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The British Journal of Diabetes & Vascular Disease a diabetes prevention study
British Journal of Diabetes & Vascular Disease 2006 6: 230 The online version of this article can be found at: can be found at:
The British Journal of Diabetes & Vascular Disease
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Conlon pp 230-234:Conlon pp 230-234 15/11/06 5:29 pm Page 1 Abstract
This appears to reflect lifestyle, pathophysiological circumstances The Diabetes REduction Assessment with ramipril and intercurrent impositions. 'Pre-diabetes' is a risk factor for
and rosiglitazone Medication (DREAM) study
early cardiovascular disease and emergent microvascular distur- reported in September 2006. This international,
multicentre, randomised, double blind, placebo
Several trials have shown that the progression of 'pre-dia- controlled, 2-by-2 factorial prospective three-year study
betes' to diabetes can be deferred or possibly prevented by examined the effect of rosiglitazone (8 mg/day) and/or
appropriate lifestyle modifications, especially increased exercise, ramipril (15 mg/day) to prevent progression to type 2
weight loss and dietary prudence (table 1). Various oral antidia- diabetes in 5,269 adults with impaired glucose tolerance
betic agents and weight-reducing agents will also reduce the (IGT), impaired fasting glucose (IFG) or both. The
incidence of type 2 diabetes amongst individuals with 'pre-dia- primary end point (incidence of diabetes or death) was
betes' (table 1), including preliminary evidence with a TZD.8 reduced by 60% on rosiglitazone (11.6% on
Additionally there is evidence that ACE inhibitors are associated rosiglitazone vs. 26.0% on placebo, p<0.0001), and more
with a lower incidence of type 2 diabetes in high-risk individuals.9 subjects regained normoglycaemia on rosiglitazone
The Diabetes REduction Assessment with ramipril and rosigli- (50.5%) than placebo (30.3%, p<0.0001). Ramipril did
tazone Medication (DREAM) study was undertaken to investi- not alter the incidence of diabetes or death (18.1% on
gate whether the TZD antidiabetic agent rosiglitazone or the ramipril vs. 19.5% on placebo) but more subjects
ACE inhibitor antihypertensive agent ramipril each alone, and in regained normoglycaemia on ramipril (42.5%) than
combination, could alter the occurrence of diabetes in individu- placebo (38.2%, p=0.001). There were no apparent
interactions between ramipril and rosiglitazone.
Although overall cardiovascular event rates were not
significantly different between rosiglitazone and
The trial was multinational, prospective, ramdomised, double placebo there was an increase in heart failure (0.5% on
blind and placebo controlled with a 2-by-2 factorial design (fig- rosiglitazone vs. 0.1% on placebo, p<0.01) and more
ure 1).13 It included 191 centres in 21 countries in North and oedema on rosiglitazone (6.8%) than placebo (4.9%,
South America, Europe, Australia and India. Participants p<0.003).
(n=5,269), were aged > 30 years and exhibited either IFG Br J Diabetes Vasc Dis 2006;6:230-4
(> 6.1 - < 7.0 mmol/L) or IGT (2 h post-75 g OGTT, > 7.8 -< 11.1 mmol/L) or both, no previous history of diabetes (except Key words: diabetes prevention, DREAM, rosiglitazone,
gestational) and no known cardiovascular disease. Baseline data are noted in table 2. All individuals received a placebo run-in, anddiet and lifestyle advice were provided throughout the trial.
Introduction
Randomisation to rosiglitazone (Avandia®, 8 mg daily) or ramipril The development of type 2 diabetes is typically preceded by a (Altace® [Tritace] 15 mg daily) or placebo were followed by twice prodromal period of many years. During this time glycaemic con- yearly visits with additional initial monitoring of ALT. Glycaemic trol gradually deteriorates and individuals exhibit IGT, IFG or status was assessed by HbA1C, FPG and OGTT, and a diagnosis both.1-3 The condition is often referred to as 'pre-diabetes' and of diabetes (FPG > 7.0 mmol/L or 2 h 75 g OGTT > 11.1 mmol/L) about 6-12% of these individuals will progress to type 2 dia- was required on two consecutive visits for confirmation. betes each year.4,5 Some individuals can remain in a 'pre-diabet- The primary outcome was a composite measure of incident ic' state for decades and some may revert to normoglycaemia.6 diabetes or death, while the secondary outcomes includedregression to normoglycaemia, individual or composite cardio-vascular events (MI, stroke, cardiovascular death, revascularisa-tion procedure, confirmed heart failure, new angina) and renal or Correspondence to: Dr Deane ConlonMediNews (Diabetes) Limited, Edgbaston House, 3 Duchess Place, composite cardiorenal events with independent adjudication to prespecified critera. The cardiorenal events will be reported at a Tel: +44 (0)121 454 4114; Fax: +44 (0)121 454 1190 The study followed subjects for a median of three years and THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE Conlon pp 230-234:Conlon pp 230-234 15/11/06 5:29 pm Page 2 Abbreviations
Figure 1. The 2-by-2 factorial design of DREAM
Rosiglitazone
Ramipril
Large trials examining the effect of diabetes prevention strategies in subjects with IGT, IFG or both Duration
Strategy
incidence of
type 2 diabetes
Key: IGT = impaired glucose tolerance; IFG = impaired fasting glucose
(10.6% vs. 25.0%), and the effect was similar irrespective of gender, age, geographical region of study, or glycaemic status at baseline (IGT, IFG or both). Rosiglitazone was more effective in the overweight and obese and more individuals receiving rosigli- tazone reverted to normoglycaemia (50.5% vs. 30.3% on place- bo, p<0.0001). The median FPG was reduced by 0.5 mmol/L andthe 2 h 75 g OGTT plasma glucose by 1.6 mmol/L on rosiglita- zone (p<0.0001 vs. placebo). Although the composite cardiovas-cular outcome was similar between the rosiglitazone and place- bo groups there was a tendency for more cardiovascular events in the rosiglitazone group. Cases of confirmed non-fatal heartfailure were higher on rosiglitazone (14 (0.5%) vs. 2 (0.1%) onplacebo, p<0.01) and peripheral oedema was commoner with rosiglitazone (6.8% vs. 4.9% on placebo, p=0.003). Systolic and data were analysed on an intention-to-treat with Cox's propor- diastolic blood pressure were lower on rosiglitazone (by 1.7 and tional hazard's model, Kaplan-Meier plots and Wilcoxon rank- 1.4 mmHg respectively) compared with placebo (p<0.0001).
