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DOI: 10.1055/s-0029-1239559
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Medical Antihyperglycaemic Treatment of Type 2 Diabetes Mellitus[*]
Update of the evidence-based guideline of the German Diabetes AssociationPublication History
Guideline originally published 05.2003
Guideline last updated 10.2008
Publication Date:
29 October 2009 (online)
Contents
Foreword 522 1. Antihyperglycaemic treatment of type 2 diabetes mellitus 523 1.1 Oral antidiabetic drugs 523 1.1.1 Non-β-cytotropic oral antidiabetic drugs 523 1.1.1.1 Metformin 523 1.1.1.2 Alpha-glucosidase inhibitors (acarbose, miglitol) 526 1.1.1.3 PPAR-γ-ligands (rosiglitazone, pioglitazone) 528 1.1.1.4 Combination therapy with non-β-cytotropic oral antidiabetic drugs 531 1.1.2 β-cytotropic medications: potassium channel blockers 531 1.1.2.1 Sulphonylureas 531 1.1.2.2 Sulphonylurea analogues (repaglinide, nateglinide) 533 1.1.2.3 Combination therapy with non-β-cytotropic oral antidiabetic drugs 534 1.1.3 DPP-4 inhibitors 534 1.2. Injectable therapies 538 1.2.1 Incretin mimetics (exenatide) 538 1.2.2 Insulin therapy 539 1.2.2.1 Indication 539 1.2.2 2 Blood glucose self-monitoring 540 1.2.2.3 Application 540 1.2.2.4 Insulin administration 540 1.2.2.5 Conventional therapy 540 1.2.2.6 Intensified conventional insulin therapy 541 1.2.2.7 Combination treatment with insulin and oral antidiabetic drugs 541 1.2.2.8 Side-effects of insulin therapy 542 2. Flowchart of antihyperglycaemic treatment of type 2 diabetes 543 2.1 Legend to flowchart 544 3. References 545 4. Appendix 1: Statement by the DDG regarding the results of the ACCORD and ADVANCE trials 553
1 Note: This updated version takes into account all evidence that was published prior to the end of 06/2008, as well as all new approvals/indications prior to the same date.
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- 264 Van Wijk JPH, de Koning EJP, Castro Carbezas M. et al . Rosiglitazone improves postprandial triglyzeride and free fatty acid metabolism in type 2 diabetes. Diabetes Care. 2005; 28 844-849 Evidence class Ib
- 265 Viswanathan P, Chaudhuri A, Bhatia R. et al . Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract. 2007; 13 444-450 Evidence class IIb
- 266 Wagstaff AJ, Goa KL. Rosiglitazone – a review of its use in the management of type 2 diabetes mellitus. Drugs. 2002; 62 1805-1837 Evidence class IV
- 267 Wan Mohamad WB, Tun Fizi A, Ismail RB. et al . Efficacy and safety of single versus multiple daily doses of glibenclamide in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2000; 49 93-99 Evidence class III
- 268 Watanabe I, Tani S, Anazawa T. et al . Effect of pioglitazone on arterosclerosis in comparison with that of glibenclamide. Diabetes Res Clin Pract. 2005; 68 104-110 Evidence class Ib
- 269 Welschen LM, Bloemendal E, Nijpels G. et al . Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: A Systematic review. Diabetes Care. 2005; 28 1510-1517 Evidence class Ia
- 270 Widen E, Erikson J, Groop L. Metformin normalizes nonoxidative glucose metabolism in insulin-resistant normoglycemic first degree relatives of patients with NIDDM. Diabetes. 1992; 41 354-358 Evidence class IIa
- 271 Willms B, Ruge D. Comparison of acarbose and metformin in patients with type-2 diabetes mellitus insufficiently controlled with diet and sulfonylureas: A randomized, placebo-controlled study. Diabetic Medicine. 1999; 16 755-761 Evidence class Ib
- 272 Wolfenbuttel BH, Sels JP, Huijberts MS. Rosiglitazone. Expert Opin Pharmacother. 2001; 2 467-478 Evidence class IV
- 273 Wright A, Burden ACF, Paisey RB. et al . Sulfonylurea inadequacy Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002; 25 330-336 Evidence class Ib
- 274 Yang WS, Jeng CY, Wu TJ. et al . Synthetic peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diab Care. 2002; 25 376-380 Evidence class Ib
- 275 Yanagawa T, Araki A, Sasamoto K. et al . Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes. Metabolism. 2004; 53 353-357 Evidence class Ib
- 276 Yki-Järvinen H, Kauppila M, Kujansuu E. et al . Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1992; 327 1426-1433 Evidence class Ib
