Medikamentöse antihyperglykämische Therapie des Diabetes mellitus Typ 2

S. Matthaei; R. Bierwirth; A. Fritsche; B. Gallwitz; H.-U. Häring; H.-G. Joost; M. Kellerer; C. Kloos; T. Kunt; M. Nauck; G. Schernthaner; E. Siegel; F. Thienel

doi:10.1055/s-0028-1098798

Diabetologie und Stoffwechsel, Table of Contents

Diabetologie und Stoffwechsel 2009; 4(1): 32-64
DOI: 10.1055/s-0028-1098798

Übersicht

Medikamentöse antihyperglykämische Therapie des Diabetes mellitus Typ 2

Update der Evidenzbasierten Leitlinie der Deutschen Diabetes-GesellschaftPharmacological Antihyperglycemic Therapy of Type 2 Diabetes mellitusUpdate of the Evidence-Based Guidelines of the German Diabetes AssociationS. Matthaei, R. Bierwirth, A. Fritsche, B. Gallwitz, H.-U. Häring, H.-G. Joost, M. Kellerer, C. Kloos, T. Kunt, M. Nauck, G. Schernthaner, E. Siegel, F. Thienel

Abstract

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References

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254 Stenman S, Groop P H, Saloranta C et al. Effects of the combination of insulin and glibencamide in type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral hypoglycaemic agents. Diabetologia. 1988; 31 206-213 , Evidenzklasse II a
255 Stettler C, Allemann S, Jüni P et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials. Am Heart J. 2006; 152 27-38 , Evidenzklasse I a
256 Stocker D J, Taylor A J, Langley R W et al. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J. 2007; 153 445.e1-445.e6 , Evidenzklasse I b
257 St. John-Sutton M, Rendell M, Dandona P et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care. 2002; 25 2058-2064 , Evidenzklasse I b
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259 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 , Evidenzklasse I b
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4. Appendix 1
Stellungnahme der DDG zu den Ergebnissen der ACCORD- und ADVANCE-Studien

4.1 Einleitung

Der Effekt einer normnahen Glukosestoffwechseleinstellung auf die Reduktion mikrovaskulärer Komplikationen (z. B. Nephropathie, Retinopathie) bei Patienten mit Typ-2-Diabetes ist gut belegt [250] [267].

Die Studienlage zum Effekt einer normnahen Glukosestoffwechseleinstellung auf makrovaskuläre Komplikationen (z. B. Myokardinfarkt, zerebraler Insult) ist im Vergleich dazu weniger fundiert und stützt sich im Wesentlichen auf die Ergebnisse der UKPDS, die nach 10 Jahren einen deutlichen Trend zur Reduktion von Myokardinfarkten aufwies, der jedoch das Signifikanzniveau knapp verfehlte (p = 0,052 [267]). Gleichzeitig wurde allerdings im intensivierten Arm der Blutzuckersenkung ein nicht signifikanter Anstieg des Schlaganfalls um relativ 11 % beobachtet. Die 10-Jahres-Nachbeobachtungsergebnisse der UKPDS werden im Rahmen des diesjährigen EASD-Kongresses präsentiert.

Vor diesem Hintergrund wurden auf dem diesjährigen Kongress der American Diabetes Association (6.–10.6.) die Ergebnisse zweier großer Studien präsentiert, die den Effekt einer normnahen Glukosestoffwechseleinstellung auf makrovaskuläre (ACCORD) bzw. makro- und mikrovaskuläre (ADVANCE) Komplikationen untersuchten. Beide Studien wurden zeitgleich mit der Präsentation im New England Journal of Medicine publiziert [262] [263].

4.2 Design und Ergebnisse der ACCORD-Studie

Die Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Studie untersuchte den Effekt einer intensivierten Einstellung des Blutzuckers, des Blutdrucks sowie der Lipide auf makrovaskuläre Komplikationen im Vergleich zu einer Standardtherapie. Die Ergebnisse der Blutdruck- und Lipidtherapie werden voraussichtlich 2010 publiziert. Aufgrund einer erhöhten Mortalität in der antihyperglykämisch intensiviert behandelten Gruppe wurde dieser Therapiearm der Studie im Februar 2008 nach 3,5 Jahren vorzeitig abgebrochen und die Ergebnisse im Juni 2008 publiziert [262].

