RSS-Feed abonnieren
DOI: 10.1055/s-2007-973603
© Georg Thieme Verlag KG Stuttgart · New York
Neuentstehung eines Diabetes mellitus unter antihypertensiver Therapie
New-onset diabetes mellitus during antihypertensive treatmentPublikationsverlauf
eingereicht: 18.01.2007
akzeptiert: 8.2.2007
Publikationsdatum:
21. März 2007 (online)

Zusammenfassung
Eine arterielle Hypertonie ist häufig mit einer Insulinresistenz vergesellschaftet und prädispositioniert zur Entwicklung eines Diabetes mellitus. Faktoren für die häufige Ko-Morbidität von Hypertonie und Diabetes umfassen die hohe Rate an Übergewicht und Adipositas bei Patienten mit Hypertonie, Hypertonie-assoziierte Veränderungen der Mikrozirkulation (Remodeling und Rarefikation), gesteigerte Aktivität des sympathischen Nervensystems bei Hypertonie und eine Reihe möglicher zellulärer Funktionsänderungen. Eine medikamentöse Hypertoniebehandlung kann die Inzidenz eines neu diagnostizierten Diabetes erhöhen (Diuretika und ß-Rezeptorenblocker), reduzieren (ACE-Hemmer und AT1-Antagonisten) oder intermediäre Effekte auslösen (Kalziumantagonisten). Die unterschiedlichen Effekte der verschiedenen Antihypertensiva auf den Kohlenhydratstoffwechsel hypertensiver Patienten lassen sich weitgehend mit der unterschiedlichen Beeinflussung der Hypertonie-assoziierten Veränderungen der Mikrozirkulation und der Sympathikusaktivität erklären. Die verschiedenen Raten an neu diagnostiziertem Diabetes mellitus bei der Therapie mit „alten” vs. „neuen” Antihypertensiva gehen über die Behandlungszeit kontinuierlich auseinander, so dass sich für die bei Hypertonie meist notwendige Langzeittherapie niedrige „numbers needed to treat” (NNT) berechnen lassen. Ein neu aufgetretener Diabetes mellitus ist in Interventionsstudien mit einer Beobachtung bis etwa 5 Jahre nicht mit einer gesteigerten Rate kardiovaskulärer Ereignisse assoziiert. Langzeitdaten zeigen jedoch überwiegend, dass ein unter Hypertoniebehandlung entstandener Diabetes prognostisch ungünstig ist. Differenzialtherapeutisch sprechen diese Befunde gegen Diuretika und b-Rezeptorenblocker und für eine Bevorzugung von ACE-Hemmstoffen und AT1-Antagonisten bei der Hypertoniebehandlung, insbesondere bei Patienten mit gesteigertem Diabetesrisiko.
Summary
Arterial hypertension is frequently associated with insulin resistance and type 2 diabetes mellitus. Factors in this close association include the high rate of overweight and obesity in hypertensive patients, hypertension-associated changes within the microvasculature (arteriolar remodelling and capillary rarefaction), increased activity of the sympathetic nervous system and a number of possible molecular and cellular changes. Drug treatment of hypertension can further increase (diuretics, beta-blockers) or decrease (ACE inhibitors, angiotensin II receptor antagonists) the rate of new-onset diabetes or may have intermediate effects (calcium-channel blockers). The differing effects of the various antihypertensive drugs on the incidence of new-onset diabetes can largely be explained by their differential effects on hypertension-associated alterations within the microvasculature and on the activity of the sympathetic nervous system. In long-term studies, the difference between "new" and "old" antihypertensive drugs in their effect on the rate of new-onset diabetes continues to grow so that small "numbers needed to treat" (NNT) can be calculated. In interventional studies lasting up to five years, new-onset diabetes is not associated with excess cardiovascular events or mortality. However, preliminary data from long-term observations predominantly suggest that new-onset diabetes during antihypertensive therapy has an unfavorable prognosis. These findings argue against diuretics and b-blockers and for suggest that ACE inhibitors and angiotensin II receptor blockers in the treatment of hypertension, especially in those patients with an increased metabolic risk.
