Management of type 2 diabetes: a multifactorial approach to a complex disease



by S. Laroche and S. Corda,France


Sylvie LAROCHE, MD

Stefano CORDA, MD, PhD
Servier International
Suresnes
FRANCE

The epidemic of type 2 diabetes is increasing dramatically throughout the world. Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) is a landmark trial that explored the appropriateness of a two-pronged therapeutic strategy consisting of intensive blood pressure lowering, based on adding a single tablet combination of perindopril/indapamide (Preterax) on top of current contemporary treatment, together with intensive glucose control, based on gliclazide modified release (Diamicron MR)—one dose of up to 4 tablets per day followed by a stepwise combination of other oral antidiabetic drugs, where necessary. The blood pressure–lowering strategy yielded strong and significant reductions in death from any cause and death from cardiovascular disease, as well as reductions in coronary and renal complications. The glucose-lowering strategy yielded a significant reduction in a composite of macrovascular and microvascular events, driven by a significant reduction in renal complications together with a reduction in cardiovascular complications, all while displaying excellent safety, with regard to hypoglycemia, and with no weight gain. These properties make Diamicron MR a key therapy for type 2 diabetes, with potential benefits over and above those achievable with good glycemic control alone. ADVANCE thus provided clear answers by confirming the value of this new, simple, and pragmatic treatment algorithm combining intensive blood pressure lowering, based on Preterax, and intensive glucose lowering, based on Diamicron MR, and by showing that their clinical benefits were additive. This therapeutic strategy constitutes a genuine multifactorial approach ensuring maximum benefit and safety for all type 2 diabetic patients.

Medicographia. 2009;31:284-294 (see French abstract on page 294)

ADVANCE: a clear answer in diabetes care

ADVANCE in the context of landmark studies

The prevalence of diabetes mellitus is assuming epidemic proportions worldwide.1 Cardiovascular disease is a common cause of morbidity and mortality in individuals with type 2 diabetes, as demonstrated by the Framingham study.2 Macrovascular and microvascular complications contribute to death, disabilities, and reduction in life expectancy in diabetes. Overall, the risk of vascular disease in people with diabetes is significantly elevated compared with that of nondiabetic individuals, due to diabetes per se as well as to risk factors, such as high blood pressure and high blood lipids.

In this context, it clearly appears that multiple risk factor management offers great potential to reduce the risks of macrovascular and microvascular disease.3 Two specific treatment modalities have been shown to reduce the risk of major macrovascular and microvascular events in individuals with diabetes: blood pressure lowering4 and blood glucose lowering.5 Many trials have looked at whether more intensive treatment regimens or newer drugs can extend the vascular disease protection provided to individuals with diabetes. Two questions were still unanswered at the time ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) started: (i) what should the magnitude of blood pressure lowering be; and (ii) which HbA1c target should blood glucose reduction aim to achieve, in view of the fact that the classic recommended targets were a systolic blood pressure (SBP) below 140 mm Hg and HbA1c below 7%.

Rationale for blood pressure lowering in type 2 diabetes

In patients with diabetes, average blood pressure levels are higher than those in nondiabetic people.4,5w A continuous relationship exists between blood pressure and development of macrovascular disease, including coronary heart disease and stroke, without any identifiable lower level of blood pressure below which risk does not decline.6 Lowering blood pressure prevents cardiovascular and renal outcomes in people with hypertension and diabetes. Blood pressure is also a major determinant of risk among those whose blood pressure is in the normal range.

At the time ADVANCE was designed, randomized clinical trials had clearly established that intensive blood pressure lowering reduced the risk of stroke and major cardiovascular events in hypertensive individuals with type 2 diabetes.7-9

UKPDS 38 (United Kingdom Prospective Diabetes Study 38) showed that tight control of blood pressure achieved a reduction in the risk of stroke and total major cardiovascular events of 30% to 40% compared with less intensive blood pressure lowering, although no clear effect on the risk of coronary heart disease was observed.4 The Hypertension Optimal Treatment (HOT) study reported a 30% reduction in the risk of total major cardiovascular events in people with diabetes.10 The Heart Outcomes Prevention Evaluation (HOPE) showed that treatment with an angiotensin-converting enzyme (ACE) inhibitor reduced stroke risk by around a third and coronary events by around a fifth among individuals with high-risk diabetes, the majority of whom had preexisting coronary heart disease, and that these results were independent of baseline blood pressure.11,12 Furthermore, in HOPE,11 there was a reduction of around a sixth in nephropathy and retinopathy in people with diabetes treated with an ACE inhibitor, while the UKPDS trial4 reported a reduction of more than a third in microvascular events (mainly in the need for retinal photocoagulation) in hypertensive patients with diabetes assigned to the more intensive blood pressure–lowering regimen.

