Sylvie LAROCHE, MD
by S. Laroche, France
The results of the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) in June 2008 highlighted the role of Diamicron MR (gliclazide modified release) as a cornerstone treatment in the clinical management of type 2 diabetes. This agent has been available since 2000 in a 30-mg strength, allowing 24-h coverage with a once-daily dosage. In ADVANCE, Diamicron MR was used in the intensified glucose-lowering strategy and showed distinctive therapeutic benefits in terms of glycemic control, HbA1c reduction (down to 6.5%), and clinical end points, with a 21% reduction in diabetic nephropathy, a 7% reduction in totalmortality, and a 12%reduction in cardiovascularmortality. Last but not least, these benefits were associated with an excellent safety profile with respect to risk of hypoglycemia and absence of weight gain. Importantly, these results were achieved using a specific, simple, and pragmatic algorithm, which led to the optimization of Diamicron MR dosage before the addition of other therapy. At the end of the study, most patients were on the maximum dosage of 120 mg (ie, 4 tablets) per day. Today, a new scored-tablet formulation of Diamicron MR is available, Diamicron MR 60 mg, ensuring improved efficacy through greater ease of use and better patient compliance. Moreover, Diamicron MR 60 mg compares favorably with other oral antidiabetic drugs, thanks to its specific antioxidant properties, giving Diamicron MR 60 mg a unique profile.
With the ever-growing pandemic of type 2 diabetes throughout the world, the burden of vascular complications is expected to rise inexorably. It is thus of the utmost importance to find therapeutic strategies that are able to stabilize, if not prevent, these types of debilitating complications. The last century was witness to staggering discoveries that completely revolutionized the clinical management of type 2 diabetes, beginning with the discovery of insulin in 1921, up to 2000, with the latest discoveries of new pharmacological targets. In parallel, the improvement in pathophysiological knowledge highlighting the role of inflammation and oxidative stress in the pathogenesis of type 2 diabetes, together with epidemiological studies, paved the way for and validated new therapeutic strategies that stress the need to treat patients as early as possible. The United Kingdom Prospective Diabetes Study (UKPDS) in newly diagnosed patients with type 2 diabetes was the first landmark trial to demonstrate the benefit of tight glycemic control inmicrovascular complications and, to a lesser extent, in a subgroup of 342 over-weight patients, in macrovascular complications.1,2 At the time, “proof of concept” was based on oral therapies, such as sulfonylureas (chlorpropamide and tolbutamide) and metformin, but also on the early use of insulin.
It was not until 2000 that a glycated hemoglobin (HbA1c) target was carefully evaluated in a series of large morbidity-mortality trials, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE)3 and Action to Control CardiOvascular Risk in Diabetes (ACCORD),4 whose results were released at the same time at the American Diabetes Association (ADA) congress in San Francisco in June 2008. The discrepancy in results regarding total and cardiovascular (CV) mortality led to numerous debates, which ended with the publication of the COllaborators oN TRials Of Lowering glucose (CONTROL) meta-analysis,5 a meta-analysis of the five megatrials on clinical outcomes advocating a “gentle” strategy like ADVANCE’s, with an individualized approach according to patient profile.
It is nowadays clear that apart from aiming to reach target HbA1c, the achievement of glycemic control is a far from simple matter. Care and consideration must be taken in choosing a therapeutic strategy with the best benefit-to-risk ratio, the greatest convenience for patients, and the best evidence for clinicians of both short- and long-term clinical benefits.
From discovery to clinical research
The story of the discoveries of oral antidiabetic drugs in the past is absolutely amazing, as many of them were not the result of a systematic, step-by-step approach, but rather more often a matter of chance. This was indeed the case for the biguanides and sulfonamides, which were first developed as anti-infectious agents in the 1940s. In the 1950s, the first generation of another important class of antidiabetic agents, the sulfonylureas, which includes tolbutamide and chlorpropamide, was brought to market. Thanks to the promise shown by the first generation, the next generation of sulfonylureas, which includes glipizide, glibenclamide, glimepiride, and gliclazide (Diamicron), was developed.
