Fenofibrate Reduces the Risk of Amputations in Patients
Добавлено: 11.09.2008, 12:41
Fenofibrate treatment in people with type 2 diabetes mellitus reduces the risk of amputations, including those associated with microvascular disease, according to new data from the FIELD study presented for the first time at the European Association for the Study of Diabetes, Rome, September 2008.(1) These findings add to other microvascular benefits demonstrated with fenofibrate in diabetic retinopathy, published in The Lancet 2007,(2) and diabetic nephropathy, published in The Lancet 2005.(3)
The FIELD study researchers showed that, over an average follow-up of 5 years, treatment with fenofibrate reduced the risk of non-traumatic amputation by 38% (p=0.011), mainly due to a reduction in amputation considered related to microvascular disease by 47% (p=0.025). Patients who had an amputation associated with microvascular disease were slightly younger and heavier and were more likely to have other microvascular disease, including diabetic eye and kidney disease.
According to Professor Keech, lead investigator of the FIELD study: "The effects of fenofibrate in reducing the risk of amputations in patients with established microvascular complications were particularly striking, and further support the important clinical benefits of fenofibrate on microvascular associated events in type 2 diabetes."
The FIELD analysis on amputations
All non-traumatic amputations that occurred during the FIELD study were reviewed by 2 clinicians blinded to study treatment. Reasons for amputation were recorded as presumed microvascular (amputations of toes or forefoot (called "minor" amputations), without embolism or existing large artery disease in the limb) or macrovascular (all other "minor" and all below-knee and above-knee ("major") amputations).
The profile of patients more likely to require amputation was:
- Male
- Longer duration of diabetes
- Higher systolic blood pressure
- Current smoker
- Previous vascular disease
- More microvascular complications
- More insulin use at baseline
All these characteristics were considerably more common than in patients who did not undergo amputation.
Among all patients with an amputation, the profile of patients with a microvascular-associated complication was:
- Slightly younger (p=0.03)
- Heavier (p<0.001)
- Slightly higher HbA1c (p=0.07)
- More other microvascular complications (p=0.002)
Significance for millions of type 2 diabetes patients
Peripheral neuropathy (nerve damage) is a serious complication of diabetes. Recent data indicate that one in 5 people with diabetes (20%) have peripheral neuropathy, irrespective of whether diabetes has been clinically diagnosed. The risk for peripheral neuropathy is about 2-fold higher than in people without diabetes.(4) The combination of peripheral neuropathy with problems associated with the blood supply to the feet can lead to foot ulcers and slow-healing wounds. Infection of these wounds can result in amputation. Every 30 seconds a limb is lost to diabetes and 40-70% of all lower extremity amputations are related to diabetes.(5)
Evidence indicates that improvements in management, specifically drug therapy, have contributed to a decline in cardiovascular mortality in patients with diabetes.(6) As people with diabetes live longer, they are more likely to experience microvascular complications of diabetes. Together with the increasing prevalence of type 2 diabetes among an ageing population,(7) the burden of microvascular complications, including diabetic neuropathy and amputation, is expected to increase substantially in the future.
