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  • ADVANCE is the largest clinical trial on diabetes ever conducted
  • Over 11,000 patients are participating in the ADVANCE study
  • These patients have come from 20 different countries
  • ADVANCE also includes four major sub-studies, looking at heart and eye function after intervention, cost-effectiveness and quality of life, and genetic factors
  • Blood pressure results: the routine administration as a fixed combination of Perindopril and Indapamide (Preterax) improves survival and reduces coronary and renal events in diabetics

ADVANCE Trial - Glucose lowering arm results

ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), the largest clinical trial ever performed in patients with type 2 diabetes worldwide, demonstrated that intensive blood glucose control using Diamicron MR (gliclazide modified release) and other drugs as required, protects patients against serious complications of the disease. In more details, the major findings of ADVANCE show that intensive glucose control strategy using Diamicron MR and other drugs:

• Safely controlled blood glucose to a mean HbA1c level of 6.5%

• Significantly reduced by 10% the overall risk of serious diabetes complications, with a 21% reduction in kidney disease and 30% reduction in the development of macroalbuminuria, a well established marker of increased cardiovascular risk. 

• Achieved a positive trend towards a reduction in the risk of cardiovascular death

New data from ADVANCE, were presented at the International Diabetes Federation (IDF) Congress. It shows that the efficacy and safety of intensive blood glucose control using Diamicron MR is maintained across a broad range of patients in different clinical settings: irrespective of age, duration of diabetes, sex, body mass index, or HbA1C at study entry, and also irrespective of initial glucose lowering treatment.


Why is the ADVANCE trialbeing conducted?   

The trial is being conducted to improve our understanding of diabetes anddiabetes treatment. While we know that controlling blood pressure and glucoselevels reduces the risk of some diabetes-related complications, there is stillsome uncertainty about the effect of these treatments on the risk of heartattack and stroke. This is what ADVANCE aims to clarify.

There is also new evidence to suggest that even tighter control of bloodpressure and glucose levels than is currently recommended might result in evengreater benefits. Moreover, this same evidence suggests that lowering bloodpressure, even in those considered to have 'normal' blood pressure, may bebeneficial in diabetes treatment.
Finally, the HbA1c threshold that should be targeted to optimize macrovascular protection still needs to beestablished.

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-yearfollow-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 (perindopril and indapamide) and Diamicron MR. (gliclazide sustaned released)

Following 6 weeks of open-label Preterax treatment,eligible patients were randomized to continue Preterax or matching placebo, and to either an intensive DiamicronMR-based glucose control regimen or usual guidelines-based glucosecontrol therapy. Follow-up is 5.5 years for the blood pressure arm and 6 yearsfor the blood glucose arm.

In the blood pressure arm, Preterax or placebo was added on top of any other therapy including other bloodpressure–lowering drugs, and any drug could be prescribed for any participant,at any time, at the discretion of his/her physician.

Diamicron MR wasused as the treatment base in the intensive arm with the aim of achieving atarget HbA1c of 6.5%or less. Diamicron MR was not recommended in the standard guidelines-based arm. In both groups, the additionof 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 acomposite of:

·        macrovascular events (cardiovascular death, nonfatal myocardialinfarction [MI] or nonfatal stroke) and

·        microvascular events (new or worsening nephropathy [developmentof macroalbuminuria, doubling of serum creatinine to at least a level of 200µmol/L, need for renal replacement therapy, or death due to renal disease] orretinopathy [development of proliferative retinopathy, macular edema, ordiabetes-related blindness, or need for retinal photocoagulation therapy]).

What are the secondary end points?   

Thesecondary 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 diseaseor nonfatal stroke)

·        total cerebrovascular events (major cerebrovascular events,transient ischemic attack, or subarachnoid hemorrhage).

·        Other secondary outcomes include: heart failure (death due toheart failure, hospitalization due to heart failure, or worsening New YorkHeart Association class), peripheral vascular disease, new or worseningnephropathy, new or worsening retinopathy, development of microalbuminuria,visual deterioration, new or worsening neuropathy, cognitive function,dementia, and hospitalizations.