The modified-release formulation of Diamicron (DiamicronMR) was first launchedas a 30mg tablet inthe year 2000. It had clear advantages in terms of pharmacokinetic and pharmacodynamic properties, improving bioavailability, enabling once-daily dosage (up to 120 mg per day), and providing less variability and better tolerability, especially with regard to hypoglycemia. Several advantages of this new formulation were subsequently demonstrated, notably regarding the safety profile by direct comparison with other second-generation sulfonylureas like glimepiride (GUIDE [GlUcose control In type 2 diabetes: Diamicronmodified release versus glimEpiride] study),6 in which there were twice as few hypoglycemic episodes with Diamicron MR. In recent years, focus has shifted toward ever better performance with the search for a formulation that combines optimal efficacy and compliance.
Nevertheless, the best demonstration of efficacy still remains the gold standard “clinical outcomes” criteria, namely vascular complications, and this was the reason for the design of the ADVANCE study, the largest study ever performed in type 2 diabetes. ADVANCE started in 2000 and its results were disclosed in Diabetologia at the prestigious ADA congress in 2008.
ADVANCE: the integration of evidence-based medicine into clinical management
_ Study design
The ADVANCE study was an investigator-initiated international trial whose design can be found in previous publications.7 In summary, ADVANCE was a combined 2×2 factorial study comparing active BP lowering with Preterax (a fixed combination of perindopril/indapamide) versus placebo, and comparing intensive glucose control with Diamicron MR (gliclazide modified release) versus conventional treatment, on major vascular outcomes in diabetes. The trial was conducted in 215 centers and 20 countries. Patients eligible for recruitment were at least 55 years of age, and had a history of microvascular and macrovascular disease or at least one CV risk factor. Patients were randomly assigned to either standard blood pressure control or reinforced blood pressure control with Preterax and to either intensive glucose-lowering therapy with an HbA1c target of 6.5% or lower, or standard glucose control. The principal treatment in the intensive glucose- lowering regimen was Diamicron MR (30 to 120 mg daily, ie, 1 to 4 tablets daily). Patients in each study group were followed up for a median of 5 years. The primary end points of ADVANCE were a composite of major macrovascular events (nonfatal stroke, nonfatal myocardial infarction, or CV death) and a composite of major microvascular events (new or worsening nephropathy or diabetic eye disease), considered together or separately. Moreover, the two treatment strategies were assessed separately as well as together (in those patients receiving both intensive regimens), so as to determine their joint effect.
Figure 1. Glucose control at baseline and after follow-up in
ADVANCE (Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation).
Modified from reference 3: ADVANCE Collaborative Group. N Engl J Med.
2008;358:2560-2572. © 2008, Massachusetts Medical Society.
_ Main results of the glucose-lowering arm
Of the 12 877 patients from Europe, Canada, Asia, and Australia registered for the study, 11 140 were randomized. Hence, the ADVANCE population was highly representative of the population of patients with diabetes worldwide, and also highly representative of daily clinical practice, patients having a mean age of 66 years and having had diabetes for about 8 years. The two treatment groups had similar blood glucose parameters at baseline, includingmean HbA1c (7.5%), and fasting plasma glucose (FPG) (8.5 mmol/L). In both groups, 32% of patients had a history of macrovascular disease and 10% had microvascular disease. CV risk factors, including mean blood pressure, serum cholesterol and triglycerides, body mass index, and cigarette smoking, were comparable in the two groups.3 At the end of follow-up, the mean HbA1c achieved was 6.5% in the intensive group and 7.3% in the conventional group. In the intensive blood glucose–lowering strategy based on Diamicron MR, the target of 6.5% was reached after 36months and wasmaintained until the end of the study. At the end of the study, over 80%of the patients had achieved an HbA1c≤7%, while 65% had reached an HbA1c target below 6.5%.8 In contrast, standard glucose lowering reduced mean HbA1c to 7.3% after 6 months and HbA1c remained stable thereafter (Figure 1).3
A new analysis presented at the International Diabetes Federation (IDF) 2009 in Montreal showed that the efficacy of Diamicron MR on HbA1c was remarkably consistent across a wide variety of subgroups, defined according to their characteristics at baseline, and in particular regardless of baseline HbA1c, body mass index (BMI), duration of disease or age, and also previous treatments and treatment regimen (P<0.0001) (Figure 2, Figures 3 and 4 page 66).8 The strongest predictor of reduction in HbA1c during follow-up was baseline HbA1c. It is also interesting to note that an increase in diabetes duration also independently correlated with a fall in HbA1c (patients with the longest diabetes duration having the most sustained efficacy on HbA1c) (Figure 3).8
Figure 2. Mean HbA1c change from baseline to final glucose visit by baseline HbA1c in ADVANCE.