Even when treated in accordance with current standards for diabetes care, patients remain at high residual risk of vascular complications. This is highlighted by evidence from the STENO-2 trial in patients with type 2 diabetes. Despite optimal control of LDL-cholesterol and diastolic blood pressure and fair glycaemic and systolic blood pressure control, microvascular disease such as diabetic retinopathy, nephropathy or neuropathy developed or progressed in up to 50% of these patients within 8 years.(8)
Fenofibrate reduces the total cardiovascular risk in patients with type 2 diabetes and atherogenic dyslipidaemia (elevated triglycerides and low HDL-cholesterol)
While current management strategies aimed at lowering LDL cholesterol with statin therapy are effective in reducing cardiovascular risk in patients with diabetes, supported by extensive evidence from a large number of well-controlled studies,(9) there are also clear limitations to statin treatment. Even at optimal statin doses, extensive evidence from large clinical trials show that 65-90% of CVD events in diabetes patients are not prevented with statin therapy.(9) This is largely because statins only partly address the abnormalities of low HDL-cholesterol and elevated triglycerides which are common in patients with type 2 diabetes. It is important to note that triglyceride and HDL-cholesterol levels are strong predictors of cardiovascular events, even in patients achieving LDL-cholesterol levels below 1.8mmol/L (70mg/dL)
Additional FIELD data presented at this year's EASD highlight that cardiovascular risk reduction with fenofibrate treatment is greatest in patients with type 2 diabetes with atherogenic dyslipidaemia (the combination of elevated triglycerides (>2.3mmmol/L) plus low high-density lipoprotein [HDL] cholesterol (<1.0mmol/L for men and <1.3mmol/L for women); fenofibrate treatment showed a 27% reduction in CVD risk in these patients.(10) The FIELD study investigators showed that in patients with marked diabetic dyslipidemia, 23 patients have to be treated with fenofibrate for 5 years to avoid one CV event (NNT = 23), which is comparable with the benefits of statin therapy already shown in landmark trials.
These new data highlight the benefits of fenofibrate on amputations, including microvascular-associated amputations. Together, with previously published data showing benefits for the eye and the kidney, these results highlight the urgent need to address residual vascular risk in patients with type 2 diabetes.
Notes to editors
About the study
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is the largest study of lipid modifying therapy ever conducted in diabetic patients with and without dyslipidaemia. It randomised 9795 patients aged 50-75 years from Australia, New Zealand and Finland with type 2 diabetes. The subjects were treated with either fenofibrate or placebo for five years.
FIELD is the first study to show that a lipid modifying agent, fenofibrate, reduces the risk of macrovascular and microvascular events in a large prospective clinical trial in patients with type 2 diabetes.(3)
In addition a sub-study was conducted in order to evaluate the development of diabetic retinopathy and the symptoms of eye disease.(2)
About diabetic amputations
Diabetes is the most common reason for lower-limb amputation that is not the result of accident, responsible for 40% to 70% of all lower-limb amputations.(5) This means that every 30 seconds a limb is lost to diabetes.(5) People with diabetes are at least 25 times more likely to suffer a lower-limb amputation than those without diabetes.(11)
The combination of diabetic neuropathy (nerve damage) and problems with blood supply to the feet predispose to the development of ulcers and slow-healing wounds, which if infected may lead to amputation. Studies suggest that up to 70% of people with diabetes have evidence of diabetic neuropathy, and about 30% of people with diabetes aged 40 years or more have impaired feeling in the feet, indicative of peripheral neuropathy.(12) The risk for peripheral neuropathy is about 2-fold higher in people with diabetes than in those without.(7) Pathological changes associated with the development of diabetic neuropathy and risk for amputation are related to poor glycaemic control and microvascular changes in the diabetic foot.(13)
Within 3 years, 30% of people with diabetes who undergo lower-limb amputation will go on to have a second amputation(14). About 70% of people with diabetes die within 5 years of amputation.(15) Lower limb amputation is also costly, both in terms of the acute cost related to the amputation, as well as ongoing management,(16, 17) and impacts substantially on quality of life.(18)
About diabetes/metabolic syndrome and the associated risks
Patients with diabetes and/or metabolic syndrome are known to be at higher cardiovascular risk, as recognised by current treatment guidelines.(19-21) Notably, diabetes is recognised as a 'coronary risk equivalent', by the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)(22), based on evidence from a number of well-designed observational studies that people with diabetes are at about 2-4-fold higher risk of premature cardiovascular mortality compared with those without diabetes.(23-25)
These patients typically have an abnormal lipid profile characterised by low high-density lipoprotein (HDL) cholesterol and elevated triglycerides, often with elevated levels of small, dense low-density lipoprotein particles, although levels of low-density lipoprotein (LDL) cholesterol are often normal. Extensive epidemiological evidence shows that elevated triglycerides(26) and low HDL cholesterol(27) are each independent predictors of cardiovascular risk.
