Correspondence
Follow-up of Intensive Glucose Control in Type 2 Diabetes
N Engl J Med 2009; 360:416-418January 22, 2009
- Article
To the Editor:
The United Kingdom Prospective Diabetes Study (UKPDS) reported by Holman et al. (Oct. 9 issue)1 shows the legacy effect of intensive glucose control (in the metformin group as well as in the group that received either sulfonylurea or insulin) on clinical outcomes in patients with newly diagnosed type 2 diabetes mellitus. The UKPDS has influenced international treatment guidelines2 leading to the recommendation of metformin as the initial pharmacologic therapy in all patients with type 2 diabetes. The original UKPDS trial compared outcome data in patients who received metformin versus conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin therapy).3 However, comparisons between the metformin group and the sulfonylurea or insulin group separately have not been reported. The recent 10-year follow-up of the UKPDS survivor cohort suggests that metformin, sulfonylurea, and insulin are potentially equivalent candidates for initial glucose-lowering therapy. To guide such treatment choices, we hope that the UKPDS will report separate between-group comparisons within the intensive-therapy group (i.e., metformin vs. sulfonylurea, metformin vs. insulin, and insulin vs. sulfonylurea) in the original 1997 study and the recent 2007 follow-up.
Søren S. Lund, M.D.
Peter Rossing, M.D., D.M.Sc.
Allan A. Vaag, M.D., Ph.D.
Steno Diabetes Center, 2820 Gentofte, Denmark
sqrl@steno.dk Drs. Lund, Rossing, and Vaag report holding equity in Novo Nordisk and being employees of the Steno Diabetes Center, an independent academic institution owned by Novo Nordisk and the Novo Nordisk Foundation; Drs. Vaag and Rossing, receiving grant support from Novo Nordisk; and Drs. Lund and Vaag, receiving lecture fees from Novo Nordisk.
No other potential conflict of interest relevant to this letter was reported.
3 References1
Holman RR ,Paul SK ,Bethel MA ,Neil HAW ,Matthews DR . Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 2008;359:1565-1576
Full Text | Web of Science | Medline2
Nathan DM ,Buse JB ,Davidson MB , et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711-1721
CrossRef | Web of Science | Medline3
UK Prospective Diabetes Study (UKPDS) Group
CrossRef | Web of Science | Medline
To the Editor:
In the original UKPDS trial, when metformin was prescribed for patients who were already receiving a sulfonylurea, there was a significant increase in the risk of diabetes-related death and death from any cause. These results were attributed to a small number of end points, and they were in contrast to the positive results associated with metformin monotherapy, which have, of course, been highly influential in shaping modern clinical practice.
The new data in the 10-year post-randomization follow-up show positive results associated with metformin in general, but no separate information has so far been provided regarding the subgroup of patients receiving combination therapy. Given the additional accumulation of end points, can the authors provide reassurance regarding this clinically important issue?
John R. Petrie, M.D., Ph.D.
University of Dundee, Dundee DD1 9SY, United KingdomTo the Editor:
The UKPDS had important methodologic limitations.1 The intervention was multifactorial intensive glucose control as compared with standard care, and the effects on blood glucose levels and complications were modest and uncertain (the number needed to treat over 10 years for the combined primary end point was 20 [95% confidence interval, 10 to 500]).2 Thus, the effects on mortality may have been due to factors other than blood glucose control. Information on accompanying treatment during the study is necessary in order to interpret the mortality data. This information is also relevant to the substudy involving the biguanide, metformin.
The results in this small group of patients have never been replicated and still stand against the results of the University Group Diabetes Program, in which the use of phenformin was associated with an increase in mortality.3 Follow-up data on the subgroup comparing the combination of sulfonylureas and metformin with sulfonylureas alone should also be reported. This combination treatment has been associated with a significant increase in mortality,2 and a recent meta-analysis provides support for continuing concerns about it.4 It is disturbing that support for the use of the most frequently used oral blood glucose–lowering agents worldwide continues to be based on weak and ambiguous evidence.