Modified from reference 8: Zoungas et al. Diabetes Res Clin Pract. 2010;89:126-133. © 2010, Elsevier Ireland Ltd.
The intensive glucose-lowering strategy based on Diamicron MR achieved its primary end point, a significant 10% relative risk reduction (RRR) in the composite of macro- and microvascular complications, compared with standard control (18% versus 20%, respectively; P=0.01), and this effect appeared to be driven by a 14% decrease in microvascular events (9.4% versus 10.9%; P=0.01), and particularly by a 21% significant reduction in renal events (new or worsening nephropathy) (P=0.006), together with a 30% decrease in macroalbuminuria (P0.001).3
Figure 3. Mean HbA1c change from baseline to final glucose visit
by diabetes duration in ADVANCE.
Modified from reference 8: Zoungas et al. Diabetes Res Clin Pract. 2010;89:
126-133. © 2010, Elsevier Ireland Ltd.
Figure 4. Change in weight by baseline BMI in ADVANCE.
DiamicroN MR Controlled Evaluation; BMI, body mass index.
Modified from reference 8: Zoungas et al. Diabetes Res Clin Pract. 2010;89:
126-133. © 2010, Elsevier Ireland Ltd.
New results presented at the European Association for the Study of Diabetes (EASD) 2010 congress showed that not only was Diamicron MR able to prevent progression to diabetic nephropathy, but that it was also able to regress macroalbuminuria and microalbuminuria to normoalbuminuria—the albuminuria of 62% of patients with baseline albuminuria in the intensively treated group regressed by at least one stage, with the majority achieving normoalbuminuria.9
Importantly, in contrast to the ACCORD results, where a significant 22% increase in total mortality was seen,4 there was not only no increase in total mortality in ADVANCE, but a 7% reduction (although this was not significant). The reduction in CV mortality (12% decrease, P=0.12) was even more pronounced. Lastly, it should be noted that the effects of study treatment on vascular outcomes were consistent across subgroups of age, sex, baseline blood pressure, baseline HbA1c, previous vascular disease, or concomitant CV medications.
_ Results from the interaction analysis
The factorial design of ADVANCE also allowed the assessment of the interaction of the two active treatment strategies (Preterax and Diamicron MR) at the end of the follow-up period of the blood pressure–lowering arm of the study (4.3 years). The effects of the two treatments were independent and fully additive, amplifying the benefits of each treatment taken separately, with a significant 24% reduction in CV mortality, a 33% reduction in renal disease, and an 18% reduction in all-cause mortality.10 It is important to stress that the benefits in terms of diabetic nephropathy are relevant in light of the strong relationship between CV events and indices of renal impairment.11
_ Safety analysis
In the intensive glucose control group, there was no weight gain, even in the obese. Severe hypoglycemia was quite uncommon, although more frequent than in the standard control group (Table I). Compared with ACCORD, there was 6 times less severe hypoglycemia even though median HbA1c was identical (6.4%) and, furthermore, the 3.5 kg gain in ACCORD puts the weight neutrality observed in ADVANCE into perspective.8
Table I. Severe hypoglycemia and weight change in the ADVANCE
and ACCORD studies.
hypoglycemia, without other apparent cause, where the individual was unable
to treat him/herself. Based on data from reference 5.
Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes;
ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
_ What did ADVANCE tell us?
The intensive glucose control strategies used in ADVANCE and ACCORD differed substantially both regarding HbA1c target and how this target was achieved.3,4 In ADVANCE, opti- mized titration of Diamicron MR up to the maximum dose was implemented before the addition of any other oral antidiabetic, which resulted in progressive rather than aggressive glucose control as seen in ACCORD. Even though the publication of several post hoc analyses of ACCORD tried to analyze the association between increased mortality, especially CV mortality, and multiple parameters, such as severe hypoglycemia and HbA1c at baseline and during follow-up,12-14 it is clear today that the treatment strategy in ADVANCE appears to be safe, whereas we still don’t understand the exact underlying cause of excess mortality in ACCORD.