- 277 Yki-Järvinen H, Rysy L, Nikkiä K. et al . Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. Ann Intern Med. 1999; 130 389-396 Evidence class Ib
- 278 Yki-Järvinen H, Dressler A, Ziemen M. et al HOE 901/3002 Study Group . Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care. 2000; 23 1130-1136 Evidence class Ib
- 279 Yki-Järvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care. 2001; 24 758-767 Evidence class IV
- 280 Yki-Järvinen H, Kauppinen-Mäkelin R, Tiikkainen M. et al . Insulin glargine or NPH combined with metformin in type 2 diabetes: The LANMET study. Diabetologia. 2006; 49 442-451 Evidence class Ib
- 281 Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004; 351 1106-1118 Evidence class IV
- 282 Yki-Järvinen H, Juurinen L, Alvarsson M. et al . Initiate Insulin by Aggressive Titration and Education (INITIATE): A randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. Diabetes Care. 2007; 30 1364-1369 Evidence class IV
- 283 Yosefy C, Magen E, Kiselevich A. et al . Rosiglitazone improves, while glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol. 2004; 44 215-222 Evidence class Ib
- 284 Zhu XX, Pan CY, Li GW. et al . Addition of rosiglitazone to existing sulfonylurea treatment in Chinese patients with type 2 diabetes and exposure to hepatitis B or C. Diab Tech Ther. 2003; 5 33-42 Evidence class Ib.
- 285 Zinman B, Hoogwerf BJ, Duran Garcia S. et al . The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med. 2007; 146 477-485 Evidence class Ib
1 Note: This updated version takes into account all evidence that was published prior to the end of 06/2008, as well as all new approvals/indications prior to the same date.
Appendix 1
Statement by the DDG regarding the results of the ACCORD and ADVANCE studies
4.1 Introduction
The effect of near normoglycaemic metabolic control on the reduction of microvascular complications (e. g. nephropathy, retinopathy) in patients with type 2 diabetes is well documented [286, 287].
On the other hand, the number of studies on the effect of near normoglycaemic metabolic control on macrovascular complications (e. g. myocardial infarction, stroke) is comparatively less extensive and is essentially based on the results of the UKPDS, which after 10 years revealed a clear downward trend in myocardial infarctions, which however did not quite reach the level of significance (p=0.052 [286]). On the other hand a non-significant rise in strokes, by 11% in relative terms, was observed in the intensified arm of blood glucose reduction. The 10-year follow-up review of the results of the UKPDS are will be presented at this year's EASD Congress.
In this context, the results of two large studies that examined the effect of close to normal glucose metabolism control on macrovascular (ACCORD) and macro- and microvascular (ADVANCE) complications were presented at this year's Congress of the American Diabetes Association (6.-10.6.). Both studies were published in the New England Journal of Medicine to coincide with the presentation [288, 289].
4.2 Design and results of the ACCORD study
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study examined the effect of intensifying control of blood glucose, blood pressure and lipids on macrovascular complications compared with standard therapy. The results of the blood pressure and lipid therapy are expected to be published in 2010. The increased rate of mortality in the group receiving intensified antihyperglycaemic therapy caused this therapy arm of the study to be discontinued prematurely in February 2008, after 3.5 years, and the results thereof were published in June 2008 [288].
A total of 10,251 patients were recruited at 77 centres in the USA and Canada. In the group receiving intensified treatment the HbA1c target value was <6.0%, in the group receiving standard therapy the target HbA1c value was in a range from 7.0–7.9%.
All approved substances with antihyperglycaemic effects (OADs, exenatde, insulin) could be used to achieve these targets, even combination therapies were unrestricted, in terms of either the number or type of substances used.
Definition of the primary endpoint:
-
Non-fatal myocardial infarction,
-
Non-fatal stroke,
-
Death from cardiovascular causes.