About fenofibrate
Fenofibrate is marketed widely by Solvay Pharmaceuticals as LIPANTHYL(R) and LIPIDIL(R), and marketed by Abbott Laboratories in the USA as TRICOR(R).
References
1. Colman P, Rajamani,K., Li, L.-P. ,D'Emden, M. ,Voysey, M. ,Keech, A. . Benefits of long-term fenofibrate therapy on amputations in type 2 diabetes mellitus in the FIELD trial European Association for the Study of Diabetes (EASD). Rome, Italy; 2008.
2. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. Nov 17 2007;370(9600):1687-1697.
3. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. Nov 26 2005;366(9500):1849-1861.
4. Gregg EW, Gu Q, Williams D, de Rekeneire N, Cheng YJ, Geiss L, Engelgau M. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. Sep 2007;77(3):485-488.
5. IDF. Position statement: The diabetic foot: amputations are preventable. International Diabetes Federation. Available at: http://www.idf.org/home/index.cfm?node=1408. Accessed 9 July 2008.
6. Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med. Aug 7 2007;147(3):149-155.
7. Sloan FA, Bethel MA, Ruiz D, Jr., Shea AM, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med. Jan 28 2008;168(2):192-199; discussion 199.
8. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. Jan 30 2003;348(5):383-393.
9. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. Jan 12 2008;371(9607):117-125.
10. O'Brien R, Scott, R. ,Best, J. ,Taskinen, M.-R. ,Pardy, C. ,Ehnholm, C. ,Keech, A. . The clinical value of metabolic syndrome and its components in established type 2 diabetes mellitus: the FIELD trial Paper presented at: European Association for the Study of Diabetes (EASD); September 2008, 2008; Rome, Italy.
11. IDF. Diabetes Atlas. Available at: http://www.eatlas.idf.org/. Accessed 4 August, 2008.
12. NIH. National Diabetes Statistics, 2007. Available at: http://diabetes.niddk.nih.gov/dm/pubs/statistics/. Accessed 4 August, 2008.
13. Davis WA, Norman PE, Bruce DG, Davis TM. Predictors, consequences and costs of diabetes-related lower extremity amputation complicating type 2 diabetes: the Fremantle Diabetes Study. Diabetologia. Nov 2006;49(11): 2634-2641.
14. Philbin TM, Leyes M, Sferra JJ, Donley BG. Orthotic and prosthetic devices in partial foot amputations. Foot Ankle Clin. Jun 2001;6(2):215-228.
15. Schofield CJ, Libby G, Brennan GM, MacAlpine RR, Morris AD, Leese GP. Mortality and hospitalization in patients after amputation: a comparison between patients with and without diabetes. Diabetes Care. Oct 2006;29(10):2252-2256.
16. O'Brien JA, Patrick AR, Caro JJ. Cost of managing complications resulting from type 2 diabetes mellitus in Canada. BMC Health Serv Res. Mar 21 2003;3(1):7.
17. von Ferber L, Koster I, Hauner H. Medical costs of diabetic complications total costs and excess costs by age and type of treatment results of the German CoDiM Study. Exp Clin Endocrinol Diabetes. Feb 2007;115(2):97-104.
18. Willrich A, Pinzur M, McNeil M, Juknelis D, Lavery L. Health related quality of life, cognitive function, and depression in diabetic patients with foot ulcer or amputation. A preliminary study. Foot Ankle Int. Feb 2005;26(2):128-134.
19. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith Jr SC, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev. Nov-Dec 2005;13(6):322-327.
20. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. May 2006;23(5):469-480.
21. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet. Sep 24-30 2005;366(9491):1059-1062.
22. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. Dec 17 2002;106(25):3143-3421.
23. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. Feb 1993;16(2):434-444.
24. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. Apr 2001;24(4):683-689.
25. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. Jan 14 2006;332(7533):73-78.
26. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. Jan 30 2007;115(4):450-458.
