How should future guidelines implement the results of ADVANCE?

by M. Marre, France

Michel MARRE, MD, PhD
Service d’Endocrinologie
Diabétologie Nutrition
Groupe Hospitalier Bichat
Claude Bernard

Current guidelines for patient care in type 2 diabetes rest on randomized controlled trials and key opinion leader opinion grounded in clinical experience. The most recent guidelines (2006) and update (October 2008) were a response to the emergence of new drug classes, while the rationale for patient care continues to be informed by the United Kingdom Prospective Diabetes Study (UKPDS), which was conducted in newly diagnosed type 2 diabetics recruited between 1977 and 1991 and the results of which became available in 1998. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial updates the UKPDS data on the control of blood glucose (BG) and blood pressure (BP) in the light of contemporary patient care. It also frames these data within the high vascular risk profile that applies to the vast majority of type 2 diabetics. The ADVANCE results support the goal of reducing BG and BP to near-normal levels using a sulfonylurea (gliclazide modified release [Diamicron MR]) and a fixed combination of perindopril/indapamide (Preterax) as first-line therapy. The study shows that lowering HbA1c below 6.5% improves microvascular prognosis without increasing the risk of major hypoglycemia, weight gain, or premature mortality. ADVANCE also supports the use of fixed combination antihypertensive therapy, such as Preterax, to reduce BP, while recognizing that individual patient risk profiles, rather than set BP thresholds, should inform clinical decisions on antihypertensive treatment.

Medicographia. 2009;31:266-271 (see French abstract on page 271)

The basis of current guidelines for type 2 diabetic patient care

Type 2 diabetes (T2D) is a condition defined by a degree of hyperglycemia known to enhance microvascular risk.1 Evidence for a causal relationship between high blood glucose (BG) and microvascular risk (with particular regard to kidney and retina) is based on three sources: follow-up studies,2 experimental medicine,3 and randomized controlled trials. In T2D, the case for reducing microvascular disease by reducing BG rests on a single such trial: the United Kingdom Prospective Diabetes Study (UKDPS).4 This was conducted in newly diagnosed diabetics three decades ago, before HbA1c entered clinical use (baseline HbA1c was retrospectively extrapolated from fasting BG levels). These results supported the concept of primary intervention on BG. Thus, current guidelines for T2D care were extrapolated from data obtained in newly diagnosed T2D patients, when we now know that abruptly reducing BG in uncontrolled type 1 diabetics with established microangiopathy can accelerate microvascular lesions in the initial months5 or years6 following intervention.

A major impetus for BG control in T2D is the associated high risk of cardiovascular (CV) disease. All traditional CV risk factors are usually elevated in T2D. However, there is no clear causal relationship between high BG and CV disease: BG reduction in UKPDS did not reduce the risk of stroke or CV and all-cause mortality, although its benefit in reducing the risk of nonfatal myocardial infarction was close to being significant (P=0.057).4

Based on an epidemiological analysis of the UKPDS data relating HbA1c levels to microvascular and CV risk and the HbA1c level achieved in the intensive BG arm, the current American Diabetes Association and European Association for the Study of Diabetes (ADA/EASD) recommendation is to reduce HbA1c to 7%.7 Other guidelines, eg, from the International Diabetes Federation Task Force and American Association of Clinical Endocrinologists, have proposed an upper limit of 6.5%,8,9 given the linear relationship between HbA1c achieved and CV risk found in the epidemiological analysis of UKPDS.10 But association is far from causation. Cohort studies in the general population support the concept that fasting BG begins to be associated with CV risk at values >110 mg/dL.11 The BG interval between 110 and 126 mg/dL is associated with higher insulin levels and concomitant increases in all CV risk factors.12 This association between CV risk factors and dysglycemia is purely epidemiological. An ongoing intervention study with the insulin analog glargine is assessing the effect of reducing fasting BG to normal (<5 mmol/L) on CV risk reduction.13 UKPDS suggested that the only CV benefit in T2D was achieved in overweight patients in the metformin arm, by reducing weight and insulin resistance.14 Meanwhile, the 2008 ADA/EASD consensus statement remains somewhat vague as to the best means of lowering HbA1c below 7%.15 Further studies were thus clearly needed to justify lowering HbA1c below 6.5%, an ambitious goal in subjects already at risk and with several years of T2D already behind them.

Another major determinant of microvascular risk, and CV risk in general, is high blood pressure (BP). Current recommendations to reduce BP below 130/80 mm Hg in all T2D and below 125/75 mm Hg in proteinuric T2D are unsupported by direct evidence. Data from the BP arm of UKPDS were obtained in the 40% of participants with established hypertension (BP >160/90 mm Hg). Those allocated to the intensive BP arm were reduced to 145/85 mm Hg, ie, far above levels now recommended16 and themselves based on an epidemiological analysis of UKPDS data.17 The MIcroalbuminuria, Cardiovascular and Renal Outcomes in the Heart Outcomes Prevention Evaluation (MICRO-HOPE) showed that an angiotensin- converting enzyme (ACE) inhibitor, ramipril 10 mg/day, reduced CV risk by 20% to 25% versus placebo in high-risk subjects, but reduced conventionally measured BP by only 3 mm Hg.18 Thus, there was room for strengthening the evidence from the hypertensive participants in UKPDS that reducing BP, irrespective of its value, reduces microvascular and CV risk in T2D.