4.2.1 Results of the ACCORD study ([Table 1])
|
Parameter |
Intensified (n=5 128) (at end of study) |
Standard (n=5 123) (at end of study) |
Relative riskreduction (%) |
p-value |
|
HbA1c (%) |
6.4 |
7.5 |
<0.001 | |
|
Antihyperglycaemic therapy used | ||||
|
combination therapies for patients w/o insulin (no. of substance groups*) | ||||
|
1 or 2 (n pat. (%)) |
2798 (54.6) |
3224 (62.9) | ||
|
3 (n pat.(%)) |
3030 (59.1) |
1681 (32.8) | ||
|
4 or 5 (n pat.(%)) |
539 (10.5) |
109 (2.1) | ||
|
combination therapies for patients with insulin (no. of substance groups *) | ||||
|
0 (n pat.(%)) |
916 (17.9) |
892 (17.4 | ||
|
1 or 2 (n pat. (%)) |
3311 (64.6) |
2375 (46.4) | ||
|
3 (n pat.(%)) |
2668 (52.0) |
834 (16.3) | ||
|
4 or 5 (n pat.(%)) |
526 (10.3) |
64 (1.2) | ||
|
Side effects (selection) | ||||
|
severe hypoglycaemia requiring external assistance (n pat.(%)) |
830 (16.2) |
261 (5.1) |
< 0.001 | |
|
severe hypoglycaemia requiring assistance from medical staff (n pat.(%)) |
538 (10.5) |
179 (3.5) |
< 0.001 | |
|
Parameter |
intensified (n=5,128) (at end of study) |
standard (n=5,123) (at end of study) |
relative riskreduction (%) |
p-value |
|
weight gain (kg) |
3.5 |
0.4 |
<0.001 | |
|
weight gain >10 kg (n pat.(%)) |
1399 (27.8) |
713 (14.1) |
< 0.001 | |
|
Primary and secondary endpoints | ||||
|
primary endpoint (n pat. (%)) |
352 (6.9) |
371 (7.2) |
10 |
0.16 |
|
all-cause mortality (n pat. (%)) |
257 (5.0) |
203 (4.0) |
−22 |
0.04 |
|
cardiovascular death (n pat. (%)) |
135 (2.6) |
94 (1.8) |
−35 |
0.02 |
|
non-fatal myocardial infarction (n pat. (%)) |
186 (1.1) |
235 (4.6) |
24 |
0.004 |
|
non-fatal stroke (n pat. (%)) |
67 (1.3) |
61 (1.2) |
−6 |
0.74 |
|
heart failure (fatal / non-fatal) (n pat. (%)) |
152 (3.0) |
124 (2.4) |
−18 |
0.17 |
|
* the following substance groups were defined: | ||||
|
Metformin | ||||
|
Secretogogues (sulphonylureas, glinides) | ||||
|
Thiazolidindione (preferably rosiglitazone) | ||||
|
Alpha-glucosidase inhibitors | ||||
|
Incretins (exenatide, sitagliptin) |
4.2.2 Summary
The primary endpoint was reduced non-significantly by 10% in relative terms (p=0.16). The main reason for this trend was a significant relative reduction of 24% (p=0.004) in the risk of non-fatall myocardial infarctions.
The cause(s) of the significantly increased mortality (relative increase 22%, p=0.04) is (are) currently unknown and must be investigated in subsequent analyses. It is still unclear whether
-
undetected hypoglycaemia (increased sympathotonus >> arrythmias >>death) against the background of hyperglycaemias requiring external assistance experienced by 16.2% of patients (3.1 times greater than standard therapy),
-
the marked weight gain in a large subgroup of the patients (27.8% gained > 10 kg over the course of the study; > 70% of the patients in the group receiving intensified treatment received insulin + thiazolidindione combination therapy),
-
interferences within the polypharmacotherapy used (at the end of the study ∼70% of the patients who were not treated with insulin and ∼60% of those who were treated with insulin were receiving combination therapy consisting of 3, 4, or 5 OADs,
-
or the speed with which the HbA1c target value was achieved
-
might have been a factor in this respect.
4.3 Design and results of the ADVANCE study
The Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study examined the effect of intensifying control of blood sugar and blood pressure on macrovascular and microvascular complications in comparison with a standard therapy. The results of the intensified blood pressure therapy were published in 2007 [290]. In all, 11,140 patients were recruited at 215 centres in 20 countries (particularly in Australia, Asia, Europe, Canada).