Wherewere the patients being recruited?   

In total, 11 140 participants have been recruited from 215 centers in 20participating 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 werethe exclusion criteria?   

Patients were ineligible if they had any contraindication to any of the studytreatments, had a HbA1c ≤ 6.5%,a definite indication for long-term insulin therapy at study entry, or werecurrently 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 patientswith a broad range of blood pressure values were included in ADVANCE.
There was also no blood pressure goal. ADVANCE shows the benefits of Preteraxin 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 thepatients in ADVANCE had a history of hypertension, and 75% of the patients werereceiving other blood pressure–lowering drugs at baseline.

Why wasPreterax* {perindopril/indapamide}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 ofHypertension/European Society of Cardiology (ESH/ESC) guidelines recommendcombination 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 Treatmentin Hypertension Evaluation (STRATHE) study. Preterax was compared with conventional treatment strategies, including monotherapies (angiotensinreceptor blockers, calcium channel blockers, and ß-blockers), but alsocombination 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

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 effectson the microcirculation. The progressive stiffening of large arteries thatoccurs with age contributes to the greater importance of systolic bloodpressure 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 stiffnessand pulse wave reflection, which are major determinants of systolic bloodpressure.5 Specific effects, on the microcirculation in particular, were also demonstrated in the Zucker rat,6 inwhich Preterax significantly improved renal perfusion. The effects of Preterax on large vessels and on the microcirculation thus constituted further evidence ofits efficient blood pressure reduction and target-organ protection. Moreover,thePREteraxin 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 


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 {gliclazide MR}has been selected for the ADVANCE trial?   

There are a number of reasons why DiamicronMR 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 DiamicronMR ensures rapid and tight glycemic control that is maintained in the long-term, thanks to its unique antioxidant properties.10-13Moreover,Diamicron MR has a better safety profile, for the same degree of efficacy,  than 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,18reduction 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 withDiamicron 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, orother 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,{perindopril/ indapamide} 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 arethe macrovascular and microvascular benefits of Preterax (in terms of theprimary end point)?   

Preterax significantlyreduces by 9% the primary macrovascular (MI, stroke, cardiovascular death) and microvascular (new or worsening nephropathy or retinopathy) composite end pointof ADVANCE. The beneficial effects on the combined macro- and microvascular endpoint 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 bloodpressure 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.