Schlüsselwörter
antihypertensive Therapie - Diabetes - unerwünschte Nebenwirkungen
Key words
antihypertensive treatment - diabetes - side effects
Literatur
- 1
Kannel W B, Wilson P W, Zhang T J.
The epidemiology of impaired glucose tolerance and hypertension.
Am Heart J.
1991;
121
1268-1273
MissingFormLabel
- 2
Sowers J R, Epstein M, Frohlich E D.
Diabetes, hypertension and cardiovascular disease: an update.
Hypertension.
2001;
37
1053-1059
MissingFormLabel
- 3
Gress T W, Nieto J. et al. for the Atherosclerosis Risk in Communities Study .
Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus.
N Engl J Med.
2000;
342
905-912
MissingFormLabel
- 4
Mancia G, Grassi G, Zanchetti A.
New-onset diabetes and antihypertensive drugs.
J Hypertens.
2006;
24
3-10
MissingFormLabel
- 5
Taylor E N, Hu F B, Curhan G C.
Antihypertensive medications and the risk of incident type 2 diabetes.
Diabetes Care.
2006;
29
1065-1070
MissingFormLabel
- 6
Elliot W J, Meyer P M.
Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.
Lancet.
2007;
369
201-207
MissingFormLabel
- 7
Kearney P M, Whelton M, Reynolds K. et al .
Global burden of hypertension: analysis of worldwide data.
Lancet.
2005;
365
217-223
MissingFormLabel
- 8
Zimmer P, Alberti K GMM, Shaw J.
Global and societal implications of the diabetes epidemic.
Nature.
2001;
414
782-787
MissingFormLabel
- 9
Must A, Spadano J, Coakley E H. et al .
The disease burdon associated with overweight and obesity.
JAMA.
1999;
282
1523-1529
MissingFormLabel
- 10
Doll S, Paccaud F, Bovet P, Burnier M, Wietlisbach V.
Body mass index, abdominal adiposity and blood pressure: Consistency of their association
across developing and developed countries.
Int J Obes Relat Metab Disord.
2002;
26
48-57
MissingFormLabel
- 11
Ferrannini E, Buzzigoli G, Bonadona R. et al .
Insulin resistance in essential hypertension.
N Engl J Med.
1987;
317
350-357
MissingFormLabel
- 12
Ferrranini E, Natali A.
Essential hypertension, metabolic disorders and insulin resistance.
Am Heart J.
1991;
121
1274-1282
MissingFormLabel
- 13
Laakso M, Edelman S V, Brechtel G, Baron A D.
Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man.
A novel mechanism for insulin resistance.
J Clin Invest.
1990;
85
1844-1852
MissingFormLabel
- 14
Yang Y J, Hope I D, Ader M, Bergman R N.
Insulin transport across capillaries is rate limiting for insulin action in dogs.
J Clin Invest.
1989;
84
1620-1628
MissingFormLabel
- 15
Julius S, Gudbrandsson T, Jamerson K A, Tariq S S, Andersson O.
The hemodynamic link between insulin resistance and hypertension.
J Hypertens.
1991;
9
983-986
MissingFormLabel
- 16
Serne E H, Gans R O, ter Maaten J C. et al .
Impaired skin capillary recruitment in essential hypertension is caused by both functional
and structural capillary rarefaction.
Hypertension.
2001;
38
238-242
MissingFormLabel
- 17
Antonios T F, Singer D R, Markandu N D, Mortimer P S, MacGregor G A.
Structural skin capillary rarefaction in essential hypertension.
Hypertension.
1999;
33
998-1001
MissingFormLabel
- 18
Schiffrin E L, Park J B, Intengan H D, Touyz R M.
Correction of arterial structure and endothelial dysfunction in human essential hypertension
by the angiotensin receptor antagonist losartan.
Circulation.
2000;
101
1653-1659
MissingFormLabel
- 19
Düsing R, Göbel B, Weißer B, Dittrich D, Kraemer S, Vetter H.
Mechanismus und Bedeutung der arteriolären Media-Hypertrophie/Hyperplasie bei der
arteriellen Hypertonie. Rolle des Na/H-Antiports.