Insgesamt 10 251 Patienten wurden in 77 Zentren in den USA und Kanada rekrutiert.

Der HbA1c-Zielwert betrug in der intensiviert behandelten Gruppe < 6,0 %, in der Standardtherapiegruppe sollte ein HbA1c-Wert im Bereich von 7,0–7,9 % angestrebt werden.

Um diese Zielwerte zu erreichen, waren sämtliche zugelassenen antihyperglykämisch wirksamen Substanzen (OADs, Exenatide, Insulin) einsetzbar, auch Kombinationstherapien waren vom Studienprotokoll her weder von der Zahl noch von der Art der eingesetzten Substanzen eingeschränkt.

Definition des primären Endpunktes:

nicht-tödlicher Myokardinfarkt
nicht-tödlicher zerebraler Insult
Tod kardiovaskulärer Ursache

4.2.1 Ergebnisse der ACCORD-Studie ([Tab. 1])

*Tab. 1* Ergebnisse der ACCORD-Studie.
Parameter	intensiviert (n = 5 128) (bei Studienende)	Standard (n = 5 123) (bei Studienende)	relative Risikoreduktion (%)	p-Wert
HbA1c (%)	6,4	7,5		< 0,001
verwendete antihyperglykämische Therapie
Kombinationstherapien bei Pat. ohne Insulin (Zahl der Substanzgruppen*)
1 oder 2 (n Pat. [%])	2 798 (54,6)	3 224 (62,9)
3 (n Pat.[%])	3 030 (59,1)	1 681 (32,8)
4 oder 5 (n Pat.[%])	539 (10,5)	109 (2,1)
Kombinationstherapien bei Pat. mit Insulin (Zahl der Substanzgruppen*)
0 (n Pat. [%])	916 (17,9)	892 (17,4)
1 oder 2 (n Pat. [%])	3 311 (64,6)	2 375 (46,4)
3 (n Pat.[%])	2 668 (52,0)	834 (16,3)
4 oder 5 (n Pat. [%])	526 (10,3)	64 (1,2)
Nebenwirkungen (Auswahl)
schwere Hypoglykämien mit Fremdhilfe (n Pat. [%])	830 (16,2)	261 (5,1)		< 0,001
schwere Hypoglykämien mit Fremdhilfe durch med. Personal (n Pat. [%])	538 (10,5)	179 (3,5)		< 0,001
Gewichtszunahme (kg)	3,5	0,4		< 0,001
Gewichtszunahme > 10 kg (n Pat. [%])	1 399 (27,8)	713 (14,1)		< 0,001
primärer und sekundäre Endpunkte
primärer Endpunkt (n Pat. [%])	352 (6,9)	371 (7,2)	10	0,16
Gesamtmortalität (n Pat. [%])	257 (5,0)	203 (4,0)	– 22	0,04
Tod kardiovaskulär (n Pat. [%])	135 (2,6)	94 (1,8)	– 35	0,02
nicht-tödlicher Myokardinfarkt (n Pat. [%])	186 (1,1)	235 (4,6)	24	0,004
nicht-tödlicher zerebraler Insult (n Pat. [%])	67 (1,3)	61 (1,2)	– 6	0,74
Herzinsuffizienz (tödlich / nicht-tödlich) (n Pat. [%])	152 (3,0)	124 (2,4)	– 18	0,17
* folgende Substanzgruppen wurden definiert: Metformin, Sekretagoga (Sulfonylharnstoffe, Glinide), Thiazolidindione (präferenziell Rosiglitazon), Alpha-Glucosidase-Inhibitoren, Inkretine (Exenatide, Sitagliptin)

4.2.2 Zusammenfassung

Der primäre Endpunkt wurde um relativ 10 % nicht signifikant gesenkt (p = 0,16). Hauptursache für diesen Trend war eine signifikante relative Risikoreduktion für nicht-tödliche Myokardinfarkte um 24 % (p = 0,004).

