Blutzucker-Senkung und kardiovaskulärer Vorteil: Was wissen wir heute?

Zusammenfassung

Die Frage, ob eine alleinige Blutzuckersenkung die kardiovaskuläre Ereignisrate bei langjährigen Typ 2 Diabetikern beeinflussen kann, wird nach wie vor kontrovers diskutiert. Neue Erkenntnisse liefern die Studien ACCORD, ADVANCE, VADT und die UKPDS-Nachbeobachtung. Die drei erstgenannten Untersuchungen machen deutlich, dass mikrovaskulärer und makrovaskulärer Benefit einer strengen BZ-Kontrolle getrennt beurteilt werden müssen: Während der günstige Einfluss auf mikrovaskuläre Komplikationen wie die diabetische Nephropathie unstrittig ist, bleibt der generelle makrovaskuläre Nutzen in diesen Megastudien weiterhin fraglich und muss im Zusammenhang mit dem individuellen globalen Risiko betrachtet werden. Demgegenüber konnten die Langzeitergebnisse der Diabetesinterventionsstudie DIS und die UKPDS-Nachbeobachtung zeigen, dass eine frühzeitige intensivierte BZ-Einstellung das kardiovaskuläre Outcome durchaus nachhaltig positiv verändert – der Einfluss kommt aber erst nach einem relativ langen Zeitraum von ein bis zwei Jahrzehnten zum Tragen. Erstmalig wurde in der PROactive-Studie der kardiovaskuläre Nutzen einer antidiabetischen Einzelsubstanz (Pioglitazon) beim fortgeschrittenen Diabetes mit multiplen Manifestationen einer Makroangiopathie nachgewiesen. Hier zeigte sich bereits nach knapp 3 Jahren ein makrovaskulärer Benefit. Allerdings stellte sich dieser nicht primär als Resultat der Blutzuckersenkung dar, sondern als therapeutischer Nutzeffekt der komplexen Wirkungen des PPARγ-Agonisten Pioglitazon auf Insulinresistenz, Lipoproteinspektrum, Blutdruck, Endothelfunktion und auf Biomarker der subklinischen Entzündung. Dies macht deutlich, dass wir pleiotrope Effekte antidiabetischer Substanzen auf das metabolische Syndrom und die Auswirkungen auf kardiovaskuläre Endpunkte stärker in Therapieentscheidungen einbeziehen sollten. Für diese komplexen Fragestellungen wird eine breite wissenschaftliche Evidenz in Form von Endpunktstudien angestrebt, die für die allermeisten Antidiabetika bisher jedoch nicht verfügbar ist.

Abstract

It is still a much debated question whether antidiabetic therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with advanced type 2 diabetes. New findings result from ACCORD, ADVANCE and VADT. These trials reveal that microvascular and macrovascular effects of intensive glucose lowering have to be considered separately: Glycemic control convincingly demonstrated to have a protective impact on microvascular complications, especially nephropathy. However, macrovascular benefits remain doubtful in these megatrials and have to be considered in connection with the individual global risk. On the other hand, the Diabetes Intervention Study (DIS) and UKPDS 10-year follow-up results yielded better cardiovascular outcomes for those patients who received intensive glucose-lowering therapy very early after diabetes diagnosis, but the favourable influences did not manifest until a time period of 1 – 2 decades. For the first time, the cardiovascular benefit of an antidiabetic substance (pioglitazone) could be verified in the large-scale outcome-trial PROactive for patients with advanced diabetes and multiple manifestations of macroangiopathy. The results provide strong support for a beneficial influence on macrovascular complications just under 3 years of treatment. Nevertheless, the positive findings did not result from better glycemic control, but from the complexity of effects of PPARγ agonist pioglitazone on insulin resistance, lipoprotein spectrum, blood pressure, endothelial function and biomarkers of subclinical inflammation. It is obvious that we need to integrate such pleiotropic effects on metabolic syndrome and cardiovascular disease to improve the quality of drug-therapy decisions. This, in turn, requires a growing body of evidence from large, long-term outcome trials – but appropriate data are still unavailable for the vast majority of antidiabetic drugs.