Klin Wochenschr.
1988;
66
1151-1159
MissingFormLabel
- 20
Struijker-Boudier H A.
Arteriolar and capillary remodeling in hypertension.
Drugs.
1999;
59
37-40
MissingFormLabel
- 21
Rosei E A, Rizzoni D, Castellano M. et al .
Media: lumen ratio in human small resistance arteries is related to forearm vascular
resistance.
J Hypertens.
1995;
13
341-347
MissingFormLabel
- 22
Serne E H, Gans R O, ter Maaten J C, ter Wee P M, Donker A J, Stehhouwer C D.
Capillary recruitment is impaired in essential hypertension and relates to insulin’s
metabolic and vascular actions.
Cardiovasc Res.
2001;
49
161-168
MissingFormLabel
- 23
Serne E H, Stehhouwer C D. et al .
Microvascular function relates to insulin sensitivity and blood pressure in human
subjects.
Circulation.
1999;
99
896-902
MissingFormLabel
- 24
Mancia G, Grassi P, Parati G, Zanchetti A.
The sympathetic nervous system in human hypertension.
Acta Physiol Scand (Suppl).
1997;
640
117-121
MissingFormLabel
- 25
DeQuattro V, Feng M.
The sympathetic nervous system: the muse of primary hypertension.
J Hum Hypertension.
2002;
(Suppl 1)
16
64-69
MissingFormLabel
- 26
Christensen N J.
The role of catecholamines in clinical medicine.
Acta Med Scand.
1979;
(Suppl)
624
9-18
MissingFormLabel
- 27
DeFronzo A.
Insulin resistance, hyperinsulinemia, and coronary artery disease: a complex metabolic
web.
J Cardiovasc Pharmacol.
1992;
(Suppl 1)
20
1-16
MissingFormLabel
- 28
Hansson L, Lindholm L H. et al .
Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy
on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention
Project (CAPPP) randomized trial.
Lancet.
1999;
353
611-616
MissingFormLabel
- 29
Hansson L, Lindholm L, Ekbom T. et al .
Randomized trial of old and new antihypertensive drugs in elderly patients. cardiovascular
mortality and morbidity: The Swedish Trial in Old Patients with Hypertension-2 study.
Lancet.
1999;
354
1751-1756
MissingFormLabel
- 30
Wing L M, Reid C M, Ryan P. et al. for the Second Australian National Blood Pressure Study Group .
A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics
for hypertension in the elderly.
N Engl J Med.
2003;
348
583-592
MissingFormLabel
- 31
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group .
Major outcomes in high-risk hypertensiven patients randomized to angiotensin-converting-enzyme
inhibitor or calcium channel blocker vs. diuretic.
JAMA.
2002;
288
2981-2997
MissingFormLabel
- 32
Hansson L, Hedner T, Lund-Johansen P. et al. for the Nordil Study Group .
Randomized trial of effects of calcium antagonists compared with diuretics and beta-blockers
on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL)
study.
Lancet.
2000;
356
359-365
MissingFormLabel
- 33
Mancia G, Brown M J, Castaigne A. et al .
Outcomes with nifedipine GITS or co-amilozide in hypertensive diabetics and nondiabetics
in intervention as a goal in hypertension (INSIGHT).
Hypertension.
2003;
41
431-436
MissingFormLabel
- 34
Dahlöf B, Devereux R B, Kjeldsen S E. et al., the LIFE Study Group .
Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction
in hypertension study (LIFE): a randomised trial against atenolol.
Lancet.
2002;
359
995-1003
MissingFormLabel
- 35
Lindholm L H, Ibsen H, Borch-Johnsen K. et al .
Risk of new-onset diabetes in the losartan intervention for endpoint reduction in
hypertension study.
J Hypertens.
2002;
20
1879-1886
MissingFormLabel
- 36
Pepine C J, Handberg E M, Cooper-DeHoff R M. et al .
A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy
for patients with coronary artery disease. The International Verapamil-Trandolapril
Study (INVEST): a randomized controlled trial.
JAMA.
