How can the results of ADVANCE be applied to daily clinical practice?



Interview with J. Bringer, France


Jacques BRINGER,MD
Centre Hospitalier
Regional Universitaire
de Montpellier
Montpellier, FRANCE

The increasing number of therapies available to treat type 2 diabetes has heightened the complexity of choosing the appropriate pharmaceutical approach in diabetes. Guidelines and algorithms for the initiation and adjustment of therapy have to be derived from well-controlled clinical trials that compare various diabetes treatment regimens. However, clinical decision making must be individualized according to the benefits of therapeutic choices weighed against the risks and costs, for a specific diabetic patient. The trio of goals usually targeted are to attain glucose levels close to those of the nondiabetic range, without inducing hypoglycemia and while preventing exaggerated weight gain. Tight glycemic control is critical in preventing specific microvascular complications associated with diabetes, which induce loss of vision, kidney failure, and amputations. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study demonstrated the feasibility of an appropriate joint intensive management strategy, which reduced nephropathy without significantly increasing the number of severe adverse events. It remains clear that the prevention of macrovascular complications in diabetes requires an aggressive, multifactorial approach against modifiable cardiovascular risk factors.

Medicographia. 2009;31:295-298 (see French abstract on page 298)

Background and rationale

The United Kingdom Prospective Diabetes Study (UKPDS)1 has confirmed the benefit of improved glucose control in reducing macrovascular disease and has also showed that tightly controlled blood pressure reduces the progression of both microvascular disease and macrovascular disease. There was also the suggestion that tight glycemic control can reduce cardiovascular disease, as shown by the 10-year posttrial monitoring of patients after the end of the controlled study. Despite an early loss of initial glycemic difference, an emergent risk reduction for myocardial infarction and, thus, for any cause of death appeared during the follow-up. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE)2 trial was designed specifically to test whether tight glucose control can reduce macrovascular disease. ADVANCE also examined the effect of blood pressure lowering in all type 2 diabetic subjects, regardless of their initial level of blood pressure. The fact that the trial was conducted in many different countries, including developing countries, and included 11140 people allowed the investigators to judge the practicality of this approach in everyday practice around the world.

Patient profile

All participants had type 2 diabetes, were older than 55 years, and had at least one additional risk factor, such as a previous cardiovascular event, high cholesterol, or smoking. Recruitment began in June 2001 and was completed in March 2003 with the inclusion of 11 140 randomized participants.3 Over half (57%) of the participants were male and the mean age at baseline was 66 years. The diagnosis of diabetes was made 8 years, on average, before study entry. At baseline, 32% and 10% of patients had a past history of macrovascular and microvascular disease, respectively. Mean blood pressure at baseline was 145/81 mm Hg; mean HbA1c was 7.5%; and body mass index at baseline was 28.

ADVANCE monitoring: special consideration in the intensive group

The target blood glucose level was an HbA1c _6.5% in the intensive group (it was considered unethical to set any target for the standard group).This reflected real practice, one of the basic aims of this large scale trial. More interesting, however, was the question of how feasible it would be to attain good HbA1c control in large and varied populations. The pragmatic and open design of ADVANCE gave investigators the freedom to develop as many initiatives, in addition to gold standard treatment (depending on the stage of their disease), as they wanted to improve patients’ diet, exercise, and education. In the ADVANCE intensive group and in the Diabetes Control and Complications Trial (DCCT) model, patients were increasingly better managed and coached by their doctors and nurses. There was specific follow-up by dieticians both for diet and for weight control, patients were encouraged to restart or step up their physical activity, and they systematically received dedicated educational programs. All of them were trained to use home blood glucose monitoring. As DCCT suggested, achieving better glucose control than that of standard treatment requires not only a stepwise approach to drug choice, but also time and experienced staff to coach every patient properly.

What is the current evidence regarding BP and glucose lowering on macro- and microvascular disease?