Die Ursache(n) für die signifikant erhöhte Mortalität (relativer Anstieg um 22 %, p = 0,04) ist (sind) zzt. nicht bekannt und müssen in weiteren Analysen untersucht werden. Ob in diesem Zusammenhang

unerkannte Hypoglykämien (Steigerung des Sympathotonus >> Arrhythmien >> Tod) vor dem Hintergrund der bei 16,2 % der Patienten aufgetretenen Hypoglykämien mit Fremdhilfe (Faktor 3,1 vs. Standardtherapie),
die deutliche Gewichtszunahme bei einer großen Subgruppe der Patienten (27,8 % nahmen > 10 kg im Verlauf der Studie zu; > 70 % in der intensiviert behandelten Gruppe hatten eine Insulin + Thiazolidindion Kombinationstherapie),
die Interferenzen der verwendeten Polypharmakotherapie (bei Studienende hatten ∼ 70 % der nicht mit Insulin und ∼ 60 % der mit Insulin behandelten Patienten eine 3-, 4-, oder 5-fach-OAD-Kombinationstherapie,
oder die Geschwindigkeit der HbA1c-Zielwerterreichung

eine Rolle gespielt haben könnten, ist zzt. nicht geklärt.

4.3 Design und Ergebnisse der ADVANCE-Studie

Die Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE)-Studie untersuchte den Effekt einer intensivierten Einstellung des Blutzuckers und des Blutdrucks auf makrovaskuläre und mikrovaskuläre Komplikationen im Vergleich zu einer Standardtherapie. Die Ergebnisse der intensivierten Blutdrucktherapie wurden in 2007 publiziert [197].

Insgesamt 11 140 Patienten wurden in 215 Zentren in 20 Ländern (insbesondere Australien, Asien, Europa, Kanada) rekrutiert.

Der HbA1c-Zielwert betrug in der intensiviert behandelten Gruppe < 6,5 %, in der Standardtherapie Gruppe sollte ein HbA1c-Wert von 7,5 % erreicht werden.

Um diese Zielwerte zu erreichen, war für die intensiviert behandelte Gruppe folgendes Prozedere vorgesehen:

Intensivierung nicht-pharmakologischer Therapie-Optionen
Therapieeskalation durch behandelnden Arzt auf dem Boden der HbA1c- und Nüchtern-BZ-Werte unter Berücksichtigung folgender Empfehlungen:
Eskalation der Gliclazid-MR Dosis
Hinzunahme anderer OADs
Hinzunahme eines lang-wirkenden Insulins
Intensivierte Insulintherapie (multiple insulin injection therapy)

Definition des primären Endpunktes:

nicht-tödlicher Myokardinfarkt
nicht-tödlicher zerebraler Insult
Tod kardiovaskulärer Ursache
Nephropathie
Retinopathie

4.3.1 Ergebnisse der ADVANCE-Studie ([Tab. 2])

*Tab. 2* Ergebnisse der ADVANCE-Studie.
Parameter	intensiviert (n = 4 828) (bei Studienende)	Standard (n = 4 741) (bei Studienende)	relative Risikoreduktion (%)	p-Wert
HbA1c (%)	6,5	7,3		< 0,001
verwendete antihyperglykämische Therapie
Gliclazid (n Pat.[%])	4 209 (90,5)	80 (1,6)
andere SH (n Pat. [%])	89 (1,9)	2 606 (57,1)
Metformin (n Pat.[%])	3 455 (73,8)	3 057 (67,0)
Thiazolidindione (n Pat.[%])	788 (16,8)	495 (10,9)
Acarbose (n Pat. [%])	891 (19,1)	576 (12,6)
Glinide (n Pat. [%])	58 (1,2)	127 (2,8)
Insulin (n Pat.[%])	1 953 (40,5)	1 142 (24,1)
Nebenwirkungen (Auswahl)
schwere Hypoglykämien (% / Jahr))	0,7	0,4		< 0,05
Gewichtszunahme (kg)	0,0	– 1,0		< 0,05
primärer und sekundäre Endpunkte
primärer Endpunkt (n Pat. [%])	1 009 (18,1)	1 116 (20,0)	10	0,01
Gesamtmortalität (n Pat. [%])	498 (8,9)	533 (9,6)	7	0,28
Tod kardiovaskulär (n Pat. [%])	253 (4,5)	289 (5,2)	12	> 0,05
nicht-tödlicher Myokardinfarkt (n Pat. [%])	153 (2,7)	156 (2,8)	2	> 0,05
nicht-tödlicher zerebraler Insult (n Pat. [%])	214 (3,8)	209 (3,8)	– 2	> 0,05
Herzinsuffizienz (n Pat. [%])	220 (3,9)	231 (4,1)	5	> 0,05
Nephropathie (Neuauftreten oder Progression) (n Pat [%])	230 (4,1)	292 (5,2)	21	0,006
Retinopathie (Neuauftreten oder Progression) (n Pat. [%])	332 (6,0)	349 (6,3)	5	> 0,05