Shortly after the publications of the ADVANCE and ACCORD results, a series of meta-analyses were undertaken to assess and to give a broader perspective of the effect of intensive glucose lowering on macrovascular outcomes by combining the data of several large morbidity-mortality trials (UKPDS, ADVANCE, ACCORD, the Veterans Affairs Diabetes Trial [VADT], and the PROspective pioglitAzone Clinical Trial In macroVascular Events [PROACTIVE] study).5,15,16 By far, the most interesting of these meta-analyses is the CONTROL meta-analysis,5 as it was performed in collaboration with the investigators of each megatrial and analyzed with source data. CONTROL found very consistent results in terms of CV event risk reduction (10% decrease), in particular a decrease in nonfatal myocardial infarction (17% reduction) with no significant effect on stroke or total mortality, although there was heterogeneity between the different trials both in terms of populations studied and therapeutic strategies. A favorable decreasing trend in terms of CV event mortality and morbidity and the best efficacy- to-benefit ratio was found in ADVANCE.17
In addition to randomized clinical trials (RCTs) like ADVANCE and ACCORD, observational studies are of interest as they provide physicians with a picture of daily practice and are also an important source of additional information when their results are viewed in the context of large RCTs. Several national studies have been published showing a reduction in the risk of vascular complications and death in different subsets of patients, with a trend toward a superior beneficial effect with Diamicron MR.18-21
Recent retrospective studies with very large cohorts found very consistent findings with ADVANCE, when comparing Diamicron MR with other sulfonylureas (glibenclamide and glimepiride).22,23 In particular, one nationwide study in more than 70 000 patients with type 2 diabetes that compared different glucose-lowering therapeutic strategies on the risk of overall and CV mortality. The results are particularly interesting as they show that in patients treated solely with Diamicron MR, there was a significant 67% risk reduction in total mortality and a 71% risk reduction in CV mortality, in comparison with glibenclamide.23 Another national registry, from Denmark, was presented during the last European Society of Cardiology (ESC) congress in Barcelona in 2009. It included more than 8000 Danish type 2 diabetics with a past history of myocardial infarction. All the patients included were treated with oral antidiabetic drugs in monotherapy. Of the oral antidiabetic drugs, Diamicron MR was the only sulfonylurea with a positive trend toward reduction in total mortality, whereas glimepiride and glibenclamide were associated with a significant increase in mortality.22
_ What next with ADVANCE?
Even though no significant difference in reduction in macrovascular events and mortality could be observed between the intensive and standard blood glucose–lowering treatment groups, a reduction in microvascular events in the intensive blood glucose–lowering group taking Diamicron MR became obvious from the 5th year of treatment onward. The patients in ADVANCE may require much longer follow-up to demonstrate clear benefits in CV outcomes, given that the UKPDS long-termfollow-up took16 to 20 years to demonstrate a clearcut significant difference in death and myocardial infarction.24
Moreover, it is important to consider the lower-than-anticipated rate of events in ADVANCE (less than 3% per year) resulting from the improvement in the multifactorial management of patients with diabetes. This was associated with the lower than anticipated difference in HbA1c between the intensive and conventional glucose-lowering arms, which may have further limited the possibility of demonstrating a significant effect on macrovascular events. The long-term follow-up of ADVANCE (ADVANCE-ON) has been designed to observe the posttrial effect of intensive glucose lowering with Diamicron MR over a 5-year period, in ADVANCE patients worldwide.25 The two primary outcomes are death from any cause and major CV events. The expected results should confirm the beneficial effects of an intensive glucose-lowering strategy in the long term.
_ ADVANCE risk engine
Providing tools to help clinicians achieve optimal management of their patients with diabetes is fundamental. In the past, the development of risk engines for CV risk estimation were based on two important trials: Framingham (CV risk in patients with an impaired lipid profile) and UKPDS (newly diagnosed diabetic patients). However, clinical management of type 2 diabetes has profoundly changed over the last few decades, owing to results of landmark studies (UKPDS, Steno 2) that shed light on the importance of multifactorial treatment that targets all CV risk factors. As a result, the UKPDS and Framingham risk engines are no longer adequate for the modern management of type 2 diabetes.
