Endocrinology and Diabetes Open Access

ISSN 2631-374X

Metabolic Correction As a Proposed Approach for Reduction of Complications and Costs of Diabetes Care in Puerto Rico

Jorge R. Miranda-Massari1, Michael J. González3*, Francisco J. Jiménez Ramírez1, Jorge Duconge2, Heriberto Marín4, Myriam Z. Allende-Vigo5, Ricardo Aguirre6, Miguel J. Berdiel7, Iván Paz ND8, Carlos Cidre MD9

1Department of Pharmacy Practice, School of Pharmacy, Medical Sciences Campus, UPR, San Juan, PR

2Department of Basic Science, School of Pharmacy, Medical Sciences Campus, UPR, San Juan, PR

3Department of Human Development, School of Public Health, Medical Sciences Campus, UPR, San Juan, PR

4Department of Administration of Health Services, School of Public Health, Medical Sciences Campus, UPR, San Juan, PR

5Division of Endocrinology, School of Medicine, Medical Sciences Campus, UPR, San Juan, PR

6Department of Business Administration, Sagrado Corazón University, San Juan, PR

7Clínica Berdiel, Ponce, PR

8Clínica Novis, San Juan, PR

9Clínica Dr Cidre, Guaynabo, PR

Corresponding author

Michael J Gonzalez
Department Human Development
Medical Sciences Campus
School of Public Health
University of Puerto Rico
GPO Box 365067, San Juan P.R 00936-5067
Tel: 787-758-2525 x 1405
Email: michael.gonzalez5@upr.edu

  • Received Date: 30 August, 2017
  • Accepted Date: 28 January, 2018
  • Published Date: 31 January, 2018

DOI:   10.31021/edoa.20181103

Article Type:   Case Report

Manuscript ID:   EDOA-1-103

Publisher:   Boffin Access Limited

Volume:   1.1

Journal Type:   Open Access

Copyright:   © 2018 González MJ, et al.
Creative Commons Attribution 4.0


Miranda-Massari JR, González MJ, Jiménez Ramírez FJ, Duconge J, Marín H, et al. Metabolic Correction As a Proposed Approach for Reduction of Complications and. Costs of Diabetes Care in Puerto Rico. Endocrinol Diabetes Open Access. 2018 Jan; 1(1):103


Diabetes is among the leading causes of death and disability worldwide. In the United States, diabetes is a principal cause of kidney failure, non-traumatic lower-extremity amputations, and blindness among adults.In Puerto Rico, given the even higher prevalence of this condition than in most countries, implementation of innovative, science-based and cost effective strategies is urgent. Despite the implementation of accepted treatment guidelines that include diet and medications, the prevalence of the disease, its complications and costs continue to rise. In this concept paper, costs estimate of diabetes and its complications in Puerto Rico are presented and discussed. A brief discussion of the limitations of current treatment guidelines and how metabolic correction may help overcome some of those limitations are included. Finally, we briefly discuss how the implementation of metabolic correction may reduce the costs of diabetes and its complications.


Diabetes, Metabolic Correction, Diabetes Cost

Diabetes Background and Statistics

Diabetes Mellitus (DM), a metabolic disease characterized by glucose and insulin abnormalities, often leads to many complications such as heart disease, stroke, hypertension, blindness, kidney disease, nerve disease and many others. This condition is among the leading causes of death and disability worldwide [1]. In the United States, diabetes is a principal cause of kidney failure, non-traumatic lower-extremity amputations, and blindness among adults [2].In the US population the prevalence of DM is 8.3% (2011) and ranks as the 7th cause of death [3]. Globally, it has been estimated that 366 million people had diabetes, 50% of them undiagnosed in 2011 with estimated projections of 552 million people with diabetes by the year 2030 [4]. In Puerto Rico, the scenario related to DM is much worse, having a prevalence of 12.9% (approximately 500,000 persons) for 2009 and reaching the 3rd cause of death [5-10].

The Cost of Diabetes

The social cost of Diabetes Mellitus (DM) in the USA for 2012 was $245 billion ($176 billion in direct medical cost and $69 billion in loss of productivity)[11]. Of that cost, $47 billion are for chronic diabetes-related complications [11,12]. Complications of Diabetic Peripheral Neuropathy (DPN) as it continues its natural course, produces increasing pain, loss of sensation, ulcers, infections, amputations and death. In addition to suffering, disability and loss of productivity, there is a very significant economic impact related to the treatment of DPN and its complications. In USA alone, it has been estimated that more than 5,000,000 patients suffer from DPN, and the total annual cost of treating the disease and its complications is over $10 billion [13]. There is another concern with people that do not yet meet the diagnostic criteria of diabetes, but have blood glucose in the upper level of normal values. It has been shown that these people have increased risk of other diseases (such as cancer, nerve, kidney, cardiovascular and others) [14-17]. It has been estimated that the cost of pre-diabetes for the 57 million adult population in 2007 in the USA exceeded $ 25 billion [10,18].