27. Assmann G, Schulte H, Cullen P, Seedorf U. Assessing risk of myocardial infarction and stroke: new data from the Prospective Cardiovascular Munster (PROCAM) study. Eur J Clin Invest. Dec 2007;37(12) :925-932.
Distributed by PR Newswire on behalf of CTC, University of Sydney
The FIELD study researchers showed that, over an average follow-up of 5 years, treatment with fenofibrate reduced the risk of non-traumatic amputation by 38% (p=0.011), mainly due to a reduction in amputation considered related to microvascular disease by 47% (p=0.025). Patients who had an amputation associated with microvascular disease were slightly younger and heavier and were more likely to have other microvascular disease, including diabetic eye and kidney disease.
According to Professor Keech, lead investigator of the FIELD study: "The effects of fenofibrate in reducing the risk of amputations in patients with established microvascular complications were particularly striking, and further support the important clinical benefits of fenofibrate on microvascular associated events in type 2 diabetes."
The FIELD analysis on amputations
All non-traumatic amputations that occurred during the FIELD study were reviewed by 2 clinicians blinded to study treatment. Reasons for amputation were recorded as presumed microvascular (amputations of toes or forefoot (called "minor" amputations), without embolism or existing large artery disease in the limb) or macrovascular (all other "minor" and all below-knee and above-knee ("major") amputations).
The profile of patients more likely to require amputation was:
- Male
- Longer duration of diabetes
- Higher systolic blood pressure
- Current smoker
- Previous vascular disease
- More microvascular complications
- More insulin use at baseline
All these characteristics were considerably more common than in patients who did not undergo amputation.
Among all patients with an amputation, the profile of patients with a microvascular-associated complication was:
- Slightly younger (p=0.03)
- Heavier (p<0.001)
- Slightly higher HbA1c (p=0.07)
- More other microvascular complications (p=0.002)
Significance for millions of type 2 diabetes patients
Peripheral neuropathy (nerve damage) is a serious complication of diabetes. Recent data indicate that one in 5 people with diabetes (20%) have peripheral neuropathy, irrespective of whether diabetes has been clinically diagnosed. The risk for peripheral neuropathy is about 2-fold higher than in people without diabetes.(4) The combination of peripheral neuropathy with problems associated with the blood supply to the feet can lead to foot ulcers and slow-healing wounds. Infection of these wounds can result in amputation. Every 30 seconds a limb is lost to diabetes and 40-70% of all lower extremity amputations are related to diabetes.(5)
Evidence indicates that improvements in management, specifically drug therapy, have contributed to a decline in cardiovascular mortality in patients with diabetes.(6) As people with diabetes live longer, they are more likely to experience microvascular complications of diabetes. Together with the increasing prevalence of type 2 diabetes among an ageing population,(7) the burden of microvascular complications, including diabetic neuropathy and amputation, is expected to increase substantially in the future.
Even when treated in accordance with current standards for diabetes care, patients remain at high residual risk of vascular complications. This is highlighted by evidence from the STENO-2 trial in patients with type 2 diabetes. Despite optimal control of LDL-cholesterol and diastolic blood pressure and fair glycaemic and systolic blood pressure control, microvascular disease such as diabetic retinopathy, nephropathy or neuropathy developed or progressed in up to 50% of these patients within 8 years.(8)
Fenofibrate reduces the total cardiovascular risk in patients with type 2 diabetes and atherogenic dyslipidaemia (elevated triglycerides and low HDL-cholesterol)
While current management strategies aimed at lowering LDL cholesterol with statin therapy are effective in reducing cardiovascular risk in patients with diabetes, supported by extensive evidence from a large number of well-controlled studies,(9) there are also clear limitations to statin treatment. Even at optimal statin doses, extensive evidence from large clinical trials show that 65-90% of CVD events in diabetes patients are not prevented with statin therapy.(9) This is largely because statins only partly address the abnormalities of low HDL-cholesterol and elevated triglycerides which are common in patients with type 2 diabetes. It is important to note that triglyceride and HDL-cholesterol levels are strong predictors of cardiovascular events, even in patients achieving LDL-cholesterol levels below 1.8mmol/L (70mg/dL)
Additional FIELD data presented at this year's EASD highlight that cardiovascular risk reduction with fenofibrate treatment is greatest in patients with type 2 diabetes with atherogenic dyslipidaemia (the combination of elevated triglycerides (>2.3mmmol/L) plus low high-density lipoprotein [HDL] cholesterol (<1.0mmol/L for men and <1.3mmol/L for women); fenofibrate treatment showed a 27% reduction in CVD risk in these patients.(10) The FIELD study investigators showed that in patients with marked diabetic dyslipidemia, 23 patients have to be treated with fenofibrate for 5 years to avoid one CV event (NNT = 23), which is comparable with the benefits of statin therapy already shown in landmark trials.