Blood pressure lowering

Blood pressure is a major determinant of the risk of cardiovascular complications among patients with type 2 diabetes, not only in hypertensive individuals, but also in normotensive people with diabetes. Observational studies confirm that there is a strong and continuous relationship between blood pressure and the risk of vascular disease, both macro- and microvascular. These studies also show that there is no lower threshold of blood pressure below which risk does not continue to fall. Indeed, for every 10 mm Hg drop in systolic blood pressure, UKPDS4 observed a 12% decrease in the risk of myocardial infarction and a similar decrease in the risk of microvascular disease (diabetic nephropathy and retinopathy). However, no differences were observed between angiotensin- converting enzyme (ACE) inhibitor and â-blocker randomized patients. In the Hypertension Optimal Treatment (HOT) trial,5 which randomized a calcium antagonist versus conventional treatment, cardiovascular events were reduced by 51% in the diabetic subgroup. The conclusion of these studies is that blood pressure lowering, regardless of the agent used, is also effective in reducing the incidence of diabetic complications.

ADVANCE6 demonstrated that routine administration of a fixed combination of perindopril and indapamide to individuals with type 2 diabetes reduced blood pressure by 5.6/2.2 mm Hg, the risk of major vascular events by 9%, and deaths (by 14% for all-cause mortality and by 18% for cardiovascular mortality). The administration of this simple treatment on top of all other indicated therapies, including other blood pressure– lowering drugs, statins, aspirin, and stringent glucose-lowering therapy, also produced a clear reduction in the number of total coronary events (14%), total renal events (21%), and in new microalbuminuria cases.

Blood glucose lowering

Most diabetologists seem to be in agreement that an HbA1c level of 7%, the current recommendation in American guidelines, is still an appropriate goal. However, if patients can attain lower levels than this without the use of overly aggressive drug regimens, this would be beneficial in terms of microvascular complications. New data from three trials comparing intensive versus standard glucose lowering were reported at the American Diabetes Association 2008 scientific sessions: The Action to Control CardiOvascular Risk in Diabetes (ACCORD) trial7—which was stopped early because of increased mortality in the intensive group, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial,8 and the Veterans Affairs Diabetes Trial (VADT).9

After the results, a position statement of the American Diabetes Association, the American College of Cardiology, and the American Heart Association10 said that the “ADVANCE trial has added evidence of the benefit of intensive glucose lowering on microvascular complications by demonstrating a significant reduction in the risk of new or worsening albuminuria when median HbA1c was lowered to 6.3% compared with standard glycemic control achieving an HbA1c of 7% (median).” The results also show a trend toward a reduction in cardiovascular deaths (8.9% in the intensive group and 9.6% in the standard group). The 6.5% goal for HbA1c was reached with a low incidence of severe hypoglycemic events (less than that observed 10 years ago in the nonintensive group of UKPDS) and no change in body weight. In contrast with ADVANCE, the results from ACCORD indicate an increase in cardiovascular deaths. However, a similar mean HbA1c value was obtained in both ACCORD and ADVANCE, and there were no obvious or major differences between the populations in both studies. It looks as if the therapeutic strategies may explain these discrepancies in the results, in particular those regarding cardiovascular mortality.

The HbA1c goal for the intensive treatment group of ACCORD was _6%, but it was _6.5% in ADVANCE. The rate and type of decrease in blood glucose were also different for the two studies:
♦ Progressive in ADVANCE, decreasing from 7.5% to 6.9% HbA1c after one year and then on to the base level of 6.5% after 3 years.
♦ Abrupt in ACCORD, decreasing from 8.3% to 6.4% HbA1c after 1 year.

The treatment strategies were different, too: in ADVANCE, it was based on gliclazide 30 mg modified release (MR)—up to 4 tablets at breakfast for 70% of patients—and low glitazone (17%) and insulin use (40%) versus an aggressive strategy in ACCORD, using multiple antidiabetic oral agents (3 to 5 classes in 69.5% of cases), rosiglitazone (91%), and insulin (77%), but no gliclazide 30 mg MR.

Weight and weight increase were different in both trials. The mean body mass index (BMI) at inclusion differed, with a BMI of 32 kg/m2 in ACCORD and 28 kg/m2 in ADVANCE. Mean weight increase reached 3 kg in the ACCORD intensive treatment group (27% of patients gained more than 10 kg) whereas no significant weight change was observed in ADVANCE. In addition, the rate of severe hypoglycemic events was different between the 2 studies.

ADVANCE, with its specific, intensive, and progressive strategy based on gliclazide MR, provides evidence that reaching a 6.5% HbA1c goal in type 2 diabetes, even in those at high cardiovascular risk, is feasible with a low rate of side effects and shows that this strategy permits the reduction of serious long-term complications, in particular nephropathy.

