Why is the ADVANCE trial being conducted?

The trial is being conducted to improve our understanding of diabetes and diabetes treatment. While we know that controlling blood pressure and glucose levels reduces the risk of some diabetes-related complications, there is still some uncertainty about the effect of these treatments on the risk of heart attack and stroke. This is what ADVANCE aims to clarify.
There is also new evidence to suggest that even tighter control of blood pressure and glucose levels than is currently recommended might result in even greater benefits. Moreover, this same evidence suggests that lowering blood pressure, even in those considered to have ‘normal’ blood pressure, may be beneficial in diabetes treatment.
Finally, the HbA1c threshold that should be targeted to optimize macrovascular protection still needs to be established.
The ADVANCE trial is expected to provide answers to these questions.

What is the study design?

ADVANCE is a multicenter, randomized, controlled trial, with a 5- to 6-year follow-up. More than 11 000 patients are included. Its 2 × 2 factorial design allows for determination of the benefits of the 2 study treatments: Preterax and Diamicron MR.
Following 6 weeks of open-label Preterax treatment, eligible patients were randomized to continue Preterax or matching placebo, and to either an intensive Diamicron MR-based glucose control regimen or usual guidelines-based glucose control therapy. Follow-up is 5.5 years for the blood pressure arm and 6 years for the blood glucose arm.
In the blood pressure arm, Preterax or placebo was added on top of any other therapy including other blood pressure–lowering drugs, and any drug could be prescribed for any participant, at any time, at the discretion of his/her physician.
Diamicron MR was used as the treatment base in the intensive arm with the aim of achieving a target HbA1c of 6.5% or less. Diamicron MR was not recommended in the standard guidelines-based arm. In both groups, the addition of any antidiabetic therapy was possible, except for the addition of another sulfonylurea in the intensive group.

What are the primary end points?

The primary study end points, taken separately or jointly, are defined as a composite of:
– macrovascular events (cardiovascular death, nonfatal myocardial infarction [MI] or nonfatal stroke) and
– microvascular events (new or worsening nephropathy [development of macroalbuminuria, doubling of serum creatinine to at least a level of 200 µmol/L, need for renal replacement therapy, or death due to renal disease] or retinopathy [development of proliferative retinopathy, macular edema, or diabetes-related blindness, or need for retinal photocoagulation therapy]).

What are the secondary end points?

The secondary study end points include:
– all-cause mortality
– cardiovascular death
– major coronary events (death due to coronary heart disease [including sudden death] and nonfatal MI)
– total coronary events (major coronary events, silent MI, coronary revascularization, or hospital admission for unstable angina)
– major cerebrovascular events (death due to cerebrovascular disease or nonfatal stroke)
– total cerebrovascular events (major cerebrovascular events, transient ischemic attack, or subarachnoid hemorrhage).
– Other secondary outcomes include: heart failure (death due to heart failure, hospitalization due to heart failure, or worsening New York Heart Association class), peripheral vascular disease, new or worsening nephropathy, new or worsening retinopathy, development of microalbuminuria, visual deterioration, new or worsening neuropathy, cognitive function, dementia, and hospitalizations.

Where were the patients being recruited?

In total, 11 140 participants have been recruited from 215 centers in 20 participating countries.

What were the inclusion criteria?

The study included adults with type 2 diabetes, aged 55 years or older, with an increased risk of cardiovascular disease. Individuals were eligible irrespective of baseline blood pressure, baseline glucose concentration, or their requirement for background angiotensin-converting enzyme (ACE) inhibitor treatment. All eligible participants underwent run-in therapy for 6 weeks, and only patients who tolerated run-in therapy and were at least 90% compliant with treatment were subsequently randomized.

What were the exclusion criteria?

Patients were ineligible if they had any contraindication to any of the study treatments, had a HbA1c ≤ 6.5%, a definite indication for long-term insulin therapy at study entry, or were currently participating in another clinical trial.

What are the key dates of the ADVANCE trial?

– Start of the study: June 2001
– End of patient recruitment: March 2003
– End of the study: December 2007
– End of follow-up for the Preterax arm: June 2007
– Disclosure of Preterax arm results: September 2007
– End of follow-up for the Diamicron MR arm: December 2007
– Disclosure of Diamicron MR arm results: June 2008

Was eligibility dependent on blood pressure?

Eligibility for the trial was not dependent on blood pressure, and patients with a broad range of blood pressure values were included in ADVANCE.
There was also no blood pressure goal. ADVANCE shows the benefits of Preterax in type 2 diabetic patients, irrespective of their blood pressure at baseline.

How many hypertensive and normotensive subjects were included?

There is no blood pressure target in ADVANCE. We only know that 69% of the patients in ADVANCE had a history of hypertension, and 75% of the patients were receiving other blood pressure–lowering drugs at baseline.

Why was Preterax* selected for the ADVANCE trial?