4.3.2 Zusammenfassung

Der primäre Endpunkt wurde um relativ 10 % signifikant gesenkt (p = 0,01). Hauptursache für diesen Effekt war eine signifikante Reduktion der Nephropathie um relativ 21 % (p = 0,006).

Die Gesamtmortalität wurde um relativ 7 % nicht signifikant gesenkt (p = 0,28). Die makrovaskulären Ereignisse wurden um relativ 6 % nicht signifikant gesenkt (p = 0,32).

Die Zahl der schweren Hypoglykämien lag in der intensiviert behandelten Gruppe mit 0,7 % / Jahr höher als in der Standardtherapie-Gruppe (0,4 % / Jahr).

In der intensiviert behandelten Gruppe kam es zu keiner Gewichtszunahme, in der Standardtherapie-Gruppe betrug die Gewichtsreduktion im Mittel 1,0 kg.

4.4 Vergleichende Betrachtung von ACCORD und ADVANCE

[Tab. 3] zeigt eine Gegenüberstellung wesentlicher Parameter beider Studien.

*Tab. 3* Vergleich der ACCORD- und ADVANCE-Studie.
Studien-Charakteristika	ACCORD	ADVANCE
Patienten Charakteristika bei Studienbeginn
Zahl der Studienteilnehmer	10 251	11 140
Alter (Jahre)	62	66
Diabetesdauer (Jahre)	10	8
HbA1c (Mittelwert) (%)	8,3	7,3
Anteil mit makrovaskulären Vorerkrankungen (%)	35	32
Angaben zur Intervention
Definition primärer Endpunkt	nicht tödlicher Myokardinfarkt, nicht tödlicher Insult, Tod kardiovaskulärer Ursache	nicht tödlicher Myokardinfarkt, nicht tödlicher Insult, Tod kardiovaskulärer Ursache, Nephropathie, Retinopathie
angestrebter HbA1c-Zielwert (%)	< 6,0	≤ 6,5
mittlere Studiendauer (Jahre)	3,4	5,0
Pharmakotherapie bei Studienende (intensiviert vs. Standard) (%)
Insulin	77 vs. 55	41 vs.24
Metformin	95 vs. 87	74 vs. 67
Sekretagoga (Sulfonylharnstoff / Glinide)	87 vs. 74	94 vs. 62
Thiazolidinedione	92 vs. 58	17 vs. 11
Inkretin (Exenatide, Sitagliptin)	18 vs. 5	nicht berichtet
Statin	88 vs. 88	46 vs. 48
jedwede antihypertensive Medikation	91 vs. 92	89 vs. 88
ACE-Inhibitoren	70 vs. 72	nicht berichtet
Aspirin	76 vs. 76	57 vs. 55
Ergebnisse (intensiviert vs. Standard)
HbA1c (Mittelwert bei Studienende [%])	6,4 vs. 7,5 +	6,5 vs. 7,3 +
Mortalität
gesamt (%)	5,0 vs. 4,0 +	8,9 vs. 9,6
kardiovaskulär (%)	2,6 vs. 1,8 +	4,5 vs. 5,2
nicht-tödlicher Myokardinfarkt (%)	3,6 vs. 4,6 +	2,7 vs. 2,8
nicht-tödlicher zerebraler Insult (%)	1,3 vs. 1,2	3,8 vs. 3,8
schwere Hypoglykämie mit Fremdhilfe (ACCORD), bzw. schwere Hypoglykämie (ADVANCE) (% / Jahr)	3,1 vs. 1,0 +	0,7 vs. 0,4
Gewichtszunahme (kg)	3,5 vs. 0,4	0,0 vs. – 1,0 +
Nikotinabusus (%)	10 vs. 10	8 vs. 8
+ Der Vergleich der Intervention mit der Standardtherapie war signifikant. Modifiziert nach [57].

