Current therapeutical options in diabetes mellitus type 2 and coronary artery disease: intensive secondary prevention with focus on exercise training versus percutaneous or surgical revascularization

Abstracts

O diabetes mellitus é um dos maiores fatores de risco para a doença arterial coronariana. A doença progride mais rápido em pacientes diabéticos e está associada com pior prognóstico. Embora a cirurgia de revascularização ou intervenção percutânea com a implantação de stent garanta rápido alívio dos sintomas em pacientes com doença arterial coronariana estabelecida, não existe substancial benefício prognóstico. Uma intervenção multifatorial incluindo medidas dietéticas, controle glicêmico, tratamento anti-hipertensivo e exercícios físicos regulares tem influência positiva nos fatores de risco modificáveis, na melhora de outras funções cardiovasculares e na tolerância ao exercício livre de angina.

Diabetes mellitus; Doença arterial coronariana; Cirurgia de revascularização miocárdica; Intervenção multifatorial; Exercício físico

REVIEW ARTICLE

Current therapeutical options in diabetes mellitus type 2 and coronary artery disease: intensive secondary prevention with focus on exercise training versus percutaneous or surgical revascularization

Las opciones terapeuticas actuales en la diabetes mellitus 2 y la enfermedad coronaria: la prevención secundaria intensiva con el enfoque en el entrenamiento del ejercicio contra la revascularización quirurgica y percutanea

Sebastian Sixt; Nicolai Korff; Gerhard Schuler; Josef Niebauer

University of Leipzig - Heart Center, Department of Internal Medicine/Cardiology

^{Correspondence}

ABSTRACT

Diabetes mellitus is one of the major risk factors for coronary artery disease. The disease progresses faster in diabetic patients and is associated with a worse prognosis. Although bypass surgery or percutaneous interventions with stent implantation provide quick symptomatic relief for patients with stable coronary artery disease, it has no substantial prognostic benefit. A multifactorial intervention including dietary measures, blood-glucose control, anti-hypertensive treatment, and regular physical exercise does have a positive influence on the modifiable risk factors, and improves among others cardiovascular fitness and angina-free exercise tolerance.

Key words: Diabetes mellitus. Coronary artery disease. Coronary artery bypass graft. Stent implantation. Multi-factorial intervention. Physical exercise.

RESUMEN

La diabetes mellitus es uno de los factores de riesgo mayores para la enfermedad de la arteria coronaria. La enfermedad progresa más rápidamente en los pacientes diabéticos y está asociada con uno de los más peores pronósticos. Aunque la cirugía de desviación o las intervenciones percutaneas con la implantación del stent proporcionan un alivio sintomático rápido para los pacientes con esta enfermedad de la arteria coronaria establecida, no tiene el beneficio de un pronóstico sustancial. Una intervención multi-factorial que incluye las medidas dietéticas, mando de sangre-glucosa, el tratamiento del antihipertensivo y ejercicio físico regular tiene una influencia positiva en los factores de riesgo modificables, y mejora entre otros la aptitud cardiovascular y la tolerancia del ejercicio libre de anginas.

Palabras-clave:Diabetes mellitus. Enfermedad coronaria. Injertos coronarios de la desviación. Implantación de stent. Intervención multi-factorial. Ejercicio físico.

EPIDEMIOLOGY

Diabetes mellitus type 2 is one of the most common diseases in industrialized countries and is one of the main risk factors for the development of micro- and macrovascular diseases. Vascular complications are causes of death in up to 80% of these patients and 75% of deaths are due to coronary artery disease^(1,2).

Patients with diabetes mellitus type 2 develop more often diffuse multivessel coronary disease and heart failure. After a myocardial infarction their outcome is worse and mortality is higher than in normoglycemic patients⁽³⁾. Currently, it is being discussed controversially which therapy is best for these patients (see table 1).