With respect to Puerto Rico, there is no published or official estimate of the social cost of DM. However, in an unpublished report submitted by Dr Marín to the Center of Diabetes of Puerto Rico in 2012, the annual social cost of DM for the adult population was estimated to be $2,290 million [19]. Out of this, $1,559 million (68%) were in direct costs to the healthcare system and $731 million (32%) were for indirect costs due to productivity loss. From the direct costs, 56.9% was generated by patients older than 64, and for indirect costs, 89% was generated by patients younger than 65. The per capita (per person) annual social cost of DM patients was estimated in $6,351, distributed in $4,324 for direct costs and $2,027 for indirect costs. Per capita annual costs among the older patients (over 64 years old) were $6,825; for middle age (45 to 64) were $6,124, and for younger patients (18 to 44) were $5,800 [18].

Diabetes medical costs are expected to maintain a constant growth during the next years. Evidence to this fact is the trend demonstrated by a recent market study that shows diabetes care sales having a Compound Annual Growth Rate (CAGR) higher than that of the general pharmaceutical industry sales. The study estimated that while the total pharmaceutical prescription sales (are) expected to have a growth rate 3.6% CAGR by the year 2015, diabetes care will experience a CAGR of 7.8% for the same period [20]. Recently, Standard & Poor’s estimated that the annual market for diabetes drugs will hit $58 billion by 2018, from about $35 billion today (2013)[20]whereas a Transparency Market Research study estimated the market for diabetes drugs and devices to attain a size of $114.3 billion by 2016, following a growth rate of 18.2% [21]. (Table 1)

Table 1

Table 1: Estimates of Social Costs of Diabetes in Puerto Rico for the year 20101
1.Dr. Heriberto Marin used estimates for the social costs of Diabetes in the United States as based to generate estimates for Puerto Rico. The source used for the US was the following: United States Economic Cost of Diabetes in the U.S. in 2007, American Diabetes Association, Diabetes Care, Volume 31, Number 3, March 2008. In order to generate the estimates for Puerto Rico the following steps were taken: 1) the number of adult diabetic patients in Puerto Rico by age group was obtained from the BRFSS, 2)the average direct and indirect cost by patient were imputed from the US, 3) costs were aggregated for each age group to generate total costs, 4) figures were inflated to the year 2010 using the price indexes for Puerto Rico, and 5) all figures were adjusted downward using the fact that Medicare payments in Puerto Rico are in average 60% of those in the US.
2.According to the Behavioral Risk Factor Surveillance System (BRFSS) for 2010. http://www.cdc.gov/brfss/

The World Health Organization latest published numbers on diabetes prevalence showed that diabetes is a growing global problem, with high and increasing costs to society and the individual [22]. Mayor pharmaceutical companies are incurring in substantial capital investment responding to what they have recognized as the growing diabetes epidemic. Keeping the diabetes care cost low is of great concern, especially since 80% of people with diabetes live in low to middle-income countries [22,23].

Diabetes Clinical Data (Limitations of Clinical Treatment Guidelines)

Current Clinical Management Guidelines of DPN are based on adequate glucose control and symptomatic pain relief [24]. Careful glycemic control could delay the onset or slow the progression of diabetic neuropathy in patients with diabetes mellitus, but it does not completely prevent the progression of the disease [15]. Elevated glucose levels are a fundamental biochemical abnormality, but not the only metabolic abnormality implicated in the DM pathophysiology.

In order to be able to reduce complications of DPN, it is crucial to improve or correct the metabolic conditions that lead to the pathology present in this condition. The first step toward this end must be an appropriate diet that will foster insulin sensitivity, reduction of blood glucose and glycation and reduction of inflammation. In order to accomplish this, carbohydrates must be well controlled in balance with healthy sources of proteins and fats. These are necessary macro- changes. However, micro-changes are often needed for the fine tuning of metabolism and achieving healthy state. These changes are key to further improve metabolism. Proper diet is the fundamental basis of health, providing a balance of macro and micronutrients. The metabolic needs of any particular person are a balance of the combination of external factors (contaminants, microorganisms and other stressors) and the body’s own internal factors (genetically determined individual metabolic capacity). In certain circumstances, diet alone might not be enough to account for these unmet metabolic needs, and allow re-establishing a healthy physiology. An innovative, scientific-based approach aimed to correct the biochemical abnormalities of the disease denominated “Metabolic Correction” has been proposed.25-30 The main objective of this publication is to present Metabolic Correction as a cost effective therapy to complement current therapeutic methods.

