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INSULIN OR ORAL ANTI-DIABETIC AGENT FOR PATIENTS WITH

DIABETIC FOOT ULCER?

Norlaila Mustafa, MD

1st November 2014, IJN

OVERVIEW

� Epidemiology of diabetes

� Complications of diabetes

� Diabetic foot ulcers (DFU)

� Hyperglycaemia and outcomes

� Anti-diabetic agents and their issues

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AN EPIDEMIC OF DIABETES

• By 2030 the number of people with diabetes globally will rise to an estimated

552 MILLION The International Diabetes Foundation, IDF Diabetes Atlas, 5th ed.: http://www.idf. org/diabetesatlas/5e/the-global-burden (Accessed 2-23-12)

TOP 10 COUNTRIES BY DIABETES CASES IN THE WESTERN PACIFIC REGION

Country Cases(million)

1. China 92.3

2. Indonesia 7.6

3. Japan 7.1

4. Philippines 4.3

5. Thailand 3.4

6. Republic of Korea 3.2

7. Vietnam 3.2

8. Malaysia 2.1

9. Australia 1.9

10. Myanmar 1.8

Adapted from International Diabetes Federation. Diabetes Atlas Update 2012 .Available from http://www.idf.org/sites/default/files/IDF_WP_5E_Update_FactSheet.pdf (accessed 9 Jan 2013)

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STATUS OF DIABETES MELLITUS IN MALAYSIA 1986-2011

1986 NHMS

I

1996 NHMS

II2006 NHMS III 2011 NHMS IV

Age group (years)

>35 >30 > 18>18 -<30

>30 > 18 >30

Diabetes prevalence (%)

6.3 8.3 11.6 1.4 14.9 15.2 20.8

1. Letchuman et al. Med J Malaysia , 65:3 ; 2010; 2. Lee JF and Hussein Z. Diabetes – the new Malaysian epidemic? Available from: http://thestar.com.my/health/story.asp?file=/2012/7/22/health/11702759&sec=health (accessed 5 Oct 2012); Liow TL. Strengthening Malaysia’s Healthcare System: The Way Forward, Government Seeking Public Views. Available from: http://www.liowtionglai.com/index.php?option=com_content&view=article&id=206%3Astrengthening-malaysias-healthcare-system-the-way-forward-government-seeking-public-views&catid=4%3Afeatured&Itemid=15&lang=en (accessed 5 Oct 2012)

COMPLICATIONS OF DIABETES

HEART DISEASE & STROKEBoth the risk for stroke and heart disease related deaths are 2 to 4 times higher in

adults with diabetes

HYPERTENSIONIn 2005-2008, 67% of adults with

diabetes had high blood pressure or used prescription medications for hypertension

BLINDNESS & EYE PROBLEMSDiabetes is the leading cause of new cases of blindness among adults aged 20-74

years

KIDNEY DISEASEDiabetes was the leading cause of kidney failure , accounting for 44% of all new

cases of kidney failure in 2008

NERVOUS SYSTEM DISEASE About 60% to 70% of diabetics have some form of nervous system damage

LOWER-LIMB AMPUTATIONSNearly 30% of all people with diabetes 40 years or older have impaired sensation in

their feet

National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ ndfs_2011.pdf. Accesse8 February 2012.

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COMPLICATIONS OF DIABETES

� Patients with diabetes take an average of 4-5 MEDICINES A DAY

� Diabetes greatly compounds A POOR QUALITY OF LIFE associated with other diseases

� A person with diabetes has about TWICE THE RISK OF DYING as a person of similar age without diabetes

National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ ndfs_2011.pdf. Accessed 8 February 2012.

Sprangers MA, de Regt EB, Andries F, et al. Which chronic conditions are associated with better or poorer quality of life? J Clin epidemiol. 2000;53:895- 907.

Wee H-L, Cheung Y-B, Shu-Chuen Li1, Kok-Yong Fong K-Y, Thumboo J. The impact of diabetes mellitus and other chronic medical conditions on health-related Quality of Life: Is the whole greater than the sum of its parts? Health and Quality of Life Outcom es 2005, 3:2

Leichter S, Faulkner S, Camp J. On the Cost of Being a Diabetic Patient: Variables for Physician Prescribing Behavior. Clinical Diabetes. 2000;18(1):42-3.