Schlüsselwörter

ACCORD - ADVANCE - VADT - UKPDS - DIS - DCCT - PROactive - RECORD - Blutzuckerkontrolle

Keywords

ACCORD - ADVANCE - VADT - UKPDS - DIS - DCCT - PROactive - RECORD - blood glucose control

Literatur

• 1 Gerstein H C, Miller M E, Byington R P et al Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes.  N Engl J Med. 2008;  358 2545-2459
• 2 Patel A, MacMahon S, Chalmers J et al ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2008;  358 2560-2572
• 3 Al Majali K, Cooper M B, Staels B, Luc G, Taskinen M R, Betteridge D J. The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients.  Diabetologia. 2006;  49 527-537
• 4 Aronoff S, Rosenblatt S, Braithwaite S, Egan J W, Mathisen A L, Schneider R L. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group.  Diabetes Care. 2000;  23 1605-1611
• 5 Berhanu P, Kipnes M S, Khan M A. et al . Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy.  Diab Vasc Dis Res. 2006;  3 39-44
• 6 Campia U, Matuskey L A, Panza J A. Peroxisome proliferator-activated receptor-gamma activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors.  Circulation. 2006;  113 867-875
• 7 Ceriello A, Johns D, Widel M, Eckland D J, Gilmore K J, Tan M H. Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes.  Diabetes Care. 2005;  28 266-272
• 8 Charbonnel B, Schernthaner G, Brunetti P. et al . Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes.  Diabetologia. 2005;  48 1093-1104
• 9 Daikeler R, Erdmann E, Forst T. et al . Wissenschaftlich Evidenz in der ärztlichen Praxis: 10 Thesen zur Wirksamkeit und Verträglichkeit einer Therapie mit Glitazonen.  Diabetes, Stoffwechsel und Herz. 2006;  6 94-99
• 10 Deeg M A, Buse J B, Goldberg R B. et al . Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia.  Diabetes Care. 2007;  30 2458-2464
• 11 Derosa G, Cicero A F, Dangelo A. et al . Thiazolidinedione effects on blood pressure in diabetic patients with metabolic syndrome treated with glimepiride.  Hypertens Res. 2005;  28 917-924
• 12 Derosa G, Cicero A F, Gaddi A, Ragonesi P D, Piccinni M N, Fogari E, Salvadeo S, Ciccarelli L, Fogari R. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome.  Diabetes Res Clin Pract. 2005;  69 5-13
• 13 Dormandy J A, Charbonnel B, Eckland D J. et al . Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.  Lancet. 2005;  366 1279-1289
• 14 Duckworth W, Abraira C, Moritz T. et al . Glucose control and vascular complications in veterans with type 2 diabetes.  N Engl J Med. 2009;  360 129-139
• 15 Erdmann E, Dormandy J A, Charbonnel B, Massi-Benedetti M, Moules I K, Skene A M. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study.  J Am Coll Cardiol. 2007;  49 1772-1780
• 16 Fernandez M, Triplitt C, Wajcberg E. et al . Addition of pioglitazone and ramipril to intensive insulin therapy in type 2 diabetic patients improves vascular dysfunction by different mechanisms.  Diabetes Care. 2008;  31 121-127
• 17 Füllert S, Schneider F, Haak E. et al . Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.  J Clin Endocrinol Metab. 2002;  87 5503-5506
• 18 Goldberg R B, Kendall D M, Deeg M A at al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.  Diabetes Care. 2005;  28 1547-1554
• 19 Hanefeld M, Brunetti P, Schernthaner G H, Matthews D R, Charbonnel B H. Study Group . QUARTET One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes.  Diabetes Care. 2004;  27 141-147
• 20 Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch H J, Lindner J. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.  Diabetologia. 1996;  39 1577-1583
• 21 Hanefeld M, Schmechel H, Schwanebeck U, Lindner J. Predictors of coronary heart disease and death in NIDDM: the Diabetes Intervention Study experience.  Diabetologia. 1997;  40 (Suppl 2) S123-124