Rationale for blood glucose lowering

Although the relationship between glycemic control and diabetic microvascular and macrovascular complications is continuous, as is the case with blood pressure lowering, it is less clear that improving blood glucose below recommended targets would translate into a further reduction in cardiovascular complications. By the time ADVANCE was planned (at the beginning of 2000), the landmark UKPDS study had already confirmed the benefit of intensive blood glucose control.5 In particular, lowering HbA1c by an average of 0.9% over 10 years resulted in a trend toward reduction of myocardial infarction (by 16%) as well as a statistically significant 25% reduction in microvascular disease that was mainly driven by a decrease in retinopathy.

More recently, the Steno 2 study highlighted the need for multifactorial risk reduction based on treatment combining an intensive glucose-lowering strategy (using Diamicron), lipid lowering, and antihypertensive treatment to reduce the risk of microvascular and macrovascular complications in high-risk patients.13 Such an approach yielded a more than 50% reduction in all major outcomes, including macrovascular disease, among individuals with diabetes randomized to a multifactorial intervention compared with conventional treatment.13,14

ADVANCE study design

ADVANCE was a combined 2_2 factorial study, conducted in 215 centers and 20 countries. The main aim of the trial was to assess the effects of lowering blood pressure and HbA1c to 6.5%, or lower, on major vascular outcomes in diabetes. Patients were at least 55 years of age and had a history of microvascular and macrovascular disease or at least one cardiovascular risk factor.7 Patients were randomly assigned to either standard blood pressure control or reinforced blood pressure control with Preterax (perindopril/indapamide) 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).7,15,16 Patients in each study group were followed up for a median of 5 years. The primary end points of ADVANCE were a composite of macrovascular events and a composite of microvascular events, considered together or separately, and 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.

The ADVANCE population was very representative of daily clinical practice, with a mean age of 66 years and a mean age of type 2 diabetes diagnosis of 58 years. The two treatment groups had similar blood glucose parameters at baseline including mean HbA1c (7.5%), and fasting plasma glucose (8.5 mmol/L). In both groups, 1 in 3 patients had a history of macrovascular disease and 1 in 10 had microvascular disease. Cardiovascular risk factors, including mean blood pressure, serum cholesterol and triglycerides, body mass index, and cigarette smoking were comparable in the two groups.15,16

Main results of the ADVANCE blood pressure– lowering arm

The main results of the blood pressure–lowering arm published in the Lancet (2007)15 are briefly summarized here. A total of 11140 individuals with type 2 diabetes were randomized.

Figure 1
Figure 1. Cardiovascular mortality reduction in ADVANCE (Action
in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation). Based on data from reference 15.

The mean duration of follow-up was 4.3 years and only 15 participants were lost to follow-up. The mean entry blood pressure was 145/81 mm Hg, with 41% having a blood pressure below 140/90 mm Hg. The reduction in blood pressure in participants assigned active treatment with Preterax was 5.6/ 2.2 mm Hg, significantly greater than the placebo group. The average SBP achieved during follow up was 140.3 mm Hg in the placebo group and 134.7 mm Hg in the active treatment group; the average diastolic blood pressure (DBP) during follow- up was 77.0 mm Hg in the placebo group and 74.8 mm Hg in the Preterax group.

Table I
Table I. Incidence of renal end points* in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation).
Reproduced from reference 17: de Galan BE et al. J Am Soc Nephrol. 18 February 2009 [Epub ahead of print]. Copyright © 2009, American Society of Nephrology.

Figure 2
Figure 2. Effects of study treatment on deaths, coronary events, cerebrovascular events, renal events, and eye events. Reproduced from reference 15: ADVANCE Collaborative Group. Lancet. 2007;370:829-840. Copyright © 2007, Elsevier Ltd.