2003;
290
2805-2816
MissingFormLabel
- 37
Lithell H, Hansson L, Skogg I. et al .
The study on cognition and prognosis in the elderly (SCOPE). Principal results of
a randomized double-blind intervention trial.
J Hypertens.
2003;
21
875-886
MissingFormLabel
- 38
Lindholm L H, Persson M, Alaupovic P. et al .
Metabolic outcome during 1 year in newly detected hypertensives: results of the antihypertensive
treatment and lipid profile in a north of Sweden efficacy evaluation (ALPINE) study.
J Hypertens.
2003;
21
1563-1574
MissingFormLabel
- 39
Dahlof B, Sever P S, Poulter N R. et al., ASCOT Investigators .
Prevention of cardiovascular events with an antihypertensive regimen of amlodipine
adding perindopril as required versus atenolol adding bendroflumethiazide as required,
in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA):
a multicentre randomised controlled trial.
Lancet.
2005;
366
895-906
MissingFormLabel
- 40
ALLHAT Collaborative Research Group .
Clinical events in high risk patients randomly assigned to calcium channel blocker
versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial.
Hypertension.
2006;
48
374-384
MissingFormLabel
- 41
Julius S, Kjeldsen S E, Weber M. et al. for the VALUE trial group .
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens
based on valsartan or amlodipine: the VALUE randomised trial.
Lancet.
2004;
363
2022-2031
MissingFormLabel
- 42
Kjeldsen S E, Julius S, Mancia G. et al .
Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high
risk hypertensive patients: the VALUE trial.
J Hypertens.
2006;
24
1405-1412
MissingFormLabel
- 43
Julius S, Weber M A, Kjeldsen S E. et al .
The valsartan antihypertensive long-term use evaluation (VALUE) trial: outcomes in
patients receiving monotherapy.
Hypertension.
2006;
48
385-391
MissingFormLabel
- 44
Savage P J, Pressel S L, Curb J D. et al .
Influence of long-term, low-dose, diuretic-based antihypertensive therapy on glucose,
lipids, uric acid, and potassium levels in older men and women with isolated systolic
hypertension. The Systolic Hypertension in the Elderly Program.
Arch Intern Med.
1998;
158
741-751
MissingFormLabel
- 45
Murphy M B, Lewis P J, Kohner E, Schumer B, Dollery C T.
Glucose intolerance in hypertensive patients treated with diuretics: a fourteen-year
follow-up.
Lancet.
1982;
2
1293-1295
MissingFormLabel
- 46
Zillich A J, Garg J, Basu S, Bakris G L, Carter B L.
Thiazide diuretics, potassium, and the development of diabetes. A quantitative review.
Hypertension.
2006;
48
219-224
MissingFormLabel
- 47
Shep Cooperative Research Group .
Prevention of stroke by antihypertensive drug treatment in older persons with isolated
systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program
(SHEP).
JAMA.
1991;
265
3255-3264
MissingFormLabel
- 48
Kostis J B, Wilson A C, Freudenberger R S, Cosgrove N M, Pressel S L, Davis B R.
Long-term effect of diuretic-based therapy on fatal outcomes in subjects with and
without diabetes.
Am J Cardiol.
2005;
95
29-35
MissingFormLabel
- 49
Bakris G L, Fonseca V, Katholi R E. et al., Gemini Investigators .
Metabolic effects of carvedilol vs. metoprolol in patients with type 2 diabetes mellitus
and hypertension: a randomized controlled trial.
JAMA.
2004;
292
2227-2236
MissingFormLabel
- 50
Celik T, Iyisoy A, Kursaklioglu H. et al .
Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance,
plama adiponectin and soluble P-selectin levels in hypertensive patients.
J Hypertens.
2005;
24
591-596
MissingFormLabel
- 51
The Heart Outcomes Prevention Evaluation Study Investigators .
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients.
N Engl J Med.
2000;
342
145-153
MissingFormLabel
- 52
The Peace-Trial Investigators .
Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
N Engl J Med.
2004;
351
2058-2068
MissingFormLabel
- 53
The European Trial on Reduction of Cardiac Events with Perindopril among Patients
with Stable Coronary Artery Disease Investigators .