The HbA1c target value in the group receiving intensified treatment was <6.5%, the target value for the standard treatment group was 7.5%. In order to achieve these targets, the following procedure was established for the intensified treatment group:
-
Intensification of non-pharmacological therapy options
-
Escalation of therapy by attending physision on the basis of HbA1c and fasting blood sugar levels, taking into account the following recommendations:
-
Escalation of the gliclazid-MR dose
-
Supplementing with other OADs
-
Supplementing with a long-acting insulin
-
Intensified insulin therapy (multiple insulin injection therapy)
Definition of the primary endpoint:
-
Non-fatal myocardial infarction
-
Non-fatal stroke
-
Death from cardiovascular causes
-
Nephropathy
-
Retinopathy
|
Parameter |
Intensified (n=4 828) (at end of study) |
Standard (n=4 741) (at end of study) |
Relative risk reduction (%) |
p-value |
|
HbA1c (%) |
6.5 |
7.3 |
<0.001 | |
|
Antihyperglycaemic therapy used | ||||
|
gliclazid (n pat. (%)) |
4209 (90.5) |
80 (1.6) | ||
|
other SU (n pat. (%)) |
89 (1.9) |
2606 (57.1) | ||
|
metformin (n pat.(%)) |
3455 (73.8) |
3057 (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.(%)) |
1953 (40.5) |
1142 (24.1) | ||
|
Side effects (selection) | ||||
|
severe hypoglycaemia (%/year) |
0.7 |
0.4 |
<0.05 | |
|
weight gain (kg) |
0.0 |
−1.0 |
<0.05 | |
|
Primary and secondary endpoints | ||||
|
primary endpoint (n pat. (%)) |
1009 (18.1) |
1116 (20.0) |
10 |
0.01 |
|
all-cause mortality (n pat. (%)) |
498 (8.9) |
533 (9.6) |
7 |
0.28 |
|
cardiovascular death (n pat. (%)) |
253 (4.5) |
289 (5.2) |
12 |
>0.05 |
|
non-fatal myocardial infarction (n pat. (%)) |
153 (2.7) |
156 (2.8) |
2 |
>0.05 |
|
non-fatal stroke (n pat. (%)) |
214 (3.8) |
209 (3.8) |
−2 |
>0.05 |
|
heart failure (n pat. (%)) |
220 (3.9) |
231 (4.1) |
5 |
>0.05 |
|
nephropathy (recurrence or progression) (n pat (%)) |
230 (4.1) |
292 (5.2) |
21 |
0.006 |
|
retinopathy (recurrence or progression) (n pat. (%)) |
332 (6.0) |
349 (6.3) |
5 |
>0.05 |
4.3.2 Summary
The primary endpoint was lowered by 10% in relative terms (p=0.01).
The main reason for this effect was a significant reduction in nephropathy, by 21% in relative terms (p=0.006).
Overall mortality was lowered non-significantly, by 7% in relative terms (p=0.28). Macrovascular events were lowered non-significantly, by 6% in relative terms (p=0.32).
The number of severe hypoglycaemia in the group receiving intensified therapy was 0.7%/year, higher than in the group receiving standard therapy (0.4%/year).
The group receiving intensified therapy experienced no weight gain, the group receiving standard therapy experienced an average weight loss of 1.0 kg.