Treatment with Preterax reduced the risk of the combined composite primary microvascular and macrovascular outcomes by 9% (0% to 17%) (P=0.41). The reductions in the primary macrovascular and microvascular outcomes, analyzed separately, were of similar magnitude, though no longer significant.15 Preterax also significantly reduced all-cause mortality by 14% (P=0.025) and cardiovascular mortality by 18% (P=0.027) (Figures 1 and 2), while achieving a substantial reduction in total coronary events (14%; P=0.02), total renal events (21%; P=0.0001), and new-onset microalbuminuria (21%; P=0.001) (Table I).17 No statistically significant reduction in cerebrovascular events or microvascular eye disease was evidenced; however, a trend in favor of treatment was observed concerning total cerebrovascular events.15

When analyzed separately, reductions in macrovascular and microvascular events were similar, but did not achieve statistical significance. The 9% overall reduction in the risk of major macrovascular or microvascular events was driven by an 18% reduction in the risk of death from cardiovascular disease, largely contributing to the 14% reduction in total mortality. Based on ADVANCE data, it appears that 1 death would be prevented over 5 years in every 79 patients treated with the study drugs. In a recent subanalysis, Preterax was shown to significantly reduce the risk of renal events by 21% (P<0.0001). Progression of albuminuria was reduced by 22% (P<0.0001) and regression of albuminuriawasincreased by 16% (P=0.002). Furthermore, the rate of renal events decreased log-linearly with decreasing achieved follow-up blood pressure, down to levels of SBP below 110 mm Hg.17

Main results of the intensive blood glucose–lowering strategy with Diamicron MR

In ADVANCE, intensive blood glucose lowering based on Diamicron MR progressively lowered mean HbA1c to the target of 6.5% after 36 months, a level that was maintained until the end of the study. More than 60% of the patients achieved an HbA1c target below 6.5%. In contrast, standard glucose lowering reduced mean HbA1c to 7.3% after 6 months and this figure remained stable thereafter (Figure 3).16

Figure 3
Figure 3. Glucose control at baseline and after follow-up in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation).
Reproduced from reference 16: ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. Copyright © 2008, Massachusetts Medical Society.

Intensive glucose control with Diamicron MR induced a significant 10% relative risk reduction (RRR) in the combined primary end point of macrovascular and microvascular events, compared with standard control (18% versus 20%, respectively; P=0.01). Considering each component of the primary end point separately, intensive glucose control yielded a 14% RRR of major microvascular events (9.4% versus 10.9%; P=0.01) and a 6% RRR in major macrovascular events (10.0% versus 10.6%; P=0.32). In addition, the Diamicron MR–based intensive glucose-lowering strategy showed a beneficial impact on renal events, with a 21% significant reduction in new or worsening nephropathy (P=0.006), and, in particular, a 30% decrease in macroalbuminuria (P<0.001) and a 9% decrease in microalbuminuria (P=0.018). Importantly, there was a trend toward reduction in total mortality (7%, P=0.28), with an even more pronounced reduction in cardiovascular mortality (12% decrease, P=0.12) (Figure 4).

The effects of study treatment were consistent across subgroups by age, sex, baseline blood pressure, baseline HbA1c, previous vascular disease, or concomitant cardiovascular medications.15,16

Combined treatments, joint effects

The factorial design of ADVANCE also allowed the assessment of the interaction of the two treatment strategies (Preterax and Diamicron MR) at the end of the follow-up period for the blood pressure–lowering arm of the study (4.3 years). The effects of the two treatments were independent of one another and fully additive for all prespecified clinical outcomes, including the primary outcome. In particular, the additive effects of treatment with Preterax and Diamicron MR amplified the benefits of each treatment taken individually, with a significant 24% reduction in cardiovascular mortality, a 33% reduction in renal disease, and an 18% reduction in all-cause mortality.18

Blood pressure and glucose reduction in ADVANCE in the light of existing evidence

Blood pressure results with Preterax

In the ADVANCE blood pressure–lowering arm, the fixed combination of Preterax (perindopril and indapamide) reduced the risk of death and major macrovascular or microvascular events in a broad range of patients with type 2 diabetes. The benefits were achieved against a background of excellent contemporary treatment, which, by the end of follow-up, included nonstudy blood pressure–lowering drugs (in 75% of participants), statins, aspirin (in around half of all participants), and one or more glucose-lowering agents (in more than 90% of participants), including insulin in a third of patients.

In ADVANCE, the overall event rate in the combined composite primary macrovascular and microvascular end point was only 4% per year, ie, much lower than that reported by previous large-scale blood pressure–lowering trials in type 2 diabetes. Indeed, the benefits observed in ADVANCE are all the more remarkable as the baseline blood pressure values and incidence of macrovascular and microvascular events, as well as mortality, were themselves lower than in those other studies.