Metabolic Correction As a Therapeutic Tool for Diabetes

Metabolic correction is the utilization of a synergistic combination of micronutrients and cofactors in the active forms and doses that maximize the function of metabolic enzymes in most individuals. Metabolic correction helps improve or rectify biochemical disruptions associated with a diversity of dysfunctional mechanisms that lead to degenerative states. Metabolic correction is the fine tuning of the cellular biochemistry by means of specific nutritional supplementation with the goal of improving cellular, tissue, organ, system and organism function [29].

Pathophysiologic mechanisms implicated in diabetic neuropathy include: increased polyol pathway with accumulation of sorbitol and reduced Na+/K+- ATPase activity, microvascular damage and hypoxia due to nitric oxide deficit and increased oxygen free radical activity. Moreover, there is a decrease in glutathione and the increase in homocysteine. Clinical trials in the last two decades have demonstrated that the use of specific nutrient cofactors can correct some of these metabolic derangements, improving symptom control and providing further benefits such as improved sensorium, blood flow and nerve regeneration. There is substantial evidence on those nutrient cofactors such as lipoic acid, acetyl-L-carnitine, benfotiamine and the combination of active B vitamins, L-methylfolate, methylcobalamin and pyridoxal-6-phosphate, providing important benefits for patients with diabetic neuropathy [31-36]. Metformin, the first line drug in the management of diabetes type 2, uses folic acid and B12 for its metabolism, therefore people with poor nutrient intake, gastrointestinal malabsorption and metabolic susceptibilities may be at risk of drug-induced nutrient depletion when using this form of therapy [37,38]. In addition, there is a high prevalence of the polymorphic gene mutation of MTFHR in the Hispanic population [39,40]. This could pose a significant risk for depletion of the active form of folic acid, as well as an increase in homocysteine both linked to an increased risk of developing DPN.

Health and Economic Projections of the Utilization of Metabolic Correction As a Therapeutic Tool for Diabetes

The health benefits of metabolic correction can be divided into its impact in the complications of the condition and in the reduction of adverse drug events. One such complication is the elevated risk of cardiovascular diseases observed in diabetes patients. Therefore safer diabetes treatment needs to be sought. Recognizing this need, the US Food and Drug Administration published guidelines for the industry requesting that entities with drugs under review or to be developed for treatment of diabetes prove that such drugs do not increase adverse events of cardiovascular outcomes [41].

The integration of Metabolic Correction in the management of people with medical conditions such as diabetes or at risk for serious complications such as DPN, constitutes a new paradigm. Considering the whole cost of the management of the pre-diabetic and diabetics including the cost of medications, the management of the adverse effects of medications and the cost of complications; the use of metabolic correction is expected to improve outcomes beyond current accepted guidelines and reduce overall cost. Considering the published literature on concerning the effect of individual nutrients on diabetic peripheral neuropathy, a synergistic formulation based on the concept of metabolic correction would be expected to result in improved outcomes. The evidence in published reports pertaining to the reduction of the complications of DM amounts to 10-20% when integrated as part of a judicious treatment [31-36]. A metabolic correction formula is expected to improve glucose levels as well as other biochemical parameters providing better blood supply, improving nitric oxide status, reducing homocysteine and improving cellular aerobic energy. Overall, this is expected to result in reduced morbidity and mortality, improved quality of life and increased productivity in the affected population.

Cost of Medication related morbidity and mortality (MM) in ambulatory patients in the USA has increased more than two-fold from $76 billion/yr in 1995 to $177 billion/yr in 2001 [42,43]. At this rate of increase, the Cost of Medication related MM should surpass $700 billion by 2013 [44]. There are no estimates of Cost of Medication related MM for Puerto Rico, but adjusting for the differential in payment in costs between USA and PR it could be estimated between $2,000-$4,000 million.

Scholars in pharmaco-economics have proposed the concept of Pharmaceutical Care (PC) as a way to improve health care and reduce cost [45,46]. Despite the importance of PC, its ability to decrease costs has a limit in the vicinity of 20-30%. Its limitations are related to its inability to prevent the progress of the disease and the effect of medication-induced nutrient depletion. Interestingly enough, there are indications that intensive lifestyle interventions can prevent or delay the onset of diabetes related complications in people with diabetes [46]. We propose Metabolic Correction as a complementary concept to PC to produce further improvements in both clinical outcomes and cost reductions related to medication MM. This concept has cost savings implications not only in the creation of public policies, but for the individual decisions. Patients have to pay medical visits, once their health insurance exceeds the of a visit and treatment. For some patients this may have significant economic costs since they have to pay full for their follow up treatment.