AORTO-CORONARY BYPASS GRAFT

There have been great achievements and new developments in cardiac surgery over the last years. Today, arterial grafts (A. mammaria interna, A. radialis) are used as bypasses, and this is supported among others by a subgroup analysis of the BARI 1 study⁽⁴⁾, which could show that diabetic patients who underwent bypass surgery after a myocardial infarction had a better survival rate when arterial instead of venous grafts were used^(5,6).

Also a growing number of operations is being performed minimal invasively and without heart-lung-machine whenever possible. These break-throughs minimize operation-induced trauma and thus lower postoperative complication rates as well as faster mobilization. As was shown in recent studies these modern surgical techniques result in faster symptomatic relief but do not improve the survival rate when compared to percutaneous treatment (PTCA)^(1,5).

CORONARY ANGIOPLASTY AND STENT IMPLANTATION

Percutaneous coronary intervention is the therapy of choice for patients with unstable angina pectoris or an acute myocardial infarction⁽⁷⁾. If the stenosis is located in the left main stem or the left anterior descending artery revascularization is associated with a significantly higher survival rate. Therefore, from a prognostic point of view surgical or interventional revascularization is mandatory in these patients⁽⁸⁾. For patients with stable coronary artery disease and a stenosis in other segments of the coronary vascular system clear evidence is lacking^(9,10).

It was shown in the RITA-2 study that benefit from PTCA is greatest in highly symptomatic patients in terms of angina and reduced cardiorespiratory fitness. Patients with fewer and milder symptoms do not profit from revascularization. No improved performance on stress tests after PTCA could be shown in patients with a good pre-interventional performance. Additionally, not only could no prognostic benefit be documented in the PTCA group for asymptomatic or only mildly symptomatic patients, but there was even a significantly higher risk for cardiac death or myocardial infarction after an average of 2.7 years⁽¹¹⁾.

Therefore, PTCA with stent implantation in patients with stable coronary artery disease must be seen as a strictly symptomatic therapy providing fast relief of symptoms without any prognostic benefit⁽¹²⁾. Although no restenosis was initially found in studies on sirolimus-eluting stents⁽¹³⁾, more recent data shows a restenosis rate of up to 9% (18% for diabetics and up to 38% for insulin-dependent diabetics) in stented coronary arteries with complex lesions⁽¹⁴⁾.

MULTIFACTORIAL SECONDARY PREVENTION

In patients with stable coronary artery disease and no hemodynamically relevant stenoses of the coronary main stem or left anterior descending artery conservative therapy is a therapeutic option. This treatment strategy takes into account the multifactorial pathogenesis of the disease and aims for a positive influence on all modifiable risk factors (figure 1).

BLOOD-GLUCOSE CONTROL

The importance of an early diagnosis of diabetes was shown in the United Kingdom Prospective Diabetes Study (UKPDS). The results show that it is necessary to keep HbA1c levels < 6.0 mmol/l in order to reduce the incidence of cardiovascular events⁽¹⁾. These data were confirmed by a study by Hu et al. in 84941 nurses where it could be demonstrated in a subgroup with a low risk profile (body mass index < 25, healthy diet, > 30 min physical exercise/d, non-smokers, > half a drink/d) that the incidence of diabetes mellitus type 2 was significantly lower than for the rest of the nurses⁽¹⁵⁾. It was also shown that 91% of the newly developed diabetics could have been prevented by a life-style common to the subgroup of nurses with a low risk profile.

Tuomilehto et al.⁽¹⁶⁾ studied 522 overweight patients with impaired glucose tolerance to find out the influence of diet counselling and the recommendation to exercise regularly on the incidence of type 2 diabetes mellitus. After 4 years the incidence of newly developed diabetes was significantly lower in the intervention group (11%) as compared to the control group (23%).

Another study compared the influence of a healthy life-style with prevention or delay of the occurrence of diabetes by metformin⁽¹⁶⁾. After an average of 2.8 years it was shown that a healthy life-style could prevent diabetes mellitus type 2 more effectively (58%) than a metformin therapy (31%).