Figure 4
Figure 4. Effects of intensive glucose-lowering therapy on primary end points in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation).
Modified after reference 16: ADVANCE Collaborative Group. N Engl J Med. 2008; 358:2560-2572. Copyright © 2008, Massachusetts Medical Society.

ADVANCE findings showed that Preterax achieved a further reduction in blood pressure and macrovascular and microvascular events on top of that elicited by the standard background treatment, and which, over a period of 5 years, would avert 1 major vascular event among every 66 patients. Blood pressure lowering in ADVANCE started where UKPDS left off: in the intensive blood pressure–lowering arm of UKPDS, the systolic blood pressure at study end was 145 mm Hg. SBP in ADVANCE was lowered from 145 to 136 mm Hg. A further re- duction in mortality, cardiovascular events, and renal events as well as an impressive reduction in microalbuminuria (the largest ever in a hypertensive/normotensive population) were reported. These effects of Preterax are important in view of the high risk of progression to end-stage renal failure and premature death in patients who develop diabetic nephropathy, as well as emerging evidence of substantial cardiovascular risks associated with the progression of renal impairment.19 ADVANCE also goes beyond MICRO-HOPE (MIcroalbuminuria, Cardiovascular and Renal Outcomes in the Heart Outcomes Prevention Evaluation) in showing that Preterax provided further efficacy on top of all other preventive therapies, including ACE inhibition.11,15 Lastly, ADVANCE goes well beyond studies carried out with angiotensin receptor blockers (ARBs) in diabetic hypertensive populations with albuminuria (IRMA, IDNT, and RENAAL: respectively, IRbesartan for MicroAlbuminuria in type 2 diabetes; Irbesartan in Diabetic Nephropathy Trial; and Reduction of Endpoints in Noninsulin-dependent diabetes mellitus with Angiotensin II Antagonist Losartan).20-22 Although these studies did show benefits, these were limited to the progression of nephropathy, without any evidence of reduction in total and cardiovascular mortality. A recent meta-analysis comparing the effects of ACE inhibitors and ARBs has confirmed that these two classes of drugs have similar effects on renal outcomes, but, whereas ACE inhibitors reduce all-cause mortality compared with placebo, ARBs do not, and actually increase the absolute risk of myocardial infarction.23,24

ADVANCE results of intensive glucose lowering with Diamicron MR in the context of other morbidity-mortality trials

In the blood glucose–lowering arm of ADVANCE,16 intensive blood glucose lowering with Diamicron MR achieved progressive and sustained blood glucose control, as evidenced by a reduction in HbA1c levels to 6.5%, and lower, with no weight gain and very acceptable levels of hypoglycemia over 5 years’ follow-up. These findings contrast with those reported by the ACCORD trial (Action to Control CardiOvascular Risk in Diabetes), which was prematurely terminated due to excess deaths in the intensive therapy group, presumably related to adverse cardiovascular events associated with hypoglycemia when aiming at normal HbA1c levels (<6%) too rapidly, suggesting that aggressive glucose-lowering treatment is harmful.25

In contrast to the increase in mortality reported in ACCORD, a trend toward reduction in mortality (a 7% decrease), associated with a 12% reduction in cardiovascular mortality, was observed in ADVANCE.16 The intensive glucose control strategies used in ADVANCE and ACCORD differed substantially, both regarding the HbA1c target and how this target was achieved.16,25,26 In ADVANCE, optimized titration of Diamicron MR up to the maximum dose was implemented before adding any other oral antidiabetic drug (OAD), which resulted in progressive rather than aggressive glucose control, as in ACCORD.

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 the intensive blood glucose–lowering group taking Diamicron MR became obvious from the 5th year of treatment onward. This observation suggests that the effect on macrovascular outcomes and mortality benefits may be delayed, only translating into a more dramatic reduction in macrovascular events after several years. The findings of ADVANCE may thus be explained by a “legacy” effect, simi- lar to that which occurred in UKPDS, where a recent analysis of 10 years’ follow-up showed that risk reduction for myocardial infarction and all-cause mortality with intensive glucose control became clearly significant only after long-term follow-up.27