4.4.1 Ad Patientencharakteristika

Die Patientencharakteristika zeigen, dass die rekrutierten Patientenkohorten beider Studien Ähnlichkeiten hinsichtlich Alter, Diabetesdauer und Anteil mit makrovaskulären Vorerkrankungen aufweisen. Die erreichten HbA1c-Zielwerte waren vergleichbar.

4.4.2 Ad Intensivierung der antihyperglykämischen Therapie

Die Art und Weise der durchgeführten Intensivierung der antihyperglykämischen Therapie weist deutliche Unterschiede auf: Während in der ACCORD-Studie ein polypharmakotherapeutischer Ansatz praktiziert wurde (bei Studienende hatten ∼ 70 % der nicht mit Insulin und ∼ 60 % der mit Insulin behandelten Patienten eine 3-, 4-, oder 5-fach-OAD-Kombinationstherapie), wurde in der ADVANCE-Studie ein Algorithmus verwendet, bei dem die Therapie mit lang-wirkendem Insulin ergänzt wurde, falls der HbA1c-Zielwert von < 6,5 % unter OAD's nicht mehr erreicht wurde. Falls eine weitere Therapieeskalation zur HbA1c-Zielwerterreichung notwendig wurde, wurde eine intensivierte Insulintherapie unter Verwendung von basalem und prandialem Insulin empfohlen.

4.4.3 Ad Ergebnisse zum Effekt auf Mortalität

Der in der ACCORD-Studie aufgefallene Effekt einer erhöhten Mortalität in der intensiviert behandelten Gruppe bestätigte sich in der ADVANCE-Studie bei vergleichbarer HbA1c-Zielwerterreichung nicht.

4.4.4 Ad Nebenwirkungen der intensivierten Therapie

4.4.4.1 Hypoglykämien

Die intensiviert behandelte Gruppe in der ACCORD-Studie hatte eine im Vergleich zur Standardtherapie um den Faktor 3,1 erhöhte Rate an schweren Hypoglykämien, insgesamt erlitten 16,2 % der Patienten in dieser Gruppe eine schwere Hypoglykämie.

In der ADVANCE-Studie war die Rate schwerer Hypoglykämien mit 0,7 % / Jahr geringfügig höher als in der Standardtherapiegruppe (0,4 % / Jahr), jedoch geringer als in der Standardtherapiegruppe der ACCORD-Studie (1,0 % / Jahr) – bei einem Unterschied im mittleren HbA1c-Wert von 1,0 % (6,5 % (ADVANCE (int.) vs. 7,5 % (ACCORD (std.))).

4.4.4.2 Gewichtszunahme

Die mittlere Gewichtszunahme der Patienten in der ACCORD-Studie betrug 3,5 kg, 27,8 % der Patienten wiesen eine Gewichtszunahme von > 10 kg auf.

Die Patienten in der intensiviert behandelten Gruppe in der ADVANCE-Studie wiesen keine Gewichtszunahme auf (± 0,0 kg).

4.5 Schlussfolgerungen

Die Ergebnisse der ADVANCE-Studie zeigen, dass eine intensivierte antihyperglykämische Therapie, die unter Vermeidung von Nebenwirkungen (Hypoglykämien, Gewichtszunahme) einen HbA1c-Zielwert von < 6,5 % anstrebt, mit einer signifikanten Reduktion des Neuauftretens bzw. Progression der Nephropathie um relativ 21 % assoziiert ist (NNT 91 für 5 Jahre). Makrovaskuläre Endpunkte wurden nach 5 Jahren Studiendauer nicht signifikant reduziert

Die Ergebnisse der ACCORD-Studie zeigen, dass die Absenkung des HbA1c unter 6,5 % – unter den Bedingungen dieser Studie – die Myokardinfarkt-Mortalität erhöhen kann. Die unterschiedlichen Ergebnisse der beiden Studien deuten darauf hin, dass die Art und Weise der Intensivierung der antihyperglykämischen Therapie von entscheidender Bedeutung für den Therapieerfolg ist.