How do the results apply to the management of hypertensive patients?

ADVANCE results confirm the importance of blood glucose lowering in patients with type 2 diabetes, irrespective of their baseline blood pressure. The single tablet combination of perindopril and indapamide is a practical and affordable option in most clinical settings worldwide and has the capacity to save countless lives and to reduce the burden of coronary and renal disease.

Thus, the message to clinicians is to lower blood pressure to recommended guideline goals and to use agents that are welltolerated, can be given once daily (in a single pill, if possible), and that are cost-effective.

ADVANCE glucose-lowering results: what do they change in daily clinical practice?

Following the report of a host of new data on intensive blood glucose lowering in patients with type 2 diabetes, the prevailing view of clinicians is that ultra-aggressive blood sugar–lowering regimens are not the way to go, particularly in patients with cardiovascular disease. Alternatively, a reduction in HbA1c below 7% attained by changing diet or losing weight is ideal, being both safe and beneficial.

However, ADVANCE has demonstrated that a strategy targeting lower HbA1c _6.5%—which is what European and International associations recommend—can be achievable, effective, safe, and implemented by everyone. The significant 21% decrease in renal events is important because we know the most costly and troublesome event for any diabetologist is when you send patients for renal replacement.

The ADVANCE strategy, based on the use of Diamicron MR and the stepwise use of oral antidiabetic drugs, has been clearly demonstrated as being safe and efficient.

Multifactorial approach to type 2 diabetic patients: what are the lessons from ADVANCE?

The Steno study,11 in which the glucose control regimen used Diamicron as the study sulfonylurea, demonstrated the benefits of using a multifactorial regimen that included an ACE inhibitor and cholesterol-lowering agents in individuals with type 2 diabetes over 13 years of follow-up. This regimen produced reductions of more than 50% in both macro- and microvascular disease.

The results of ADVANCE, presented at the 44th EASD meeting in Rome, emphasized that the twin strategies of blood pressure lowering and intensive glucose control appear to act independently, not only with regard to microvascular events, but also macrovascular events.

The joint effects of these two treatment strategies provide very substantial benefits, including an almost one-third reduction in nephropathy and renal events, a one-quarter reduction in cardiovascular death, and close to a one-fifth reduction in all-cause mortality.

So, for primary and secondary cardiovascular risk reduction in patients with type 2 diabetes, providers should follow the evidence-based recommendations, which include:
♦ A healthy lifestyle, which is a necessary prerequisite for obtaining optimal glycemic control, regardless of pharmaceutical options. However, on its own, this approach fails to achieve or maintain metabolic goals.
♦ Lowering HbA1c below 7%, which has been shown to reduce microvascular complications, using a strategy like ADVANCE’s that does not cause significant hypoglycemia or other adverse effects, such as exaggerated weight increase as HbA1c decreases.
♦ Lowering blood pressure, regardless of initial level, using well-tolerated and simple-to-use treatments.
♦ Using individualized, progressive, and less intense strategies for patients with cardiovascular disease, those at higher risk of hypoglycemia, and for elderly diabetics.
♦ Lipid lowering with statins.
♦ Aspirin prophylaxis.
♦ Smoking cessation.

References

1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-years follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577- 1589.
2. ADVANCE Management Committee. Study rationale and design of ADVANCE. Diabetologia. 2001;44:1118-1120.
3. ADVANCE Collaborative Group. Patients recruitment and characteristics of the study population at baseline. Diabetic Medicine. 2005;22:882-888.
4. United Kingdom Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ. 1998;317:S703-S713.
5. 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) randomized trial. Lancet. 1998;351: 1755-1762.
6. 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 randomized controlled trial. Lancet. 2007;370:829-840.
7. Action to Control Cardiovascular risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2445-2559.
8. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
9. Duckworth W, Abraira C, Moritz T, et al. Intensive glucose control and vascular complications in American Veterans with type 2 diabetes. N Engl J Med. 2009; 360:1-11.
10. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32:187-192.
11. Gaede P,Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.

Keywords: ADVANCE; blood glucose; blood pressure; clinical practice; macrovascular disease; microvascular disease; multifactorial approach; type 2 diabetes