Given the amount spent in Puerto Rico for the complications of DM ($304 million), the use of this innovative strategy (Metabolic Correction), is expected to produce savings of $30-60 million of dollars. In addition, further benefits could be expected when factoring the effect of Metabolic Correction on the cost of Medication-related MM (adverse effects). If the cost of the adverse effects is between $2 to 4 billion, then the potential savings from metabolic correction for this would be $300-600 millions. Therefore, the net savings from the use of metabolic correction is very significant because it reduces both the complications and cost of the disease and the adverse effects of the medication. The impact of Metabolic Correction of reducing adverse effects, complications and cost saving potential can be tested in various models. We have proposed and will proceed testing a simple model of Metabolic Correction in diabetic patients with modification of the type of macronutrients and proportions, hydration and supplementation (Table 1).


  1. WHO. Integrated chronic disease prevention and control. Geneva: Word Health Organization. C2018. Available from http://www. who.int/chp/about/integrated_cd/en/
  2. CDC, National Diabetes Statistics Report, 2014. Available from https://www.cdc.gov/diabetes/pdfs/data/2014-reportestimates-of-diabetes-and-its-burden-in-the-united-states.pdf.
  3. American Diabetic Association. Statistics About Diabetes. Data from the National Diabetes Statistics Report, 2014. Available from http://www.diabetes.org/diabetes-basics/ statistics/?referrer=https://www.google.com/ (Ref.)
  4. International Diabetes Federation. Diabetes: The Global Burden. Available from: http://diabetes.ufl.edu/global-impact/ (Ref.)
  5. Instituto de Estadísticas de Puerto Rico, Estado Libre Asociado de Puerto Rico.Nuevas Estadísticas de Mortalidad. Available from: http://www2.pr.gov/agencias/diabetes/Documents/Diabetes/ DIABETES%20EN%20PUERTO%20RICO.pdf (Ref.)
  6. Oficina del Censo Puerto Rico. Censo 2000. Available from https://www.census.gov/prod/2002pubs/c2kprof00-pr(s).pdf (Ref.)
  7. Instituto de Estadísticas de Puerto Rico. Informe de enfermedades crónicas, Puerto Rico 2012. Available from http://www.salud. gov.pr/Estadisticas-Registros-y-Publicaciones/Publicaciones/ Informe%20de%20enfermedades%20cr%C3%B3nicas%20 en%20Puerto%20Rico%202012.pdf (Ref.)
  8. US Census Bureau. Population Estimates. Available from: https:// www.census.gov/topics/population.html (Ref.)
  9. Behavioral Risk Factor Surveillance System (BRFSS). Available from: https://www.cdc.gov/brfss/index.html (Ref.)
  10. Diabetes. Available from: https://www.cdc.gov/diabetes/basics/ diabetes.html (Ref.)
  11. Hogan P, Dall T, Nikolov P; American Diabetes Association. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003 Mar;26(3):917-932. (Ref.)
  12. American Diabetes Association. Economic costs of diabetes in the U.S. In 2012. Diabetes Care. 2013 Apr;36:1033-1046. (Ref.)
  13. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care. 2003 Jun;26(6):1790-1795. (Ref.)
  14. Hemminki K, Li X, Sundquist J, Sundquist K. Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 2010;15: 548–555. (Ref.)
  15. Donahue RP, Abbott RD, Reed DM, Yano K. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes. 1987 Jun;36(6):689–692. (Ref.)
  16. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003 Jan;60(1):108-111. (Ref.)
  17. Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol. 2006 Aug;63:1075-1079. (Ref.)
  18. Zhang Y, Dall TM, Chen Y, Baldwin A, Yang W, et al. Medical cost associated with prediabetes. Popul Health Manag. 2009 Jun;12(3):157-163. (Ref.)
  19. Marín Heriberto A. El Costo Social de la Diabetes en Puerto Rico, Unpublished report for the Center of Diabetes of Puerto Rico, 2012.
  20. Global pharma market will reach $1.12 trillion in 2022. Available from: http://pharmaceuticalcommerce.com/business-andfinance/global-pharma-market-will-reach-1-12-trillion-2022/ (Ref.)
  21. GEN Genetic Engeneer and Biotechnology News. New Diabetes Drugs Moving Through the Pipeline. Available from: http://www. genengnews.com/keywordsandtools/print/3/33029/(Ref.)