|
Study characteristics |
ACCORD |
ADVANCE |
|
Patient characteristics at start of study | ||
|
number of study participants |
10,251 |
11,140 |
|
age (in years) |
62 |
66 |
|
duration of diabetes (in years) |
10 |
8 |
|
HbA1c (average) (%) |
8.3 |
7.3 |
|
percentage with prior macrovascular diseases (%) |
35 |
32 |
|
Intervention data | ||
|
Definition of primary endpoint |
non-fatal myocardial infarction, non-fatal stroke, death due to cardiovascular causes |
non-fatal myocardial infarction, non-fatal stroke, death due to cardiovascular causes, nephropathy, retinopathy |
|
HbA1c target value (%) |
<6.0 |
≤6.5 |
|
Average duration of study (in years) |
3.4 |
5.0 |
|
Pharmacotherapy at end of study (intensified vs. standard) (%) | ||
|
insulin |
77 vs. 55 |
41 vs. 24 |
|
metformin |
95 vs. 87 |
74 vs. 67 |
|
secretagogues (sulphonylurea / glinide) |
87 vs. 74 |
94 vs. 62 |
|
thiazolidinedione |
92 vs. 58 |
17 vs. 11 |
|
incretin based therapies (exenatide, sitagliptin) |
18 vs. 5 |
Not reported |
|
statin |
88 vs. 88 |
46 vs. 48 |
|
any antihypertensive medication |
91 vs. 92 |
89 vs. 88 |
|
ACE inhibitors |
70 vs. 72 |
Not reported |
|
aspirin |
76 vs. 76 |
57 vs. 55 |
|
Results (intensified vs. standard) | ||
|
HbA1c (average at end of study (%)) |
6.4 vs. 7.5 + |
6.5 vs. 7.3 + |
|
mortality | ||
|
all-cause |
5.0 vs. 4.0 + |
(%) 8.9 vs. 9.6 |
|
cardiovascular (%) |
2.6 vs. 1.8 + |
4.5 vs. 5.2 |
|
non-fatal myocardial infarction (%) |
3.6 vs. 4.6 + |
2.7 vs. 2.8 |
|
non-fatal stroke (%) |
1.3 vs. 1.2 |
3.8 vs. 3.8 |
|
severe hypoglycaemia requiring external assistance (ACCORD), or severe hypoglycaemia (ADVANCE) (%/year) |
3.1 vs. 1.0 + |
0.7 vs. 0.4 |
|
weight gain (kg) |
3.5 vs. 0.4 |
0.0 vs. – 1.0 + |
|
nicotine abuse (%) |
10 vs. 10 |
8 vs. 8 |
|
+ The comparison of the intervention with the standard therapy was significant. Modified according to (6) |
[Table 3] shows a comparison summary of the essential parameters of the two studies.
4.4.1 Note on patient characteristics
The patient characteristics show that the patient cohorts recruited in both studies displayed similarities in terms of age, duration of diabetes and percentage with pre-existing macrovascular diseases. The HbA1c target values achieved were comparable.
4.4.2 Note on intensifying antihyperglycaemic therapy
The ways in which antihyperglycaemic therapy was intensified present marked differences: Whereas a polypharmacotherapeutic approach was adopted in the ACCORD study (by the end of the study ∼70% of patients not treated with insulin and ∼60% of those treated with insulin were receiving combination therapies with 3, 4, or 5 OADs), the ADVANCE study used an algorithm to determine a supplementary regimen of insulin with lasting effects if the HbA1c target value of <6.5% was not achieved using OADs alone. If a further escalation in therapy became necessary in order to achieve the HbA1c target value, intensified insulin therapy using basal and prandial insulin was recommended.
4.4.3 Note on results regarding effect on mortality
The conspicuous effect of increased mortality in the group receiving intensified treatment in the ACCORD study was not observed in the ADVANCE study, which recorded comparable results for HbA1c target value achievement.
4.4.4 Note on side effects of intensified therapy
4.4.4.1 Hypoglycaemia
The group receiving intensified treatment in the ACCORD study experienced severe hypoglycaemia at a rate 3.1 times greater than the standard treatment group, overall 16.2% of the patients in this group suffered a severe hypoglycaemia episode
In the ADVANCE study, the rate of severe hypogylycaemia was 0.7%/year, slightly higher than in the standard therapy group (0.4%/year), but lower than in the standard therapy group of the ACCORD study (1.0%/year) – with a difference of 1.0% (6.5% (ADVANCE (int.) vs. 7.5% (ACCORD (std.))) in the average HbA1c value.
4.4.4.2 Weight gain
The average weight gain of patients in the ACCORD study was 3.5 kg, 27.8% of the patients experienced a weight gain of > 10 kg.
The patients in the group receiving intensified treatment in the ADVANCE study experienced no weight gain (+/- 0.0 kg).