• 22 Hanefeld M, Temelkova-Kurktschiev T. The postprandial state and the risk of atherosclerosis.  Diabet Med. 1997;  14 (Suppl 3) S6-11
• 23 Holman R R, Paul S K, Bethel M A, Matthews D R, Neil H A. 10-year follow-up of intensive glucose control in type 2 diabetes.  N Engl J Med. 2008;  359 1577-1589
• 24 Home P D, Pocock S J, Beck-Nielsen H. et al . Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.  Lancet. 2009;  373 2125-2135
• 25 Juurlink D N, Gomes T, Lipscombe L L, Austin P C, Hux J E, Mamdani M M. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study.  BMJ. 2009;  339 b2942
• 26 Lawrence J M, Reid J, Taylor G J, Stirling C, Reckless J P. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes.  Diabetes Care. 2004;  27 41-46
• 27 Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino L J, DeFronzo R A. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.  J Clin Endocrinol Metab. 2002;  87 2784-2791
• 28 Nathan D M, Cleary P A, Backlund J Y. et al . Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes.  N Engl J Med. 2005;  353 2643-2653
• 29 Nissen S E, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  N Engl J Med. 2007;  356 2457-2471
• 30 Pavo I, Jermendy G, Varkonyi T T. et al . Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes.  J Clin Endocrinol Metab. 2003;  88 1637-1645
• 31 Pfützner A, Marx N, Lübben G. et al . Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study.  J Am Coll Cardiol. 2005;  45 1925-1931
• 32 Pop-Busui R, Lombardero M, Lavis V. et al . Relation of severe coronary artery narrowing to insulin or thiazolidinedione use in patients with type 2 diabetes mellitus (from the Bypass Angioplasty Revascularization Investigation 2 Diabetes Study).  Am J Cardiol. 2009;  104 52-58
• 33 Ray K K, Seshasai S R, Wijesuriya S. et al . Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.  Lancet. 2009;  373 1765-1772
• 34 Roden M, Laakso M, Johns D. et al . Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.  Diabet Med. 2005;  22 1101-1106
• 35 Satoh N, Ogawa Y, Usui T. et al . Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect.  Diabetes Care. 2003;  26 2493-2499
• 36 Schernthaner G, Matthews D R, Charbonnel B, Hanefeld M, Brunetti P. Quartet Study Group . Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial.  J Clin Endocrinol Metab. 2004;  89 6068-6076
• 37 Schneider C A, Ferrannini E, Defronzo R, Schernthaner G, Yates J, Erdmann E. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.  J Am Soc Nephrol. 2008;  19 182-187
• 38 Szapary P O, Bloedon L T, Samaha F F. et al . Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2006;  26 182-188
• 39 Tan M H, Glazer N B, Johns D, Widel M, Gilmore K J. Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes.  Curr Med Res Opin. 2004;  20 723-728
• 40 Tan M H, Johns D, Strand J. et al . Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.  Diabet Med. 2004;  21 859-866
• 41 Wilcox R, Bousser M G, Betteridge D J, Schernthaner G, Pirags V, Kupfer S, Dormandy J. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).  Stroke. 2007;  38 865-873
• 42 Winkler K, Konrad T, Füllert S. et al . Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.  Diabetes Care. 2003;  26 2588-2594
• 43 Zietemann V, Storz P, Freytag A, Hagenmeyer E G, Gothe H. HTA Bericht zur Effektivität, zur Anwendungssicherheit und zur gesundheitsökonomischen Bewertung von Pioglitazon und Rosiglitazon bei der Behandlung des Typ 2 Diabetes mellitus. IGES Institut GmbH 2008 Berichts-Nr: HTAi006; http://gripsdb.dimdi.de/de/hta/hta_berichte/hta231_bericht_de.pdf