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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
ADOPT (A Diabetes Outcome Progression Trial)
| Henning Beck-Nielsen Odense University Hospital University of Southern Denmark Odense C, Denmark |
Click here to download PowerPoint slides of this commentary. |
Comment on:
Additional links:
A webcast from the original presentation of the results of ADOPT presented at the International Diabetes Federation (IDF) 19th World Congress in December 2006 in Cape Town, South Africa, can be seen at the IDF website: http://www.sessions2view.com/idf_library/
ADOPT slides are available at The Oxford Centre for Diabetes, Endocrinology and Metabolism: http://www.adopt-study.org/slides.php
Background
For many years, the treatment of Type 2 diabetes mimicked the treatment of Type 1 by giving insulin injections or by aiming for an improvement in insulin secretion (by giving sulfonylureas). After the release of the United Kingdom Prospective Diabetes Study (UKPDS), metformin experienced a renaissance and was in most guidelines proposed as the first drug of choice. However, as monotherapy, none of these oral treatments has been able to normalise HbA1c levels over time. One obvious reason for this is that insulin resistance plays an important pathophysiological role in the development of hyperglycaemia in people with Type 2 diabetes. Therefore, it seems obvious that insulin action must be improved in order to normalise blood glucose values. Another conclusion based on the UKPDS was that during monotherapy β-cell function declines over time, resulting in a rise in blood glucose values. An improvement in insulin action will theoretically spare the β-cells and improve insulin secretion and therefore protect against exhaustion. Introduction of thiazolidinediones (TZDs), which are agonists of the peroxisome proliferator-activated receptor-gamma (PPARγ), has for the first time given us the opportunity to improve or normalise insulin action in people with Type 2 diabetes. Thus, the aim of ADOPT was, based on these conditions, to test whether TZDs, in this case rosiglitazone, may be of benefit as initial treatment of Type 2 diabetes.
Methods and Key Results
Rosiglitazone monotherapy was compared with glyburide and metformin as initial treatment for newly diagnosed Type 2 diabetes in a double-blind, randomized, controlled trial involving 4360 people carried out in 488 centres in the USA, Canada, and 15 European countries (Clinical Trials.gov number: NCT00279045). The median duration of treatment was 4 years. The primary outcome was time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose (FPG) of more than 10 mmol/l (180 mg/dl). This value was used in order to be able to titrate the medication dose to a therapeutic goal of more than 7.8 mmol/l (140 mg/dl) FPG. Predefined secondary outcomes were the levels of FPG, HbA1c, insulin sensitivity, and β-cell function. The individuals studied were between 30 and 75 years of age, obese, and mimicked most of the typical cases of Type 2 diabetes in the Western world. Fewer than 3000 participants completed the study, which means that the dropout rate was rather high (about 40%).
Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. After 4 years, 40% of the patients receiving rosiglitazone had an HbA1c level less than 7.0 %, as compared with 36% for metformin (P=0.03) and 26% for glyburide (P<0.001). Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and oedema than either metformin or glyburide, but with fewer gastrointestinal events than metformin and with less hypoglycaemia than glyburide (P<0.001 for all comparisons).
Clinical Implications
After a trial of this size and quality, all clinicians may ask the question whether these findings should result in a re-evaluation of the guidelines for the everyday clinical management of people with Type 2 diabetes, as for example recommended by the American Diabetes Association and the European Association for the Study of Diabetes (Nathan et al 2006).
As concluded by the authors of the present study, the relative costs of the available medications, their profiles of side effects, and their potential risks and benefits should all be considered in making a choice.
The study clearly shows that all three drugs can improve the metabolic control and that they all have side effects.
- Rosiglitazone had the most pronounced effect on blood glucose values and was specifically effective in elderly and abdominally obese individuals, two groups in which insulin treatment is traditionally difficult. The well-known side effect of weight gain was seen in some individuals also. Surprisingly, the risk for congestive heart failure was not different from that seen with metformin and was rather low (serious events, 0.8%).
- Glyburide was less potent than rosiglitazone and metformin in lowering blood glucose, but surprisingly the cardiovascular side effects were the lowest in this group. The drawback of glyburide was the higher risk of hypoglycaemia, rendering it less attractive for elderly people.
- Metformin was similar to rosiglitazone in most ways, but body weight decreased as has been shown many times previously, and the side effect was the well-known gastrointestinal problems.
- Rosiglitazone and metformin improved insulin action compared with glyburide, whereas glyburide improved β-cell function slightly better than the two other drugs. For many reasons, it must be considered to be a benefit for a new drug to improve insulin action as shown by both the PROactive study (Dormandy et al 2005) and the UKPDS. Both indicated that improved insulin action may add to a lower cardiovascular risk.
- The effect on β-cell function in this trial did not favour any of the drugs, since β-cell function remained unchanged or only improved minimally.
In conclusion, ADOPT does not change the guidelines regarding the use of metformin as a first drug of choice in people with Type 2 diabetes (Nathan 2006), but rosiglitazone is a strong candidate as the second drug of choice, specifically in elderly people and in people with abdominal obesity. Rosiglitazone may be the first drug of choice in cases where metformin is contraindicated, not tolerated, or ineffective. ADOPT puts glyburide in a more positive light than recent minor studies.
However, to me, it is obvious that combination therapy is necessary to normalise blood glucose values, as both insulin action and β-cell function must be improved. Monotherapy is only effective for a short time and may still be a way to initiate treatment, but a second drug must be added as soon as HbA1c values do not reach the goal. The best type of combination therapy still needs to be studied further and awaits future trials.
References
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia 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. Diabetes Care. 2006;29:1963-1972.
This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.
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