4.5 Conclusions
The results of the ADVANCE study show that intensified antihyperglycaemiec therapy that aims to achieve an HbA1c target value of <6.5% while avoiding side effects (hypoglycaemia, weight gain) is associated with significantly reduced recurrence or progression of nephropathy, by 21% in relative terms (NNT 91 for 5 years). Macrovascular endpoints were not significantly reduced by the end of the 5-year study.
The results of the ACCORD study show that lowering the HbA1c to below 6.5% – under the conditions of this study – can increase mortality due to myocardial infarction. The differing results from these two studies indicate that the way in which antihyperglycaemic therapy is intensified is of crucial importance to the success of the therapy.
The conclusion derived from the studies for application in practical therapy is that lowering HbA1c to 6.5% as compared with a target value of 7.0% can be beneficial for the patient, but should only be aimed for provided that
-
hypoglycaemia (particularly severe hypoglycaemia) can be largely prevented,
-
the therapeutic effect is not associated with significant weight gain,
-
inadequately documented combinations of multiple oral diabetics (i. e., generally more than two) are avoided, and particularly that such multiple combinations are discontinued if treatment with insulin is begun.
The polypharmacotherapeutic procedure adopted in the ACCORD study (with the side effects described above) is not recommended in the territory for which the DDG guideline is authoritative. Instead, the guideline recommends a procedure with preferential use of a non-hypoglycaemia inducing substance (metformin) as the medium of first choice [292] and also the use of insulin, if the HbA1c target value is no longer reached with a combination therapy consisting of no more than two OADs.
In the light of the results of the ACCORD and ADVANCE studies, the DDG guideline on “Antihyperglycaemic treatment of type 2 diabetes” has been supplemented with a statement to the effect that avoidance of side effects (hypoglycaemia, significant weight gain) is a primary objective, even at the cost of allowing the HbA1c target value to remain at 7.0, if a target value of <6.5% can only be achieved with the side effects described above.
The guidelines commission will respond promptly to the publications on this subject that are expected soon (e. g. further analyses of the ACCORD study, VADT, results of the 10-year follow-up review of the UKPDS (presentation on 10.9.08 on the EASD, BARI-2D etc.), and will adapt its recommendations for treating type 2 diabetes to the latest status of published evidence as necessary, in keeping with the guidelines of the the EASD and IDF.
DDG President
DDG Managing Board
DDG Pharmacotherapy Committee
DDG Guidelines Commission
(Antihyperglycaemic treatment of type 2 diabetes mellitus)
4.6 References
1 UK Prospective Diabetes Study (UKPDS) Group . 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 – 853
2 Shichiri M , Kishikawa H , Ohkubo Y et al . Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients . Diabees Care 2000 ; 23 (Suppl.2) : B21 – B29
3 The Action to Control Cardiovascular Risk in Diabetes Study Group . Effect of Intensive Glucose Lowering in Type 2 Diabetes . N Eng J Med 2008 ; 358 : 2545 – 2559
4 The ADVANCE Collaborative Group . Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes . N Eng J Med 2008 ; 358 : 2560 – 2572
5 Patel A , McMahon S, The ADVANCE Collaborative Group . Effect of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus . Lancet 2007 ; 370 : 829 – 840
6 Dluhy RG , McMahon GT . Intensive Glycemic Control in the ACCORD and ADVANCE Trials. N Eng J Med 2008 ; 358 : 2630 – 2633
7 UKPDS Group . Eff ect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 ; 352 : 854 – 865
Correspondence
Prof. Stephan Matthaei
Spokesperson for the Panel of Experts
Quakenbrück Diabetes Centre, DDG clinical diabetes centre
Department of Diabetology, Metabolism and Endocrinology at the Christliches Krankenhaus Academic Teaching Hospital of the Hannover Medical University
Danziger Straße10
49610 Quakenbrück
Phone: ++49/5431/15 2830
Fax: ++49/5431/15 2831
Email: S.Matthaei@ckq-gmbh.de
Prof. W. A. Scherbaum
Chairman of the DDG
Guidelines Committee
Clinic for Endocrinology, Diabetology and Rheumatology at Düsseldorf University
Hospital WHO Collaborating
Centre for Diabetes European
Training Centre in Endocrinology and Metabolism
Moorenstraße 05
40225 Düsseldorf
Phone: ++49/ 211/81 17810
Fax: ++49/211/81 17860
Email: scherbaum@uni-duesseldorf.de