  22. World Health Organization (WHO). Diabetes: the cost of diabetes. Available from: www.who.int/diabetes/ (Ref.)
  23. International Diabetes Federation. IDF Diabetes Atlas. Available: www.idf.org/diabetesatlas (Ref.)
  24. American Diabetes Association. Standards of Medical Care in Diabetes 2013. Diabetes Care. 2013 Jan;36. (Suppl 1) 11-66. (Ref.)
  25. Gonzalez MJ, Miranda-Massari JR, Metabolic Correction: A Functional Explanation of Orthomolecular Medicine. J Orthomolec Med. 2012 Nov;27(1):13-20. (Ref.)
  26. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, Allende-Vigo M, Duconge J. Metabolic Correction in the Management of Diabetic Peripheral Neuropathy: Improving Clinical Results beyond Symptom Control. Curr Clin Pharmacol. 2011 Nov;6(4):206-273. (Ref.)
  27. González MJ, Miranda-Massari JR, Cintrón K, Berdiel MJ, Muñiz A. Corrección Metabólica: Estrategia Terapéutica Bioquímicofisiológica para mejorar funciones y alcanzar un estado Saludable Medicine. Galenus. 2012;32:17-19. (Ref.)
  28. Mikirova NA, Rogers AM, Taylor PR, Hunninghake RE, MirandaMassari JR, et al. Metabolic Correction for Attention Deficit/ Hyperactivity Disorder: A Biochemical-Physiological Therapeutic Approach. Functional Foods in Health and Disease. 2013;3(1):1- 20. (Ref.)
  29. González MJ, Miranda-Massari JR, Duconge J, Allende-Vigo MZ, Jiménez-Ramírez FJ, et al. Metabolic correction: a functional biochemical mechanism against disease--Part 1: concept and historical background. P R Health Sci J 2015 Mar;34(1):3-8. (Ref.)
  30. Miranda-Massari JR, González MJ, Duconge J, Allende-Vigo MZ, Jiménez-Ramírez FJ, et al. Metabolic correction: a functional biochemical mechanism against disease--Part 2: mechanisms and benefits. P R Health Sci J 2015 Mar;34(1):9-13. (Ref.)
  31. Nikolić A, Kacar A, Lavrni D, Basta I, Apostolski S. The effect of benfothiamine in the therapy of diabetic polyneuropathy. Srp Arh Celok Lek 2009 Nov-Dec;137(11-12):594-600. (Ref.)
  32. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomized, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes 2008 Nov;116(10):600-605. (Ref.)
  33. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes . 2006 Nov;29(11):2365-2370 (Ref.)
  34. Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabetes Med. 1999;16(12):1040-1043. (Ref.)
  35. Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94. (Ref.)
  36. Jacobs AM, Cheng D. Management of Diabetic Small Fiber Neuropathy with Combination L-methyl folate, methylcobalamine and pyridoxal 5’-phosphate. Rev Neurol Dis. 2011;8:39-47. (Ref.)
  37. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. 2010;340:c2181. (Ref.)
  38. Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, et al. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003 Nov;254(5):455-63. (Ref.)
  39. Barber R, Shalat S, Hendricks K, Joggerst B, Larsen R, et al. Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas hispanic populatio006E. Mol Genet Metab 2000 May;70(1):45-52. (Ref.)
  40. Pensg F, Labelle LA, Rainey BJ, Tsongalis GJ. Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. Int J Mol Med. 2001;8(5):509-511. (Ref.)
  41. FDA Guidance for Industry. Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). December 2008. Available from http://www.fda.gov/ downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/ucm071627.pdf
  42. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med. 1995 Oct;155(18):1949- 1956. (Ref.)
  43. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc. 2001 MarApr;41 (2): 192-199. (Ref.)
  44. Diabetes medications. Available from https://www.nehi.net/ bendthecurve/sup/documents/Medication_Adherence_Brief. pdf. (Ref.)
  45. Isetts BJ. Pharmaceutical care, MTM, & payment: the past, present, & future. Ann Pharmacother. 2012;46(4):S47-S56. (Ref.)
  46. Ramalho de Oliveira D, Brummel AR, Miller DB. Medication therapy management: 10 years of experience in a large integrated healthcare system. J Manag Care Pharm. 2010 Apr;16(3):185- 195. (Ref.)
  47. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther. 2008 Nov; 88(11): 1254-1264. (Ref.)