4 ReferencesIngrid Mühlhauser, M.D.
University of Hamburg, 20146 Hamburg, Germany
ingrid_muehlhauser@uni-hamburg.de 1
McCormack J ,Greenhalgh T . Seeing what you want to see in randomised controlled trials: versions and perversions of the UKPDS data. BMJ 2000;320:1720-1723
CrossRef | Web of Science | Medline2
Berger M ,Muhlhauser I . Diabetes care and patient-oriented outcomes. JAMA 1999;281:1676-1678
CrossRef | Web of Science | Medline3
The University Group Diabetes Programme
CrossRef | Web of Science4
Rao AD ,Kuhadiya N ,Reynolds K ,Fonseca VA . Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality? A meta-analysis of observational studies. Diabetes Care 2008;31:1672-1678
CrossRef | Web of Science | Medline
To the Editor:
The 20-year follow-up of the classic UKPDS showed that the benefits reported in the 10-year follow-up of the original study of tight, as compared with less tight, control of blood pressure, generally diminish over the next 10 years. In contrast, the original 10-year follow-up trends favoring the beta-blocker over the angiotensin-converting–enzyme (ACE) inhibitor1 tended to strengthen over the next 10 years, with deaths from any cause actually achieving statistical significance. This finding is important in the context of current recommendations against beta-blockers from the United Kingdom National Institute for Health and Clinical Excellence committee, which favors ACE inhibitors as first-line therapy in young and middle-aged persons with hypertension.2 It is quite possible that the ability of beta-blockers to reverse the atheromatous process3 is responsible for the strengthening late benefits in the patients assigned to receive beta-blockers rather than ACE inhibitors. The place of beta-blockade in hypertension is surely as first-line therapy in young and middle-aged persons with diastolic hypertension who tend to be overweight4 and to have a high level of sympathetic-nerve activity and cardiac output, and as second-line therapy (to a low-dose diuretic or calcium antagonist, as in the Medical Research Council Elderly Hypertension Trial, the Systolic Hypertension in the Elderly Program, and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) in elderly persons with systolic hypertension.
4 ReferencesJohn M. Cruickshank, M.A.
42 Harefield, Long Melford CO10 9DE, United Kingdom
johndtl@aol.com 1
UK Prospective Diabetes Study Group
CrossRef | Web of Science2
National Institute for Health and Clinical Excellence. NICE clinical guidelines 34: management of hypertension in adults in primary care. (Available at http://www.nice.org.uk.)
3
Sipahi I ,Tuzcu EM ,Wolski KE , et al. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10-18
Web of Science | Medline4
Franklin SS ,Pio JR ,Wong ND , et al. Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation 2005;111:1121-1127
CrossRef | Web of Science | Medline
Author/Editor Response
We reported the prespecified major outcomes from the UKPDS according to the two primary randomization categories (intensive glucose therapy or conventional glucose control), and we agree with Lund et al. and Petrie that it would be useful to present extended comparisons between individual glucose therapies and the follow-up data from the UKPDS substudy in which patients were randomly assigned to receive sulfonylurea plus metformin or sulfonylurea alone.1
The continued large-scale use of UKPDS findings to inform the recommendations of committees developing evidence-based guidelines worldwide2 is at variance with Mühlhauser's concerns about the limitations of the UKPDS. We agree, however, that more high-quality clinical trials are needed to evaluate the long-term benefits and potential risks of existing and new therapies for diabetes.
In response to Cruickshank's comment: the UKPDS showed that ACE inhibitors and beta-blockers as first-line therapy to lower blood pressure were equally efficacious with respect to macrovascular and microvascular outcomes.2 The nominally significant post-trial emergence of a reduced risk of death from any cause with previous assignment to beta-blocker therapy is encouraging but not definitive.
2 ReferencesRury R. Holman, F.R.C.P.
David R. Matthews, F.R.C.P.
H. Andrew W. Neil, F.R.C.P.
Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford OX3 7LJ, United Kingdom
rury.holman@dtu. ox. ac. uk 1
UK Prospective Diabetes Study (UKPDS) Group
CrossRef | Web of Science | Medline2
Home PD . Impact of the UKPDS -- an overview. Diabet Med 2008;25:Suppl 2:2-8
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
S. Vella, L. Buetow, P. Royle, S. Livingstone, H. M. Colhoun, J. R. Petrie. (2010) The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 53:5, 809-820
CrossRef2
Laurent Azoulay, Verena Schneider-Lindner, Sophie Dell'Aniello, Alicia Schiffrin, Samy Suissa. (2010) Combination therapy with sulfonylureas and metformin and the prevention of death in type 2 diabetes: a nested case-control study. Pharmacoepidemiology and Drug Safetyn/a-n/a
CrossRef