Accordingly, a new risk engine has been developed, the ADVANCE risk engine, based on the large and contemporary ADVANCE cohort of patients with type 2 diabetes receiving appropriate therapeutic strategies for optimal clinical man agement.26 When the ADVANCE mathematical model is applied to the Framingham and UKPDS cohorts, the predictive risk of CV events was found to be overestimated, showing the real need for a new tool to adequately predict risk in the modern clinical management of patients with type 2 diabetes.27 It is anticipated that this new model will provide a reliable and valuable tool for alleviating the ever growing burden of CV complications in diabetes.
What makes Diamicron MR 60 mg different from other drugs?
_ Unique structure and formulation
Patient compliance is of the utmost importance in the clinical management of diabetes. The once-daily formulation of Diamicron MR was one of the reasons justifying its choice in ADVANCE. Diamicron MR is the first oral hypoglycemic agent with an innovative formulation based on a hypromellose-based polymer that expands in the gastrointestinal tract to form a gel that progressively releases gliclazide over 24 hours, enabling once-daily administration before breakfast (a factor in improved patient compliance). The release of Diamicron MR 60 mg matches a circadian profile.
At the end of follow-up in ADVANCE, 70% of patients in the intensive glucose-lowering group were receiving the maximal, optimized dose of Diamicron MR of 120 mg/ day, ie, 4 tablets daily, thanks to the progressive and constant titration used in the study (Figure 5).8
In accordance with the ADVANCE results, a new formulation was developed: Diamicron MR 60 mg. Diamicron MR 60 mg is the first ever scored modified-release tablet in diabetology.The formulation boasts a unique hydrophilic modified-release matrix. This innovative matrix stores gliclazide inside millions of microunits, allowing the tablet to be scored. This in turn enables the number of tablets to be taken daily to be halved, for both better compliance and better flexibility. This new formulation has been available internationally since 2009.
_ Unique insulin secretion profile
Several studies using a variety of methods have convincingly demonstrated that the loss of the first phase of insulin secretion is one of the earliest demonstrable abnormalities in type 2 diabetes. Restoring this early peak results in improved postprandial glucose control and lower second-phase postprandial insulin levels. Diamicron MR’s pharmacokinetic profile favors this restoration and improves -cell function, restoring glucose-stimulatedinsulin secretion to a near-normal profile, ie, enhancing the first peak of insulin secretion and normalizing the late secretion phase. This has been confirmed by clamp experiments in type 2 diabetic patients as well as in isolated perfused pancreas.28,29
The molecular mechanism of action of sulfonylureas has been progressively uncovered over the last two decades. Studies with cloned pancreatic-type sulfonylurea receptors have enabled the precise characterization of the receptor interaction profiles of the different sulfonylureas and binding affinity for the different isoforms of the sulfonylurea receptors (SUR-1 in the pancreatic βcell, SUR-2A in myocardial cells, and SUR- 2B in smooth muscle cells). Diamicron binds with high affinity and high selectivity to the SUR-1 receptor and demonstrates rapidly reversible binding, in contrast to the virtually irreversible binding of glibenclamide and glimepiride under the same conditions.28-32
Figure 5. Mean daily dose of Diamicron MR in patients in the intensive glucose-lowering arm during follow-up in ADVANCE (Action in Diabetes and Vascular disease:
PreterAx and DiamicroN MR Controlled Evaluation).