Chester B. Good, MD, MPH. Polypharmacy in Elderly Patients With Diabetes. Diabetes Spectrum. 2002;15(4):240-248.

DIABETES AND FOOT

� Hospitalized Patients WITH DIABETES are 28XMORE LIKELY to have an amputation than patients without diabetes

� More than 60% of all non-traumatic LIMB AMPUTATIONS in the U.S. occur in people WITH DIABETES

National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department

of Health and Human Services, Centers for Disease Control and Prevention, 2011. Available at http://www.cdc.gov/diabetes/pubs/pdf/ ndfs_2011.pdf.

Accessed 8 February 2012.

Economic and Health Costs of Diabetes. U.S. Department of Health & Human Services website. Available at http://archive.ahrq.gov/data/hcup/highlight1/ high1. htm. Accessed 8 February 2012.

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DIABETES AND FOOT

• Nearly a quarter of people with diabetes will develop a diabetic foot ulcer (DFU).

• Despite the prevalence and disabling consequences of a DFU, many lack awareness of this serious diabetic complication.

• DFUs open the door for infection; the longer the DFU persists, the greater the risk of hospitalization and infections like MRSA.

• Diabetic patients with a DFU are at significantly increased risk for amputation and loss of life.

DFU: A SERIOUS COMPLICATION

Among all people with diabetes, UP TO 4% ANNUALLY will develop a DFU.

will develop a DFUin their lifetime

Singh N, Armstrong DG, Lipsky BA. Preventing Foot Ulcers in Patients With Diabetes. JAMA.2005;293(2):217-228

Reiber GE. Epidemiology of foot ulcers and amputations in the diabetic foot. In: Bowker JH, Pfeifer MA, eds. The Diabetic Foot. St Louis, Mo: Mosby; 2001:13-32.

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DFU: A SERIOUS COMPLICATION

• PERIPHERAL VASCULAR DISEASE & NEUROPATHY are major contributing factors to diabetic foot ulcers

• DFUs that PERSIST are predisposed to MRSA & other difficult-to-treat infections

• Patients who develop an INFECTED diabetic foot ulcer have a 55X GREATER RISK OF HOSPITALIZATION

Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29:1288-93.Ndip A, Rutter MK, Vileikyte L, et al. Dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and stage 4 or 5 chronic

kidney disease. Diabetes Care. 2010;33:1811-6. Yates C, May K, Hale T, et al. Wound chronicity, inpatient care, and chronic kidney disease predispose to MRSA infection in diabetic foot ulcers. Diabetes Care.

2009;32:1907-9.

DFU: A SERIOUS COMPLICATION

� Presence of a DFU for 30 DAYS or longer carries 4-fold risk of infection

� 85% of lower limb amputations, in patients with diabetes, ARE PRECEDED BY ULCERATION

Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29:1288-93.

Singh N, Armstrong DG, Lipsky BA. Preventing Foot Ulcers in Patients With Diabetes. JAMA.2005;293(2):217-228

Reiber GE. Epidemiology of foot ulcers and amputations in the diabetic foot. In: Bowker JH, Pfeifer MA, eds. The Diabetic Foot. St Louis, Mo: Mosby; 2001:13-32.

American Diabetes Association. Consensus development conference on diabetic foot wound care, 7-8 April 1999; Boston, MA. Diabetes Care. 1999;22:1354-60.

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DFU: A SERIOUS COMPLICATION

• In patients with diabetes, a HISTORY of foot ulcer alone INCREASED MORTALITY RISK BY 47%

IversNorway. Diabetes Care. 2010;33:2365-9.

Armstrong DG, Wrobel J, Robbins JM. Guest editorial: are diabetes-related wounds and amputations worse than cancer? Int Wound J. 2007;4(4):286-287.

en MM, Tell GS, Riise T, et al. History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag Health Study,

THE CHRONIC ULCER

• Diabetic foot ulcers often fail to heal because persistently high concentrations of pro-inflammatory cytokines in the wound

– induce high concentrations of proteases

– which degrade multiple growth factors, receptors, and matrix proteins that are essential for wound healing

• Even with good, standard wound care, healing neuropathic ulcers in patients with diabetes continues to be a challenge.