Für die praktische Therapie folgt aus den Studien, dass eine Absenkung des HbA1c auf 6,5 % gegenüber einem Zielwert von 7,0 % für den Patienten vorteilhaft sein kann, aber nur dann angestrebt werden soll, wenn

Hypoglykämien (insbesondere schwere) weitestgehend vermieden werden,
der therapeutische Effekt nicht mit einer wesentlichen Gewichtszunahme einhergeht,
wenig untersuchte Mehrfachkombinationen von oralen Antidiabetika (d. h. in der Regel mehr als zwei), und insbesondere die Beibehaltung solcher Mehrfachkombinationen bei zusätzlicher Gabe von Insulin, vermieden werden.

Das in der ACCORD-Studie praktizierte polypharmakotherapeutische Vorgehen (mit den o. g. Nebenwirkungen) wird im Verbreitungsgebiet der DDG-Leitlinie nicht empfohlen. Empfohlen wird ein Vorgehen mit präferenziellem Einsatz einer nicht-hypoglykämisierenden Substanz (Metformin) als Mittel der ersten Wahl [268] sowie der Einsatz von Insulin, falls unter einer max. 2-fach-OAD-Kombinationstherapie der HbA1c-Zielwert nicht mehr erreicht wird.

Vor dem Hintergrund der Ergebnisse der ACCORD- und ADVANCE-Studie wird der aktuelle Diskussionsentwurf der DDG-Leitlinie zur „Medikamentösen Therapie des Typ-2-Diabetes“ um die Aussage ergänzt werden, dass der Vermeidung von Nebenwirkungen (Hypoglykämien, wesentliche Gewichtszunahme) eine hohe Priorität zukommt, auch mit der Konsequenz, dass der HbA1c-Zielwert bei 7,0 belassen werden sollte, wenn ein Zielwert von < 6,5 % nur mit den o. g. Nebenwirkungen erreicht werden kann.

Die Leitlinien-Kommission wird auf in Kürze zu erwartende Publikationen zu diesem Thema (z. B. weitere Analysen der ACCORD-Studie, VADT, Ergebnisse der 10-Jahres-Nachbeobachtung der UKPDS (Präsentation am 10.9.08 auf dem EASD, BARI-2D etc.) zeitnah reagieren und die Empfehlungen zur Therapie des Typ-2-Diabetes an den aktuellen Stand der publizierten Evidenz bei Bedarf anpassen, im Einklang mit den Leitlinien der EASD und IDF.

DDG-Präsident
DDG-Vorstand
DDG-Ausschuss Pharmakotherapie
DDG-Leitlinien Kommission
(Medikamentöse antihyperglykämische Therapie des Typ-2-Diabetes)

Prof. Dr. med. S. Matthaei

Diabetes-Zentrum Quakenbrück · Klinisches Diabeteszentrum der DDG · Fachabteilung für Diabetologie, Stoffwechsel und Endokrinologie am Christlichen Krankenhaus Akademisches Lehrkrankenhaus der Medizinischen Hochschule Hannover

Danziger Str. 10

49610 Quakenbrück

Phone: 0 54 31 / 15 28 30 / 28 31

Fax: 0 54 31 / 15 28 33

Email: S.Matthaei@christliches-krankenhaus-ev.de

Prof. Dr. med. W. A. Scherbaum

Klinik für Endokrinologie, Diabetologie und Rheumatologie des Universitätsklinikums Düsseldorf
WHO Collaborating Centre for Diabetes · European Training Centre in Endocrinology and Metabolism

Moorenstrasse 05

40225 Düsseldorf

Phone: 02 11 / 8 11 78 10

Fax: 02 11 / 8 11 78 60

Email: scherbaum@uni-duesseldorf.de