The STENO-2 study investigated the influence of conservative therapy and an intensified therapy (behavioral changes aiming at weight reduction, increased physical activity and intensified pharmacological therapy) on type 2 diabetic patients with micro-albuminuria⁽¹⁷⁾. After an average study time of 7.8 years intensified therapy was able to reduce cardiovascular and microvascular events by 50%⁽¹⁷⁾ (see table 2).

In the studies mentioned physical training was only recommended but never conducted under supervision⁽¹⁷⁾. Future studies must show whether increased exercise compliance due to group exercise sessions or supervision of home exercise with the help of telemedicine can even further augment these beneficial effects. Our own data show that not only stationary but also ambulatory group training in addition to daily home exercise can further improve the risk factor profile⁽²⁹⁾.

PHYSICAL EXERCISE

The incidence of diabetes mellitus correlates inversely with the degree of physical activity. This is best documented for patients with a very high risk of developing diabetes⁽³⁰⁾. Regular physical exercise (e.g. 30 min/d of aerobic exercise at a moderate intensity) can cut the risk for impaired glucose tolerance by half and the diabetes risk by up to three quarters^(19,22).

Endurance training is possible for patients with stable coronary artery disease. It increases exercise performance, improves the cardiovascular risk profile^(31-33), reduces the cardiovascular complication rate^(34,35), improves myocardial perfusion⁽³³⁾, and also slows the progression of coronary artery disease^(32,36). Although there is no proof that endothelial dysfunction leads to atherosclerosis to date, it was shown that endothelial dysfunction is associated with increased cardiovascular mortality⁽³⁷⁾. Endothelial dysfunction can be improved by intensive physical exercise^(37-41). Not only does nitric oxide (NO) act anti-atherogenically but also a lack of NO has a pro-atherogenic effect^(40-42). Whether or not this applies to diabetics is currently being examined by us in different studies.

A meta-analysis could show that normoglycemic patients⁽⁴³⁾ profit from endurance training as part of a rehabilitation program for patients with coronary heart disease with a reduction of mortality by 31%. The importance of physical exercise, especially for diabetic patients, and the prognostic effect was demonstrated by several studies^(24,30) (see table 2). Regular physical training reduces the risk for coronary artery disease by 33% and the mortality rate by 40%⁽²¹⁾. Energy consumption should ideally be between 1000 and 2000 kcal/week which corresponds to 3-5 hours of sub-maximal endurance training per week⁽²⁰⁾.

LIPID-LOWERING TREATMENT

A lipid lowering therapy with statins is only recommended if LDL cholesterol levels are > 3.0 mmol/l⁽⁴⁴⁾. For patients with diabetes mellitus type 2 triglyceride levels are often increased and HDL serum levels are often reduced in spite of good metabolic control⁽⁴²⁾. Stammler et al. could already show that both diabetics and non-diabetics profit from a reduction of LDL cholesterol by 1 mmol/L by a linear reduction of the risk for developing coronary artery disease regardless of their initial LDL levels⁽⁴⁵⁾. However, the mortality rate for diabetics was 3 to 5 times higher when compared to the group of non-diabetics.

The data from UKPDS could confirm this linear correlation between LDL cholesterol levels and the risk for coronary heart disease⁽⁴⁶⁾.

In spite of a higher risk for cardiovascular complications in diabetic patients only a small number of diabetic patients were included in randomized studies with statins^(27,28). The Heart Protection Study compared the effects of simvastatin versus placebo on 5963 type 2 diabetics with regard to cardiovascular complications⁽²⁶⁾. Over an average time of 4.8 years simvastatin increased the time until first myocardial infarction, cerebrovascular event or need for revascularization by 22%. New manifestations of cardiovascular diseases were reduced by 33%. A reduction of cholesterol levels by 1.0 mmol/L coincided with a reduced rate of all cardiovascular complications by one quarter.