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THE CHRONIC ULCER

The larger, longer lasting DFU takes longer to heal and presents a greater opportunity:

�For infection

�For becoming a chronic non-healing wound

Zimny S, Voigt A, Schatz H, Pfohl M. Prediction of Wound Radius Reductions and Healing Times in Neuropathic Diabetic Foot Ulcers. Diabetes Care. 2003;26(3): 959- 960.

Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent Change in Wound Area of Diabetic Foot Ulcers Over a 4-Week Period Is a Robust Predictor of Complete Healing in a

12-Week Prospective Trial. Diabetes Care. 2003; 26:1879 –1882.

THE CHRONIC ULCER Healing of Neuropathic Ulcers

Results of a Meta-analysis

MEANHEALINGRATE

24.2%

30.9%

(N = 450) (N = 172)

A meta-analysis of 10 control groups in clinical trials evaluating treatments for diabetic neuropathic foot ulcers revealed that approximately 70% of

DFUs are slow to heal.

Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care. 1999; 22(5):692-695.

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HYPERGLYCEMIA AND POOR HOSPITAL OUTCOME

Metabolic stress response

↑↑↑↑ stress hormones and peptides

↑ Glucose

↓ Insulin

Immune dysfunction

Infection dissemination

Cellular injury/apoptosisInflammationTissue damage

Altered tissue wound repair

Prolonged hospital stayDisability / Death

↑ FFA↑ Ketones↑ Lactate

↑ Reactive O2 species

↑ Transcription factors

↑ Secondary mediators

Clement et al, Diabetes Care 27:553-591, 2004

HYPERGLYCEMIA IS UNDESIRABLE!

� Epidemiologic and uncontrolled observational studies suggest that hyperglycemia is associated with adverse outcomes in a wide range of hospital patients

� Interventional trials have shown that improved glycemiccontrol is associated with improved outcomes in several different patient populations, including those with:� Acute myocardial infarction� Cardiac surgery� Critical illness

� The evidence supporting metabolic control in inpatients has been reviewed

Diabetes Care 2004; 27: 553-91, Endocrine Practice 2004; 10: 77-82, and Diabetes Care 2006; 29: 1955-62

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HYPERGLYCAEMIA IN DFU

� Predispose to new infections

� Delayed wound healing

� Spreading of existing infections

� Septicaemia

FOOT INFECTIONS ARE COMMON IN DIABETICS AND ASSOCIATED WITH HIGH MORBIDITY AND

RISK OF LOWER LIMB AMPUTATION

Better glycaemic control better wound healing

A1c increased(n=101)

A1c stable/decrea

sed(n=105)

P value

All wounds healed 20.7% 26.5% <0.05

Dermal substitute-managed healed

21% 47% <0.05

Marston WA, Dermagraft Diabetic Foot ulcer Study Group

Ostomy Wound manage 2006;52:26-32.

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HOW TO ACHIEVE EUGLYCAEMIA?

� Best achieved by prescribing insulin therapy patients with DU� Long standing diabetes� Microvascular complications� As well as CAD

� DFU patients do harbour infections

� Insulin regimen can be tailor-made to suit the needs of an individual patient

THE ISSUE OF HYPOGLYCEMIA

� Fear of hypoglycemia often results in the use of non-physiologic insulin regimens (e.g. sliding scale insulin, alone)

� Using too little insulin and purposefully allowing hyperglycemia would only be appropriate if hyperglycemia were entirely benign or if adequate metabolic control were an unattainable goal

� It has been demonstrated that rates of hypoglycemia in the hospital can be reduced by using standardized, physiologic insulin regimens

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HOW TO ACHIEVE EUGLYCAEMIA?