1. Mancia G, Grassi G.Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2000;35:1021-1024.
2. Zabdetti A, Clifkova R,Fagard R, et al. Guidelines Committee. 2003 European Society ofHypertension—European Society of Cardiology guidelines for the management ofarterial hypertension. J Hypertens.2003;21:1011-1053.
3. Mancia G, De Backer G,Dominiczak A, et al. the task for the management of arterial hypertension ofthe European Society of Hypertension (ESH) and of the European Society ofCardiology (ESC). Guidelines for the management of arterial hypertension. Eur Heart J. 2007;28:1462-1536.
4. Mourad JJ, Waeber B,Zannad F, et al. Comparison of different strategies in hypertension: a low-dosecombination of perindopril/indapamide versus a sequential monotherapy or astepped-care approach. J Hypertens.2004;22:2379-2386.
5. Asmar RG, London GM,O’Rourke ME, Safar ME. Improvement in blood pressure, arterial stiffness andwave reflections with a very-low-dose perindopril/indapamide combination inhypertensive patients: a comparison with atenolol. Hypertension. 2001;38:922-926. 
6. Renaud I, Chainey A,Plante G, Chevalier J. Protection des structures et fonctions rénales chez lerat Zucker obese par l’association faiblement dosée perindopril/indapamide.Arch Mal Cœur Vaiss. 2002; 95 (Abst book): 08/Page 7
7. Mogensen CE, Viberti G,Halimi S, et al. Effects of a low-dose perindopril/indapamide on albuminuria indiabetes. Preterax in Albuminuria Regression: PREMIER. Hypertension. 2003;41:1063-1071. 
8. International DiabetesFederation Clinical Guidelines Task Force. Global guideline for type 2diabetes. Diabet Med. 2006;23: 579-593.
9. Guillausseau PJ, Greb W.24-hour glycemic profile in type 2 diabetic patients treated with gliclazidemodified release once daily. Diabetes Metab.2001;27:133-137.
10. Schernthaner G, GrimaldiA, Di Mario U, et al. GUIDE study: double-blind comparison of once-dailygliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004;34:535-542.
11. Drouin P, Standl E: forthe Diamicron MR study group. Gliclazide modified release: results of a 2-yearstudy in patients with type 2 diabetes. DiabetesObes Metab. 2004;6:414-421.
12. Harrower ADB, Wong C.Comparison of secondary failure rate between three second-generationsulfonylureas. Diabetes Res. 1990;13:19-21.
13. Satoh J, Takahashi K,Takizawa Y, et al. Comparison of period until insulin treatment betweendiabetic patients treated with gliclazide and glibenclamide. Diabet Res Clin Pract. 2005;70:291-297.
14. Kardas P. The DIACOMstudy (effect of Dosing frequency of oral Antidiabetic agents on the COMplianceand biochemical control of type 2 diabetes). DiabObes Metab. 2005;7:722-728.
15. Tessier D, Dawson K,Tétrault JP, Bravo G, Meneilly GS. Glibenclamide vs gliclazide in type 2diabetes of the elderly. Diabet Med.1994;11:974-980.
16. Kimoto K, Suzuki K,Kizaki T, et al. Gliclazide protects pancreatic β cells from damage by hydrogenperoxide. Biochem BiophysRes Commun. 2003;303:112-119.
17. Del Guerra S, Grupillo M,Masini M, et al. Gliclazide protects human islet beta-cells from apoptosisinduced by intermittent high glucose. Diabetes Metab Res Rev. 2007;23:234-238.
18. O’Brien RC, Luo M, BalazsN, Mercuri J. In-vitro and in-vivo antioxidant properties of gliclazide. J Diabetes Complications. 2000;14:201-206.
19. Jennings PE, Scott NA,Saniabadi AR, Belch JJ. Effects of gliclazide on platelet reactivity and freeradicals in type 2 diabetic patients: clinical assessment. Metabolism. 1992;41(suppl 1):36-39.
20. Fava D, Cassone-FaldettaM, Laurenti O, De Luca O, Ghiselli A, De Mattia G. Gliclazide improvesanti-oxidant status and nitric oxide-mediated vasodilation in Type 2 diabetes.Diabetic Medicine. 2002;19:752-757.
21. Katakami N, Yamasaki Y,Hayaishi-Okano R, et al. Metformin or gliclazide, rather than glibenclamide,attenuate progression of carotid intima-media thickness in subjects with type 2diabetes. Diabetologia.2004;47:1906-1913.
22. Pan NH, Lee TM, Lin MS,et al. Association of gliclazide and left ventricular mass in type 2 diabeticpatients. Diabetes ResClin Pract. 2006; 74:121-128.
23. .Johnsen SP, Monster TBM,Ilsen ML, et al. Risk and short term prognosis of myocardial infarction amongusers of antidiabetic drugs. Am J Ther. 2006;13:134-140.
24. DanchinN, Zeller M, Simon T. Impact of type of sulfonylureas on survival in diabeticpatients with acute myocardial infarction. Paper presented at: The AnnualMeeting of the European Association for the Study of Diabetes; September 17-21,2007; Amsterdam, The Netherlands. Abstract PS81.
25. Monami M, Balzi D,Lamanna C, et al. Are sulphonylureas all the same? A cohort study oncardiovascular and cancer related mortality. DiabetesMetab Res Rev. 2007;23:479-484.
26. Sadikot S. Risk ofcoronary artery disease associated with initial sulphonylurea treatment of type2 diabetes: a match case-control study. Paper presented at: The Annual Meetingof the European Association for the Study of Diabetes; September 17-21, 2007;Amsterdam, The Netherlands. Abstract PS10.

OFFICIAL WEBSITE: http://www.advance-trial.com

ediabetesmellitus@gmail.com, ediabetesmellitus@rediffmail.com.