The findings and conclusions of ADVANCE confirm and reinforce those of UKPDS28 by providing further evidence of the benefits of a multifactorial therapeutic approach combining intensive blood pressure lowering and intensive blood glucose control in patients with type 2 diabetes. Previously reported benefits of multifactorial risk management in the Steno 2 study were obtained through a combination of optimal blood pressure, glucose control, lipid modification, and antiplatelet therapy.13 Data from ADVANCE show that intensification of glycemic control to achieve HbA1c levels of less than 6.5% increase the benefits obtained with blood pressure–lowering treatment, particularly with respect to renal events. Here it should be stressed that the benefits in terms of diabetic nephropathy are important in light of the strong relationship between cardiovascular events and indexes of renal impairment (Figure 5).19

Figure 5
Figure 5. Correlation between risk of cardiovascular death and albuminuria level achieved at follow-up as evidenced in ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation).
Based on John Chalmers, oral communication, EASD 2008. Abbreviations: BMI, body mass index; HbA1c, glycated hemoglobin; UACR, urine albumin–creatinine ratio.

The substantial renal benefits observed in both arms of ADVANCE, which were magnified in the group receiving both treatment strategies, are also likely to translate into future cardiovascular benefits beyond those reported in UKPDS. High levels of albuminuria are a risk factor for cardiovascular disease in patients with type 2 diabetes,11 and treatment of albuminuria per se may reduce cardiovascular events.19 Long-term follow-up of UKPDS27 has also shown that the cardiovascular and mortality benefits of intensive glucose control emerge over time. The combined treatment strategy employed by ADVANCE would therefore be anticipated to further reduce cardiovascular risk in the long term.

Such an approach has benefits not only for people with type 2 diabetes who have hypertension29 or microalbuminuria,30 but, given the linear relationship between blood pressure and albuminuria, on the one hand, and cardiovascular risk, on the other, also for the much broader cross section of people with type 2 diabetes that are normotensive and normoalbuminuric.18

In conclusion, ADVANCE has demonstrated that the effects of intensive blood pressure lowering with Preterax and intensive blood glucose control with a Diamicron MR–based regimen in patients with type 2 diabetes are fully additive and independent of one another for all prespecified outcomes, and that they significantly reduce all-cause mortality, cardiovascular death, and renal outcomes. This suggests that the multifactorial management of type 2 diabetes should include intensive blood pressure lowering with Preterax and intensive blood glucose control with Diamicron MR, in order to reduce the overall burden of vascular disease in people with diabetes.

Excellent safety profile and weight neutrality

Administration of Preterax to patients with type 2 diabetes was well tolerated and reduced the risks of death and major vascular events, regardless of initial blood pressure level or concomitant treatments received.15

The Diamicron MR–based intensive blood glucose–lowering regimen used in ADVANCE was also well tolerated throughout the study.16 Intensive blood glucose control did not result in any weight gain, a previously reported side effect of intensive blood glucose–lowering strategies using sulfonylureas and insulin. Furthermore, only 2.7% of patients experienced at least one severe hypoglycemic episode over the 5 years of follow-up, and the average rate of severe hypoglycemic events each year was 0.7%. This is two times less than in UKPDS and six times less than in ACCORD.5,25 This low incidence of side effects was noted in spite of the fact that Diamicron MR was administered at maximal dosage (120 mg/ day) to 70% of the patients in the intensive blood glucose control group.

Preterax: rationale for choice and clinical efficacy

The fixed-dose antihypertensive combination of the ACE inhibitor perindopril and the thiazide-like diuretic indapamide (2 mg/0.625 mg and 4 mg/1.25 mg) was selected to lower blood pressure in type 2 diabetes patients in ADVANCE, the vast majority of whom were hypertensive.

This fixed dosage in one tablet, once daily, ensured optimal ease of use, thereby enhancing patient compliance. Preterax provides additional antihypertensive efficacy compared with each component used alone and with current monotherapies, with major efficacy on SBP, an important predictor of cardiovascular risk. Preterax ideally combines the vasodilatory and microcirculatory action of ACE inhibition and the volume-depletion effect of a diuretic, while minimizing potassium imbalance.

Several studies have reported conclusive evidence of the benefits of Preterax, regarding blood pressure lowering and endorgan protection, in populations at high cardiovascular risk. In clinical trials, Preterax significantly lowered blood pressure compared with other first-line therapies (atenolol, losartan, and irbesartan). This was the case in STRATHE (STRAtegies of Treatment in Hypertension: Evaluation),31 a randomized study versus current monotherapies and stepped-care therapy with different classes of antihypertensive agents, including ARBs, â-blockers, and calcium channel blockers, according to a sequential or a stepped-care strategy. In this study, the percentage of patients achieving target blood pressure was significantly higher in the Preterax group (62%) than in the sequential monotherapy (49%, P=0.02) and the steppedcare groups (47%, P<0.005) (Figure 6). Similarly, the percentage of patients in whom blood pressure was normalized without the occurrence of drug-related adverse events was also significantly higher in the Preterax group (56%) than in the sequential monotherapy (42%, P=0.002) or stepped-care (42%, P=0.004) groups, confirming the value of Preterax as a first-line treatment in essential hypertension.31 The efficacy/ safety ratio (both clinical and with regard to laboratory parameters) of Preterax was good.