� Use of oral anti diabetic agent is not contraindicated

� Patients with DFU, having long-standing diabetes may not respond to oral agents so effectively

� With infections on board, do have insulin resistant state

ORAL ANTIDIABETES AGENTS

� Oral agents can be continued in stable patients with normal nutritional intake, normal blood glucose levels, and stable renal and cardiac function. However, there are several potential disadvantages to using these medications in certain patients:

� Disadvantages of most oral agents:� Slow-acting/difficult to titrate

� Disadvantages of insulin secretagogues (e.g. sulfonylureas and meglitinides such as glyburide, glypizide, repaglinide, etc.):� Hypoglycemia if caloric intake is reduced� Some are long-acting (hypoglycemia may be prolonged)

� Disadvantages of metformin:� Lactic acidosis can occur when used in the setting of renal dysfunction,

circulatory compromise, or hypoxemia� Slow onset of action� GI complications: Nausea, diarrhea

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ORAL ANTIDIABETES AGENTS

� Disadvantages of thiazoladinediones (e.g. rosiglitazone, pioglitazone):

� Slow onset of action (2-3 weeks)

� Can cause fluid retention (particularly when used with insulin), and increase risk for CHF

� Disadvantages of alpha-glucosidase inhibitors (e.g. acarbose, miglitol)

� Abdominal bloating and flatus

� Need pure glucose to treat hypoglycemia

� Disadvantages of GLP-1 mimetics (e.g. exenatide)

� Newer agents without data to support use in the hospital

� Abdominal bloating and nausea secondary to delayed gastric emptying

OTHER ANTIDIABETES AGENTS

� Incretin-based therapies are vasodilators, increase cardiac output slightly by improving endothelial dysfunction

� GLP-1 receptor agonist causes acute significant drops in SBP

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ROLE OF ORAL AGENT

� Cannot be totally rule out

� Address insulin resistance, thus reduce insulin requirement

� Prandial regulators e.g. α-glucosidase inhibitors and glinides as an adjunct to basal insulin therapy

� DPP-4 inhibitors can be used to control post-prandial plasma glucose

J Wound Care 2005; 14(6): 277-281

Group 1(Non

diabetic)

Group 2(DM on insulin)

Group 3(DM on OHA)

P value

DNA fragmentation

40.00 ± 2.97 45.26 ± 3.21 60.8 ± 3.13 <0.01

THE EFFECT OF GLYCAEMIC CONTROL ON APOPTOSIS IN CHRONIC ULCERS IN DIABETIC PATIENTS

DNA fragmentation and morphological changes under light microscopy (apoptotic index) were used as determinants of apoptosis

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WHAT IS THE APPROPRIATE GLYCEMIC CONTROL TARGET FOR IN PATIENTS?

� Controversial!

ICU Non-ICU, Preprandial

Non-ICU, Maximum

ACCE/ACE 6.1 mmol/L 6.1 mmol/L 10 mmol/L

ADA 6.1 mmol/L 5-7.2 mmol/L 10 mmol/L

CURRENT PRACTICE ≠ ““““BEST PRACTICE””””

� Dependence on non-physiologic insulin prescribing (as opposed to insulin that mimics physiologic insulin secretion)

� Dependence on reactive strategies (e.g. sliding-scale insulin)

� Overemphasis on simplicity (particularly simplicity from the perspective of the ordering physician)

� Overemphasis on avoidance of hypoglycemia

� Lack of standardization of insulin use in the hospital

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WHAT IS THE ““““BEST PRACTICE”””” FOR MANAGING DIABETES AND HYPERGLYCEMIA?

� The answer is anticipatory, physiologic insulin dosing, prescribed as a basal/bolus insulin regimen

� This means giving the right type of insulin, in the right amount, at the right time, to meet the insulin needs of the patient

INSULIN REGIMEN� Basal bolus insulin i.e. full dose insulin

� Pre-mixed insulin twice a day

� Basal plus insulin

� Bedtime insulin plus OHAs

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CONCLUSION

� DFUs are very common diabetic complication

� Usually in long standing diabetic patients

� Hyperglycaemia is the key role in the development of DFUs

� Maintaining euglycaemia is important in treating DFUs

� Choice of agent is insulin, easy to titrate

THANK YOU FOR YOUR ATTENTION