These new data highlight the benefits of fenofibrate on amputations, including microvascular-associated amputations. Together, with previously published data showing benefits for the eye and the kidney, these results highlight the urgent need to address residual vascular risk in patients with type 2 diabetes.
Notes to editors
About the study
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is the largest study of lipid modifying therapy ever conducted in diabetic patients with and without dyslipidaemia. It randomised 9795 patients aged 50-75 years from Australia, New Zealand and Finland with type 2 diabetes. The subjects were treated with either fenofibrate or placebo for five years.
FIELD is the first study to show that a lipid modifying agent, fenofibrate, reduces the risk of macrovascular and microvascular events in a large prospective clinical trial in patients with type 2 diabetes.(3)
In addition a sub-study was conducted in order to evaluate the development of diabetic retinopathy and the symptoms of eye disease.(2)
About diabetic amputations
Diabetes is the most common reason for lower-limb amputation that is not the result of accident, responsible for 40% to 70% of all lower-limb amputations.(5) This means that every 30 seconds a limb is lost to diabetes.(5) People with diabetes are at least 25 times more likely to suffer a lower-limb amputation than those without diabetes.(11)
The combination of diabetic neuropathy (nerve damage) and problems with blood supply to the feet predispose to the development of ulcers and slow-healing wounds, which if infected may lead to amputation. Studies suggest that up to 70% of people with diabetes have evidence of diabetic neuropathy, and about 30% of people with diabetes aged 40 years or more have impaired feeling in the feet, indicative of peripheral neuropathy.(12) The risk for peripheral neuropathy is about 2-fold higher in people with diabetes than in those without.(7) Pathological changes associated with the development of diabetic neuropathy and risk for amputation are related to poor glycaemic control and microvascular changes in the diabetic foot.(13)
Within 3 years, 30% of people with diabetes who undergo lower-limb amputation will go on to have a second amputation(14). About 70% of people with diabetes die within 5 years of amputation.(15) Lower limb amputation is also costly, both in terms of the acute cost related to the amputation, as well as ongoing management,(16, 17) and impacts substantially on quality of life.(18)
About diabetes/metabolic syndrome and the associated risks
Patients with diabetes and/or metabolic syndrome are known to be at higher cardiovascular risk, as recognised by current treatment guidelines.(19-21) Notably, diabetes is recognised as a 'coronary risk equivalent', by the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)(22), based on evidence from a number of well-designed observational studies that people with diabetes are at about 2-4-fold higher risk of premature cardiovascular mortality compared with those without diabetes.(23-25)
These patients typically have an abnormal lipid profile characterised by low high-density lipoprotein (HDL) cholesterol and elevated triglycerides, often with elevated levels of small, dense low-density lipoprotein particles, although levels of low-density lipoprotein (LDL) cholesterol are often normal. Extensive epidemiological evidence shows that elevated triglycerides(26) and low HDL cholesterol(27) are each independent predictors of cardiovascular risk.
About fenofibrate
Fenofibrate is marketed widely by Solvay Pharmaceuticals as LIPANTHYL(R) and LIPIDIL(R), and marketed by Abbott Laboratories in the USA as TRICOR(R).