Body weight gain was increased by 2.2 kg more on rosiglitazonethan placebo (p<0.0001). This was associated with increased hip (but not waist) circumference. Interestingly, at one year rosiglita- After three years 79.5% of subjects on rosiglitazone and 75.4% zone reduced ALT 4.2 U/L more than placebo (p<0.0001). on ramipril were taking assigned medication. The main reasonfor lack of continuation was that subjects declined to take med- ication: 4.8% on rosiglitazone stopped due to oedema and Ramipril did not alter the primary end point of diabetes incidence 9.7% on ramipril stopped due to cough. Overall drop-out was or death (18.1% vs. 19.5% on placebo). The incidence of dia- similar between groups. The primary end point data were avail- betes was very similar in ramipril (17.1%) and placebo (18.5%) able for 94% of participants at study end. groups. However, normoglycaemia was achieved more often on Data analyses did not find any evidence of interactions ramipril (42.5% vs. 38.2% on placebo, p=0.001). The median between rosiglitazone and ramipril for any of the outcomes. FPG was not significantly altered, but the 2 h 75 g OGTT plasmaglucose was reduced by 0.3 mmol/L on ramipril (p=0.01 vs. The primary end point (incidence of diabetes or death) was The composite cardiovascular outcome was similar in the reduced by rosiglitazone (11.6%) vs. placebo (26.0%) as shown ramipril and placebo groups: systolic and diastolic blood pressure in table 3. This was due to a decrease in the incidence of diabetes were lower on ramipril (by 4.3 and 2.4 mmHg respectively) com- VOLUME 6 ISSUE 5. SEPTEMBER/OCTOBER 2006 Conlon pp 230-234:Conlon pp 230-234 15/11/06 5:29 pm Page 3 Key messages
Rosiglitazone
Ramipril
● Rosiglitazone reduced progression from IFG/IGT to type ● Rosiglitazone increased regression from IFG/IGT to ● Rosiglitazone increased the risk of heart failure ● Ramipril did not significantly alter progression of IGT/IFG to type 2 diabetes but slightly increased regression to Key: a Fasting plasma glucose < 6.1 mmol/L; * p=0.01; ** p=0.001;
*** p=0.0001 versus respective placebo; CV = cardiovascular; MI = myocardial
infarction
caemic status, not cardiovascular events, several parameters ofvascular risk were monitored. Blood pressure was reduced byrosiglitazone as noted in other studies, but a note of caution was pared with placebo (p<0.001). Body weight was not altered by struck by the increased incidence of heart failure for which an ramipril but ALT was reduced at one year by 1.1 U/L more than adequate explanation has still not emerged. The higher occur- rence of oedema was not unexpected and was not attributed toheart failure. Discussion
While ramipril did not alter the progression to type 2 dia- The DREAM study now places rosiglitazone amongst the phar- betes, an increased number of subjects regained normogly- macological agents shown to reduce progression from 'pre-dia- caemia, as might be expected from the reduced occurrence of betes' to type 2 diabetes (table 1). The effect of rosiglitazone diabetes reported during several studies with ACE inhibitors.16 appears to be similar in magnitude to lifestyle modification and This may be explained at least in part by recent evidence that concurs with trials showing that troglitazone, and more recently angiotensin II can reduce insulin sensitivity, and this is relieved by pioglitazone, can reduce the incidence of type 2 diabetes in inhibition of the renin-angiotensin system.16 A reduction in blood women with prior gestational diabetes.14 The glycaemic efficacy pressure without hypotension, and without any significant of rosiglitazone was similar irrespective of whether participants had IGT, IFG or both at the time of randomisation. There were no Diet and lifestyle are universally endorsed as interventions for apparent differences associated with gender, age or location - individuals with 'pre-diabetes'. Pharmacological interventions the latter offering an indication of overall ethnicity. Rosiglitazone with metformin, acarbose, orlistat and TZDs are not presently was more effective in those who were overweight and obese, indicated for 'pre-diabetes' although trials have recorded that potentially off-setting the increased vulnerability of these individ- such interventions can reduce progression to type 2 diabetes.
uals to develop type 2 diabetes. Nevertheless, consistent with However, the effectiveness of these agents in 'pre-diabetes' may other studies, rosiglitazone promoted a modest weight gain, be seen as encouraging for the early use of such therapies when although this was associated with increased girth of the hips diabetes emerges. The DREAM study shows that for every 1,000 people treated with rosiglitazone for about three years there will Whether the rosiglitazone is acting to defer the onset or be about four extra cases of heart failure, but 144 cases of type mask the presence of type 2 diabetes will be tested during a drug withdrawal and washout period which is ongoing. TZDs reduceinsulin resistance, which is a prominent feature of sub-diabetic References
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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