuropathy Associated With Alcoholism, in Neuroscience of Alcohol. 2019. p. 195-205.

 

 

Received on 02.12.2019           Modified on 02.04.2020

Accepted on 07.06.2020         © RJPT All right reserved