Figure 6
Figure 6. Percentage of patients achieving target blood pressure (BP) in STRATHE (STRAtegies of Treatment in Hypertension: Evaluation).
After reference 31: Mourad J et al. J Hypertens. 2004;22:2379-2386. Copyright © 2004, Lippincott Williams & Wilkins.

Hypertension is accompanied by dysfunctional changes affecting the heart, kidney, large vessel wall, and the microcirculation, which may lead to renal failure, heart failure, coronary disease, and vascular disease.

While ADVANCE was being carried out, evidence accumulated in smaller randomized trials based on intermediate end points that Preterax also reduced target-organ damage in patients at high cardiovascular risk (cardiac hypertrophy32,33 and type 2 diabetics with albuminuria34) as well as surrogate markers of cardiovascular risk, such as large artery stiffness and wave reflections (now included as surrogate markers in current guidelines).30,35

Microcirculatory alterations and arteriolar capillary rarefaction are features of hypertension that may impair coronary perfusion, despite angiographically normal coronary arteries.36 A higher risk of adverse cardiac events in patients with arterial hypertension and left ventricular hypertrophy is due to coronary microvascular dysfunction (CMD) caused by remodeling of intramural coronary arterioles and microvessel rarefaction.36 Studies with Preterax suggest that this treatment can reverse CMD, most likely by improving myocardial perfusion and remodeling, as demonstrated in hypertensive patients with and without cardiac hypertrophy.31,37 This may ultimately explain the benefits of Preterax on cardiovascular outcome and mortality in ADVANCE.

Rationale for choice and clinical efficacy of Diamicron MR

An innovative formulation allowing once-daily dosing

Compliance of patients is crucial 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-derived polymer that expands in the gastrointestinal tract to form a gel that progressively releases gliclazide over 24 hours, enabling oncedaily administration (a factor for improved patient compliance), and that releases the active ingredient synchronously with the circadian hyperglycemic profile, which ensures 24-hour blood glucose control. Thanks to progressive and constant titration, at the end of follow-up in ADVANCE, 70% of patients in the intensive glucose-lowering group were receiving the maximal and optimal dose of 120 mg/day Diamicron MR (ie, 4 tablets daily).

Diamicron MR restores a near-normal insulin secretion profile

One of the earliest demonstrable abnormalities in type 2 diabetes is the loss of the first peak of insulin secretion. Restoring this peak results in improved postprandial glucose control and lower second-phase postprandial insulin levels. Diamicron MR’s pharmacokinetic profile favors this restoration and improves â-cell function, restoring glucose-stimulated insulin 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.38,39 The physiological insulin secretion response afforded by Diamicron MR could provide one explanation for the lower hypoglycemic risk and weight neutrality reported in ADVANCE.16

Metabolic efficacy of Diamicron MR

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 Diamicron MR–based intensive therapy, and this effect was obtained progressively after 36 months and remained stable thereafter, as opposed to what was observed in UKPDS.5 This was also documented in previous studies comparing Diamicron with glibenclamide and glipizide in type 2 diabetic patients,40 as well as with glibenclamide alone.41 This latter study investigated the time interval before the initiation of insulin therapy and showed a significantly longer interval before insulin with Diamicron (mean 14.5 years) than with glibenclamide (mean 8 years) with better blood glucose control, as shown by HbA1c values (6.8% vs 7.4%, respectively, P<0.0001). These benefits may be explained by the direct protective effect of Diamicron MR on pancreatic â-cell function.42

Diamicron MR benefits in regard to macrovascular events

Diamicron MR was shown to have beneficial effects on large vessels. Diamicron or metformin significantly (P<0.05) and independently reduced the progression of average intimamedia thickness (IMT) when compared with glibenclamide in patients with type 2 diabetes.43 The antiatherogenic effect of Diamicron MR could be due to free radical–scavenging properties,44,45 restoration of endothelial function,46 reduction in platelet reactivity, and an anti-inflammatory effect.44,47-49

Diamicron MR and Preterax in practice

The ever-growing epidemic of type 2 diabetes and its complications will inevitably increase the burden of the disease, impairing quality of life and increasing mortality. For decades, the management of diabetic patients has involved refining therapeutic strategies to achieve better control of both blood glucose and cardiovascular risk factors, which include blood pressure. ADVANCE is a landmark trial, which addressed both of these issues and provided clear answers with a new, simple, and pragmatic strategy characterized by cumulative clinical benefits seen when the two treatments, Preterax and Dia-micron MR, are combined.