Another study performed a multifactorial intervention with intensified blood-glucose control, blood pressure reduction by 11 mmHg and lowering of LDL cholesterol by 0.9 mmol/L. When compared to standard therapy a significant reduction of cardiovascular (20%) and microvascular (50%) complications could be documented⁽¹⁷⁾.

Risk factors for normoglycemic patients with coronary artery disease such as dyslipoproteinemia, hypertension and obesity can be treated successfully with intensified physical exercise and individually adapted diet. However, only the impact of lipid control has been assessed so far and resulted in a reduction of cardiovascular mortality^(47,48).

CONCLUSION

Diabetic patients with acute myocardial infarction, a stenosis of the left main stem or left anterior descending artery, or severe angina benefit from revascularization, which is associated with immediate relief of symptoms and a better prognosis.

There is no such evidence for diabetic patients with stable coronary heart disease and stenosis in other cardiovascular segments, whereas more recent studies increasingly underline the importance of an intensive multifactorial intervention. Although the multifactorial approach is the only intervention that results in a slowed progression of the disease, superiority with regard to relief of symptoms or even an improved prognosis remains to be demonstrated in prospective, randomized trials, which are currently under way.

All the authors declared there is not any potential conflict of interests regarding this article.

REFERENCES

Received in 24/1/04. Approved in 30/4/04

• 1. Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9- year update of a randomized, controlled trial on die effect of improved metabolic control on complications in NIDDM. Ann Intern Med 1996;124: 136-45.
• 2. Webster MWI, Scott RS. What cardiologists need to know about diabetes. Lancet 1997;350:23-8.
• 3. Aronson D, Rayfield EJ, Cheselro JH. Mechanisms determing course and outcome of diabetic patients who have acute myocardial infarction. Ann Intern Med 1997;126:296-306.
• 4. Investigators B. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1997;96:1761-9.
• 5. Abizaid A, Costa MA, Centemero M, et al. Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients: insights from the Arterial Revascularization Therapy Study (ARTS) trial. Circulation 2001;104:533-8.
• 6. Diegeler A, Thiele H, Falk V, et al. Comparison of stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery. N Engl J Med 2002;347:561-6.
• 7. Lagerqvist B, Husted S, Kontny F, et al. A long-term perspective on the protective effects of an early invasive strategy in unstable coronary artery disease: two-year follow-up of the FRISC-II invasive study. J Am Coll Cardiol 2002;40:1902-14.
• 8. Sobel BE, Frye R, Detre KM. Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation 2003; 107:636-42.
• 9. Hueb WA, Soares PR, Almeida De Oliveira S, et al. Five-year follow-up of the medicine, angioplasty, or surgery study (MASS): a prospective, randomized trial of medical therapy, balloon angioplasty, or bypass surgery for single proximal left anterior descending coronary artery stenosis. Circulation 1999;100:II107-13.
• 10. RITA-2 RIToA. Coronary angioplasty versus medical therapy for angina: the RITA-2 trial. Lancet 1997;350:461-8.
• 11. Sculpher M, Smith D, Clayton T, et al. Coronary angioplasty versus medical therapy for angina. Health service costs based on the second Randomized Intervention Treatment of Angina (RITA-2) trial. Eur Heart J 2002;23:1291-300.
• 12. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med 1992;326:10-6.
• 13. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-80.
• 14. Moses JW, Leon MB, Pompa JJ, et al. Angiographic and clinical outcomes after a sirolimus-eluting stent compared to a standard stent in patients with complex coronary stenosis. N Eng J Med 2003; in press.
• 15. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002;25:1129-34.
• 16. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in life-style among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
• 17. 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 2003;348:383-93.
• 18. UKPDS UPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