References
1. Colman P, Rajamani,K., Li, L.-P. ,D'Emden, M. ,Voysey, M. ,Keech, A. . Benefits of long-term fenofibrate therapy on amputations in type 2 diabetes mellitus in the FIELD trial European Association for the Study of Diabetes (EASD). Rome, Italy; 2008.
2. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. Nov 17 2007;370(9600):1687-1697.
3. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. Nov 26 2005;366(9500):1849-1861.
4. Gregg EW, Gu Q, Williams D, de Rekeneire N, Cheng YJ, Geiss L, Engelgau M. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. Sep 2007;77(3):485-488.
5. IDF. Position statement: The diabetic foot: amputations are preventable. International Diabetes Federation. Available at: http://www.idf.org/home/index.cfm?node=1408. Accessed 9 July 2008.
6. Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med. Aug 7 2007;147(3):149-155.
7. Sloan FA, Bethel MA, Ruiz D, Jr., Shea AM, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med. Jan 28 2008;168(2):192-199; discussion 199.
8. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. Jan 30 2003;348(5):383-393.
9. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. Jan 12 2008;371(9607):117-125.
10. O'Brien R, Scott, R. ,Best, J. ,Taskinen, M.-R. ,Pardy, C. ,Ehnholm, C. ,Keech, A. . The clinical value of metabolic syndrome and its components in established type 2 diabetes mellitus: the FIELD trial Paper presented at: European Association for the Study of Diabetes (EASD); September 2008, 2008; Rome, Italy.
11. IDF. Diabetes Atlas. Available at: http://www.eatlas.idf.org/. Accessed 4 August, 2008.
12. NIH. National Diabetes Statistics, 2007. Available at: http://diabetes.niddk.nih.gov/dm/pubs/statistics/. Accessed 4 August, 2008.
13. Davis WA, Norman PE, Bruce DG, Davis TM. Predictors, consequences and costs of diabetes-related lower extremity amputation complicating type 2 diabetes: the Fremantle Diabetes Study. Diabetologia. Nov 2006;49(11): 2634-2641.
14. Philbin TM, Leyes M, Sferra JJ, Donley BG. Orthotic and prosthetic devices in partial foot amputations. Foot Ankle Clin. Jun 2001;6(2):215-228.
15. Schofield CJ, Libby G, Brennan GM, MacAlpine RR, Morris AD, Leese GP. Mortality and hospitalization in patients after amputation: a comparison between patients with and without diabetes. Diabetes Care. Oct 2006;29(10):2252-2256.
16. O'Brien JA, Patrick AR, Caro JJ. Cost of managing complications resulting from type 2 diabetes mellitus in Canada. BMC Health Serv Res. Mar 21 2003;3(1):7.
17. von Ferber L, Koster I, Hauner H. Medical costs of diabetic complications total costs and excess costs by age and type of treatment results of the German CoDiM Study. Exp Clin Endocrinol Diabetes. Feb 2007;115(2):97-104.
18. Willrich A, Pinzur M, McNeil M, Juknelis D, Lavery L. Health related quality of life, cognitive function, and depression in diabetic patients with foot ulcer or amputation. A preliminary study. Foot Ankle Int. Feb 2005;26(2):128-134.
19. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith Jr SC, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev. Nov-Dec 2005;13(6):322-327.
20. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. May 2006;23(5):469-480.
21. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet. Sep 24-30 2005;366(9491):1059-1062.
22. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. Dec 17 2002;106(25):3143-3421.
23. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. Feb 1993;16(2):434-444.
24. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. Apr 2001;24(4):683-689.
25. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. Jan 14 2006;332(7533):73-78.
26. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. Jan 30 2007;115(4):450-458.
27. Assmann G, Schulte H, Cullen P, Seedorf U. Assessing risk of myocardial infarction and stroke: new data from the Prospective Cardiovascular Munster (PROCAM) study. Eur J Clin Invest. Dec 2007;37(12) :925-932.
Distributed by PR Newswire on behalf of CTC, University of Sydney