Thus, the characteristics of the insulin secretion profile induced by Diamicron MR, which are close to those of the physiological profile, provide certain explanations for the lower hypoglycemia risk and weight neutrality reported in ADVANCE.3
_ β-Cell specificity and antioxidant properties
There is growing evidence that β-cell dysfunction is crucial for the development and the progression of type 2 diabetes. Both quantitative and qualitative defects have been reported in the progression of the disease, raising new demands on therapeutic approaches focused on the long-term maintenance of β-cell mass and function.33
Not only is Diamicron MR selective for pancreatic SUR-1 receptors, but gliclazide also exerts specific antioxidant prop-erties, thanks to the aminoazabicyclo-octyl ring grafted onto the sulfonylurea group, which characterizes its chemical structure. With regard to the β-cell, in vitro experiments on human pancreatic cell lines clearly demonstrate specific protection of β-cell mass and function compared with glibenclamide and glimepiride, under hyperglycemic conditions.34-36 In the last publication by Del Guerra et al,35 isolated human islet cells exposed to intermittent high glucose concentrations demonstrated decreased responsiveness to acute glucose challenge as well as deleterious effects on β-cell mass. In this experiment, gliclazide, but not glibenclamide, increased Pdx-1 (pancreatic and duodenal homeobox 1) and Ki-67 expression, markers of βcell differentiation and regeneration both at a gene and protein level, in addition to significantly increasing insulin release. This finding confirms and extends previous results on the prevention of β-cell apoptosis under the same experimental conditions.34
Sustained glycemic control is a very important goal in the management of type 2 diabetes. In ADVANCE, the target of HbA1c ≤6.5% was achieved with intensive Diamicron MR– based therapy, and this effect was obtained progressively over 36 months and remained stable thereafter, delaying the use of insulin by up to 44 months after randomization.37 This has also been documented in previous studies comparing Diamicron with other sulfonylureas, including one with glibenclamide.38 This study investigated the time interval before the initiation of insulin therapy, and found a significantly longer interval before the initiation of insulin with Diamicron (mean 14.5 years) than with glibenclamide (mean 8 years), along with better blood glucose control, as shown by HbA1c values (6.8% vs 7.4%, respectively; P<0.0001). These benefits might be explained by the direct protective effect of Diamicron MR on pancreatic β-cell function. Last but not least, the beneficial effect of Diamicron MR shown in ADVANCE regarding micro- and macrovascular end points may be partially explained by the free radical–scavenging properties of DiamicronMR. In a previous study, DiamicronMR was shown to have beneficial effects on the progression of atherosclerosis, which was assessed by the measurement of the average carotid intima-media thickness. The outcome with Diamicron MR was better than that with glibenclamide inpatients with type 2 diabetes.39 The antiatherogenic effect of DiamicronMR could be due to its antioxidant properties, which restore endothelial function, reduce platelet reactivity, and exert an anti-inflammatory effect.40-45
From international guidelines to daily practice
The past two years have seen an incredible amount of data come from megatrials such as ADVANCE and ACCORD, and it has taken time to take on board the new lessons arising from these apparently discrepant results. Now the “hot debate” phase is over, it is the time for implementation, and the new guidelines from the ADA, EASD, and IDF will undoubtedly help clinicians to realize these lessons in their daily clinical practice.
The ADVANCE intensive glucose-lowering strategy based on Diamicron MR proved to be the most pragmatic and most practical, as well as being the strategy with the best benefitto- risk ratio, for ensuring efficient and long-term sustained lowering of HbA1c down to 6.5% in a representative population of patients with type 2 diabetes. Not only was glycemic control achieved, but Diamicron MR–based therapy was also proven to protect patients from vascular complications, especially nephropathy (with a 21%decrease), and even to regress albuminuria to normoalbuminuria (in 62% of patients with albuminuria at baseline).
New guidelines are now focusing on the need to tailor clinical management to the different phenotypes in the wide and heterogeneous population of patients with type 2 diabetes. Subgroup analysis in the ADVANCE population showed very consistent results with Diamicron MR, whatever the patient profile at baseline, together with an excellent safety profile.
Only a stepwise approach with a safe, proven, and effective strategy will enable the medical community to curb the growing diabetes pandemic worldwide. Diamicron MR 60 mg offers a unique solution with the best combination of efficacy, safety, and weight neutrality, while offering patients an innovative formulation to help compliance. This therapeutic strategy constitutes a key step in a multifactorial approach ensuring maximum benefit and safety for all type 2 diabetic patients. _
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Keywords: diabetes; intensive glucose lowering; diabetic complications; vascular complications; nephropathy; treatment; clinical management; clinical trial; ADVANCE; gliclazide MR