• 19. Hu FB, Manson JE, Stampfer MJ, et al. Diet, life-style, and the risk of type 2 diabetes mellitus in women. N Engl J Med 2001;345:790-7.
• 20. Hu FB, Sigal RJ, Rich-Edwards JW, et al. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. Jama 1999;282:1433-9.
• 21. Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation 2003;107:2435-9.
• 22. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Lee CD, Blair SN. The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men. Ann Intern Med 1999;130:89-96.
• 23. Hu FB, Stampfer MJ, Solomon C, et al. Physical activity and risk for cardiovascular events in diabetic women. Ann Intern Med 2001;134:96-105.
• 24. Batty GD, Shipley MJ, Marmot M, Smith GD. Physical activity and cause-specific mortality in men with type 2 diabetes/impaired glucose tolerance: evidence from the Whitehall study. Diabet Med 2002;19:580-8.
• 25. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med 2000;132:605-11.
• 26. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005-16.
• 27. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-20.
• 28. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation 1998;98:2513-9.
• 29. Peschel T, Beitz F, Tarnok A, Niebauer J. Diabetes mellitus type 2 is associated with upregulation of atherogenic surface markers: normalization through exercise training. Circulation 2002;106:712.
• 30. Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS Jr. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 1991;325:147-52.
• 31. Niebauer J, Hambrecht R, Velich T, et al. Predictive value of lipid profile for salutary coronary angiographic changes in patients on a low fat diet and physical exercise program. Am J Cardiol 1996;78:163-7.
• 32. Niebauer J, Hambrecht R, Velich T, et al. Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention: role of physical exercise. Circulation 1997;96:2534-41.
• 33. Schuler G, Hambrecht R, Schlierf G, et al. Myocardial perfusion and regression of coronary artery disease in patients on a regimen of intensive physical exercise and low fat diet. J Am Coll Cardiol 1992;19:34-42.
• 34. Haskell WL, Aldermann EL, Fair J, et al. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1994;89:975-90.
• 35. Ornish D, Scherwitz LW, Billings JH, et al. Intensive life-style changes for reversal of coronary heart disease. Jama 1998;280:2001-7.
• 36. Schuler G, Hambrecht R, Schlierf G, et al. Regular physical exercise and low-fat diet. Effects on progression of coronary artery disease. Circulation 1992;86:1-11.
• 37. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-906.
• 38. Niebauer J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am Coll Cardiol 1996; 28:1652-60.
• 39. Niebauer J, Maxwell AJ, Lin PS, et al. Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training. Am J Physiol 1999;276:H1346-54.
• 40. Niebauer J, Dulak J, Chan JR, Tsao PS, Cooke JP. Gene transfer of nitric oxide synthase: effects on endothelial biology. J Am Coll Cardiol 1999;34:1201-7.
• 41. Niebauer J, Maxwell AJ, Lin PS, Wang D, Tsao PS, Cooke JP. NOS inhibition accelerates atherogenesis: reversal by exercise. Am J Physiol 2003;285:H535-40.
• 42. Feener EP, King GL. Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. Heart Fail Monit 2001;1:74-82.
• 43. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2000:CD001800.
• 44. Gohlke H, Kubler W, Mathes P, et al. [Policy paper on primary prevention of cardiovascular diseases. Current draft of 3/25/2003 issued by the Executive Committee of the German Society of Cardiology, Heart and Circulation Research. Edited by the Prevention Project Group on behalf of the Executive Committee]. Z Kardiol 2003;92:522-3.
• 45. 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 1993;16:434-44.
• 46. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). Bmj 1998;316:823-8.
• 47. Laakso M, Lehto S, Penttilä I, Pyörälä K. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993;88:1421-30.
• 48. Syvänna M, Taskinen MR. Lipids and lipoproteins as coronary risk factor in non-insulin-dependent diabetes mellitus. Lancet 1997;350:20-3.

Publication Dates

• Publication in this collection
  13 Aug 2004
• Date of issue
  June 2004

History

• Accepted
  30 Apr 2004
• Received
  24 Jan 2004