When ADVANCE was set up, it was already clear that combination therapies were needed to effectively control blood pressure. The rates of blood pressure control in the hypertensive population remained very low, and in the case of diabetic patients, in whom tighter blood pressure control is needed, this was even more urgent.1 Preterax was thus selected for ADVANCE, and, since the beginning of the trial, much new evidence has further strengthened the rationale for this choice.
Recent international guidelines, such as the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines recommend combination therapy,2-3 mostly second line but also first-line in the case of Preterax. A strong argument behind this decision was the interesting results of the STRAtegies of Treatment in Hypertension Evaluation (STRATHE) study. Preterax was compared with conventional treatment strategies, including monotherapies (angiotensin receptor blockers, calcium channel blockers, and ß-blockers), but also combination therapies, which are frequently used in everyday clinical practice. After a 9-month follow-up, the control rate in the Preterax group (62%) was significantly higher than in the comparison group (Figure 1).4
In addition to this superior blood pressure control, Preterax has specific benefits, explained in part by its action on large arteries, and in part by its effects on the microcirculation. The progressive stiffening of large arteries that occurs with age contributes to the greater importance of systolic blood pressure as a predictor of cardiovascular risk, and to the difficulty of lowering systolic blood pressure. The PREterax in regression of Arterial Stiffness in a cOntrolled double-bliNd (REASON) study demonstrated the beneficial effects of Preterax on large artery stiffness and pulse wave reflection, which are major determinants of systolic blood pressure.5 Specific effects, on the microcirculation in particular, were also demonstrated in the Zucker rat,6 in which Preterax significantly improved renal perfusion. The effects of Preterax on large vessels and on the microcirculation thus constituted further evidence of its efficient blood pressure reduction and target-organ protection. Moreover, the PREterax in albuMInuria rEgRession (PREMIER) study has confirmed that, in a population of subjects with type 2 diabetes, very similar to that used in ADVANCE, Preterax was more effective than enalapril in reducing albumin excretion and retarding the progression of cardiovascular diseases (Figure 2).7

Figure 1: normalization rates at the end of the study with the 3 treatment strategies


Figure 2: serious cardiovascular events during 1 year’s treatment with Preterax versus enealpril.

The specific properties of Preterax, along with its acknowledgement by international guidelines, make it a rational choice for the ADVANCE trial.
* Preterax is also registered under the following brand names: BiPreterax, Noliprel, Noliprel Forte, Prelectal, Prelectal Forte, Coversyl Plus and Biprel.

Why Diamicron MR has been selected for the ADVANCE trial?

There are a number of reasons why Diamicron MR was chosen as diabetes treatment in this landmark study.
Firstly, Diamicron MR is a new sulfonylurea and so, with metformin, is the current standard first-line treatment for type 2 diabetes mellitus.8 Since 30% of the diabetic population presents with either poor tolerance to metformin or a contraindication (mainly renal impairment), the use of metformin would have introduced a bias as these patients would have been excluded.
As well as this, Diamicron MR is a modified-release gliclazide (30-120 mg) which provides effective 24-hour oral glucose control with a single intake at breakfast, which is from 2 to 4 tablets in most patients.9 Ample experience has accrued with Diamicron MR in diabetes care, and several studies show that Diamicron MR ensures rapid and tight glycemic control that is maintained in the long-term, thanks to its unique antioxidant properties.10-13 Moreover, Diamicron MR has a better safety profile, for the same degree of efficacy, than all other sulfonylureas.10,14-15
Secondly, Diamicron MR’s unique antioxidant properties16,17 ensure direct cardiovascular protection, mainly through inhibition of oxidation of low-density-lipoprotein cholesterol,18 reduction in platelet reactivity,19 and decreased free radical production.20 This helps explain why Diamicron MR is able both to attenuate the progression of carotid atherosclerotic plaques21 and to reduce cardiac left ventricular mass22 in type 2 diabetic patients.
These clinical advantages provide a rational explanation for the greater cardiovascular benefits and survival improvements that have been observed with Diamicron MR versus old sulfonylureas (glibenclamide, glipizide, tolbutamide) in various retrospective analyses.23-26

Were ADVANCE participants allowed to take other medications?

In ADVANCE, Preterax or placebo was added on top of any other therapy (including aspirin, statins, or other blood pressure–lowering drugs), and any drug could be prescribed for any participant, at any time, at the discretion of the patient’s physician.
At baseline, 75% of the patients in each arm were receiving a blood pressure–lowering drug, 91% an oral hypoglycemic drug, 35% a lipid-lowering therapy, and 47% aspirin or an antiplatelet agent.
The concomitant treatments were adapted during follow-up, taking into account any newly available evidence (for example, 28% of the participants were on statins at baseline, and 68% are at present), and according to local guidelines.
In this way, ADVANCE has a pragmatic approach and, therefore, the findings will have direct implications for clinical practice.

What are the patient benefits with Preterax, as shown in ADVANCE?

Preterax, on top of current treatments for type 2 diabetes, saves lives among diabetic patients, and reduces cardiac and renal events. As was concluded in a publication in The Lancet: “if the benefits seen in ADVANCE were applied to just half the population with diabetes worldwide, more than a million deaths would be avoided over 5 years.”

What are the macrovascular and microvascular benefits of Preterax (in terms of the primary end point)?

Preterax significantly reduces by 9% the primary macrovascular (MI, stroke, cardiovascular death) and microvascular (new or worsening nephropathy or retinopathy) composite end point of ADVANCE. The beneficial effects on the combined macro- and microvascular end point are driven by reductions in cardiovascular death and nephropathy.

What was the blood pressure decrease that was achieved in ADVANCE?

The mean 5.6/2.2 mm Hg decrease in systolic blood pressure/diastolic blood pressure compared with baseline was significant. At the end of the follow-up, patients in the Preterax arm had a mean blood pressure of 134/78 mm Hg.


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