Regarding blood pressure control

The benefits observed in ADVANCE make a compelling case for Preterax, the single tablet combination of perindopril and indapamide, on top of all other treatments, irrespective of initial blood pressure and other characteristics. This treatment yielded strong and significant reductions in deaths from any cause and deaths from cardiovascular disease, as well as reductions in coronary and renal outcomes. The benefits relative to blood pressure lowering and end-organ damage protection observed in ADVANCE were consistent with those reported with the combination of perindopril and indapamide in trials based on intermediate end points, both in hypertensive and in diabetic hypertensive individuals.32-34 Preterax thus has the potential to save many lives across the world: for every 1 million individuals with type 2 diabetes receiving this treatment, 15 000 vascular deaths, 13 300 coronary events, and 50 000 renal events could be avoided and 12 650 lives saved.

Regarding blood glucose control

The clinical efficacy of Dia-micron MR in the treatment of type 2 diabetes, confirmed by ADVANCE, together with its excellent safety profile (with respect to hypoglycemia) and no weight gain, results from significant additional properties. These include reduction in oxidative stress, protection of human islet â cells against apoptosis, and direct vascular properties. These additional properties make Diamicron MR a key therapy for type 2 diabetes, with potential benefits over and above those achieved by good glycemic control alone. Diamicron MR was chosen as the basis for the intensive glucose-lowering strategy in ADVANCE because of its excellent efficacy and safety, weight neutrality, innovative formulation enabling once-daily dosing, and absence of contraindications in patients with renal impairment and in elderly patients.

ADVANCE proved the efficacy of a very simple treatment algorithm combining blood-glucose lowering with Diamicron MR, one dose of up to 4 tablets per day, followed by the stepwise addition of other OADs, if necessary, together with a single tablet per day of Preterax on top of all other concomitant cardiovascular treatments. This therapeutic strategy provides the most effective and safe multifactorial approach for ensuring maximum benefit in all type 2 diabetic patients.