Efficacy of Perindopril in reduction of cardiovascular events in stable coronary artery
disesase.
Lancet.
2003;
362
782-788
MissingFormLabel
- 54
Dagenais G R, Pogue J, Fox K. et al .
Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular
systolic dysfunction or heart failure: a combined analysis of three trials.
Lancet.
2006;
368
581-588
MissingFormLabel
- 55
The Dream Trial Investigators .
Effect of ramipril on the incidence of diabetes.
N Engl J Med.
2006;
355
1551-1562
MissingFormLabel
- 56
Lindholm L H, Persson M, Alaupovic P. et al .
Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive
Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
J Hypertens.
2003;
21
1563-1574
MissingFormLabel
- 57
Schiffrin E L.
Remodeling of resistance arteries in essential hypertension and effects of antihypertensive
treatment.
Am J Hypertens.
2004;
17
1192-1200
MissingFormLabel
- 58
Savoia C, Touyz R M, Endemann D H. et al .
Angiotensin receptor blocker added to previous antihypertensive agents on arteries
of diabetic hypertensive patients.
Hypertension.
2006;
48
271-277
MissingFormLabel
- 59
Sihm I, Schroeder A P, Aalkjaer C, Mulvany M J, Thygesen K, Lederballe O.
Effect of antihypertensive treatment on cardiac and subcutaneous artery structure:
a comparison between calcium channel blocker and thiazide-based regimens.
Am J Hypertens.
1998;
11
263-271
MissingFormLabel
- 60
Olsen M H, Fossum E, Hoieggen A. et al .
Long-term treatment with Losartan versus atenolol improves insulin sensitivity in
hypertension: ICARUS, a LIFE substudy.
J Hypertens.
2005;
23
891-898
MissingFormLabel
- 61
Grossman E, Messerli F H.
Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood
pressure.
Am J Cardiol.
1997;
80
1453-1458
MissingFormLabel
- 62
Fogari R, Zoppi A, Corradi L. et al .
Effects of different dihydropyridine calcium antagonists on plama norepinephrine in
essential hypertension.
J Hypertens.
2000;
18
1871-1875
MissingFormLabel
- 63
Lindqvist M, Kahan T, Melcher A. et al .
Long-term calcium antagonist treatment of humans with mibefradil or amlodipine increases
sympathetic nerve activity.
J Hypertens.
2007;
25
169-175
MissingFormLabel
- 64
de Champlain J, Karas M, Toal C, Nadeau R, Larochelle P.
Effects of antihypertensive therapies on the sympathetic nervous system.
Can J Cardiol.
1999;
(Suppl A)
15
8A-14A
MissingFormLabel
- 65
Cooper M E, Tikellis C, Thomas M C.
Preventing diabetes in patients with hypertension: one more reason to block the renin-angiotensin
system.
J Hypertens.
2006;
(Suppl 1)
24
S57-S63
MissingFormLabel
- 66
Düsing R, Lehnert H.
Diabetogenic effect of antihypertensive treatment: primum nil nocere.
Nephrol Dial Transplant.
2004;
19
531-534
MissingFormLabel
- 67
Alderman M H, Cohen H, Madhavan S.
Diabetes and cardiovascular events in hypertensive patients.
Hypertension.
1999;
33
1130-1134
MissingFormLabel
- 68
Dunder K, Lind L, Zethelius B, Berglund L, Lithell H.
Increase in blood glucose concentration during antihypertensive treatment as a predictor
of myocardial infarction: population based cohort study.
BMJ.
2003;
326
681-685
MissingFormLabel
- 69
Verdecchia P, Reboldi G, Angeli F. et al .
Adverse prognostic significance of new diabetes in treated hypertensive subjects.
Hypertension.
2004;
43
963-969
MissingFormLabel
Prof. Dr. med. Rainer Düsing
Universitätsklinikum Bonn, Medizinische Poliklinik
Wilhelmstraße 35-37
53111 Bonn
Telefon: 0228/28722343
Fax: 0228/28722593
eMail: duesing@uni-bonn.de