References

1. International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels, Belgium: International Diabetes Federation; 2006.
2. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234.
3. Lawes CM, Parag V, Bennett DA, et al; Asia Pacific Cohort Studies Collaboration. Blood glucose and risk of cardiovascular disease in the Asia Pacific Region. Diabetes Care. 2004;27:2836-2842.
4. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713 [Erratum. BMJ. 1999;318:29].
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-853.
6. Adler A, Stratton IM, Neil H, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.
7. MacMahon S; ADVANCE Management Committee. Study rationale and design of ADVANCE: Action in Diabetes and Vascular disease–Preterax and Diamicron MR Controlled Evaluation. Diabetologia. 2001;44:1118-1120.
8. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990:335: 827-838.
9. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of angiotensin converting enzyme inhibitors, calcium antagonists and other blood pressure lowering drugs on mortality and major cardiovascular morbidity. Lancet. 2000;356:1955-1964.
10. Hansson L, Zanchetti A, Carruthers S, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762.
11. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000; 355:253-258.
12. HOPE (Heart Outcomes Prevention Evaluation) Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.
13. Gaede P, Vedel P, Larsen N, Jensen G, Parving H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003; 348:383-393.
14. Gaede P, Lund-Andersen H, Parving H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-91.
15. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE Trial): a randomised controlled trial. Lancet. 2007;370:829-840.
16. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
17. De Galan BE, Perkovic V, Ninomiya T, et al; ADVANCE Collaborative Group. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 18 February 2009 [Epub ahead of print].
18. Perkovic V, Ninomiya T, de Galan B, et al. Joint Effects of routine blood pressure lowering and intensive glucose control in the ADVANCE trial. J Am Soc Nephrol. 2008 Nov;19(11). Abstract.
19. Gerstein HC, Mann JF, Yi Q, Zinman B, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;25;286421-286426.
20. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAALS Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
21. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
22. Parving HH, Lehnert H, Brochner-Mortensen J, et al; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878.
23. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004;329:828-831.
24. Strauss MH, Hall AS. Angiotensin receptor blockers may increase the risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;114: 838-854.
25. ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
26. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glucose control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes trials. A position statement of the ADA and a scientific statement of the American College of Cardiology Foundation and the AHA. Diabetes Care. 2009;32:187-192.
27. Holman RR, Paul SK, Bethel A, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359;1577-1589.
28. Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006;49:1761-1769.
29. Bakris GL, Weir MR, Shanifar S, et al; RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy. Arch Intern Med. 2003; 163:1555-1565.
30. Mancia G, DeBacker G, Dominiczak A, et al; Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 Guidelines for the Management of Arterial Hypertension. J Hypertens. 2007;25:1105-1187.
31. Mourad J, Waeber B, Zannad F, et al; STRATHE Trial Investigators. Comparison of different therapeutic strategies in hypertension: a low dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped care approach. J Hypertens. 2004;22:2379-2386.
32. Dahlöf B, Gosse P, Guéret P, et al; PICXEL Investigators. Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PICXEL study. J Hypertens. 2005;23:2063-2070.
33. De Luca N, Mallion JM, O’Rourke MF, et al; REASON Project. Regression of left ventricular mass in hypertensive patients treated with perindopril/indapamide as a first-line combination. The REASON echocardiography study. Am J Hypertens. 2004;17:660-667.
34. Mogensen CE, Viberti G, Halimi S, et al; Preterax in Albuminuria Regression (PREMIER) Study Group. Effect of low-dose perindopril/indapamide on albuminuria in diabetes. Preterax in Albuminuria Regression: PREMIER. Hypertension. 2003;41:1063-1071.
35. Asmar RG, London GM, O’Rourke ME, et al; REASON Project Coordinators and Investigators. Improvement in blood pressure, arterial stiffness and wave reflection with a very-low-dose perindopril/indapamide combination in hypertensive patients: a comparison with atenolol. Hypertension. 2001;38:922-926.
36. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007; 356:2324-2325.
37. Neglia D, Frommei E, Ghinoe S, et al. Coronary microvascular dysfunction in hypertensive patients with left ventricular hypertrophy can be reversed by treatment with a fixed combination of perindopril and indapamide. Eur Heart J. 2009. Submitted.
38. Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type 2 diabetes and the effect of gliclazide therapy. Metabolism. 1989;38: 767-772.
39. Gregorio F, Ambrosi F, Cristallini S, Pedetti M, Filipponi P, Santeusanio F. Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic A- and B-cell function. Diabetes Res Clin Pract. 1992;18:197-206.
40. Harrower ADB, Wong C. Comparison of secondary failure rate between three second-generation sulfonylureas. Diabetes Res. 1990;13:19-21.
41. Satoh J, Takahashi K, Takizawa Y, et al. Comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide. Diabetes Res Clin Pract. 2005;70:291-297.
42. Del Guerra S, Grupillo M, Masini M, et al. Gliclazide protects human islet betacells from apoptosis induced by intermittent high glucose. Diabetes Metab Res Rev. 2007;23:234-238.
43. 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 2 diabetes. Diabetologia. 2004;47:1906-1913.
44. O’Brien RC, Luo M, Balazs N, Mercuri J. In vitro and in vivo antioxidant properties of gliclazide. J Diabetes Complications. 2000;14;201-206.
45. Gribble FM, Reimann F. Sulphonylurea action revisited: the post-cloning era. Diabetologia. 2003;46:875-891.
46. Fava D, Cassone-Faldetta M, Laurenti O, et al. Gliclazide improves anti-oxidant status and nitric oxide-mediated vasodilation in type 2 diabetes. Diabetic Med. 2002;19:752-757.
47. Okouchi, Okayama N, Omi H, et al. The antidiabetic agent, gliclazide, reduces high insulin-enhanced neutrophil-transendothelial migration through direct effects on the endothelium. Diabetes Metab Res Rev. 2004;20:232-238.
48. Drzewoski J, Zurawska-Klis M. Effect of gliclazide modified release on adiponectin, interleukin 6, and tumor necrosis factor alpha plasma levels in individuals with type 2 diabetes. Curr Med Res Opin. 2006;22:1921-1926.
49. Rakel A, Renier G, Roussin A, Buithieu J, Mamputu JC, Serri O. Beneficial effects of gliclazide modified release compared with glibenclamide on endothelial activation and low-grade inflammation in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9:127-129.