Challenges to current guidelines

Current international guidelines are based on little evidence of a relationship between BG and BP levels or of clinical outcome, beyond UKPDS data. All other sources are short-term studies with surrogate primary end points. In addition, there is no consensus for a preferred drug class, based on clinical events. UKPDS used established antidiabetic drugs (although acarbose was used for only 3 years).19 Insulin and sulfonylureas performed equally well, while metformin performed better in terms of myocardial infarction and death, but did not achieve significance for microvascular end points.14 There are no studies using clinical end points with new classes of drugs, except for pioglitazone.20 This prompted the authors of the ADA/EASD consensus to propose a two-tiered approach to T2D therapy: first-line therapy, based on a well-validated core of established drugs (metformin, sulfonylureas, and insulin), and newer therapies, for meeting glycemic goals in individual patients only, using thiazolidinediones (TZDs), glucagon-like peptide 1 (GLP1) agonists, á-glucosidase inhibitors, glinide, pramlintide, and dipeptidyl peptidase 4 (DPP-4) inhibitors, whose rationale is based on their mode of action and effect on BG, body weight, BP, and other risk factors in short-term studies.15

Current guidelines suffer from insufficient investigation into the benefit of intensive BG lowering in T2D of several years standing with or without established micro- and/or macrovascular disease (secondary prevention). Until 2008, not a single study had tested this recommendation in this specific, yet prevalent, setting. The guidelines were simply tailored to individual needs and preferences.15 Recently, however, the UKPDS group released excellent news: 10 years after completion of the study, the benefit of good glycemic control remained imprinted in patients’ body memories (“legacy effect”), with significantly reduced relative risks of micro-vascular disease, myocardial infarction, and all-cause mortality.21 Thus, an intensive BG-lowering regimen appears an excellent investment for improving long-term outcome in T2D.

A similar situation exists for BP: current recommendations are only partially evidence-based, since UKPDS intervention targeted patients with both T2D and hypertension (possibly different diseases, despite speculation as to their common roots).22,23 Although epidemiological analysis suggests that reducing BP benefits normotensive patients with T2D,17 there is no direct evidence for this assumption. Strategies confined to hypertensive patients suggest that ambitious objectives (eg, reducing diastolic BP below 80 mm Hg, as in the Hypertension Optimal Treatment [HOT] study) may benefit patients with T2D more than those without T2D.24 UKPDS provided no evidence supporting one particular drug class over another.25

ADVANCE: new findings and progress

Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) used a 2_2 factorial design to study the impact on micro- and macrovascular outcomes, both jointly and separately, of intensive lowering of BP, on the one hand, and BG, on the other, in T2D patients at high CV risk.26 Intensive BP intervention was based on the use of Preterax/Bipreterax, a fixed combination of indapamide, a thiazide-like diuretic (0.625 mg, then 1.25 mg/ day), and perindopril, an angiotensin-converting enzyme (ACE) inhibitor (2 mg, then 4 mg/day), compared on a double-blind parallel basis to placebo, on top of ongoing treatment. Perindopril could also be added, up to 4 mg/day, if the investigator considered it advisable. Since the inclusion criteria did not require a given BP value, about one third of subjects were normotensive.

The BG intervention aimed at reducing HbA1c to _6.5% versus usual treatment based on local recommendations. Gliclazide modified release (Diamicron MR), a long-acting sulfonylurea, was used as first-line therapy in the intensive arm at a goal-appropriate dose, plus any other antidiabetic drugs, including insulin, in order to achieve the _6.5% target. According to the parallel, randomized, open, blinded evaluation design, the same medications were allowed in the control arm— including all sulfonylureas, with the exception of gliclazide— if required. Participants were selected primarily on the basis of their risk profile (age, diabetes duration, and previous micro- or macrovascular disease), ie, the BG arm was essentially a secondary intervention study.

Figure 1
Figure 1. Results of the ADVANCE glucose reduction arm: comparison with UKPDS. ADVANCE, with more than 11 000 patients, is the largest ever prospective study carried out in type 2 diabetes for the prevention of vascular disease.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study.
Modified from reference 17: Adler AI, Stratton IM, Neil HA, et al. BMJ. 998;317:703-713. [Erratum. BMJ. 1999;318:29.] Copyright © 1998, BMJ Publishing Group Ltd.

In the BP arm, reducing systolic BP by 5.6 mm Hg reduced the composite primary end point by 9%, with relative risk reductions of 18% in CV mortality, 14% in all-cause mortality, 18% in new or worsening nephropathy, and 21% in new microalbuminuria. 27 These results were achieved across all subgroups, whether defined by sex, age, previous/no micro- or macrovascular disease, baseline BP, HbA1c, lipids, or use/ nonuse of cardioprotective drugs. In particular, no difference in benefit was seen between normotensives and hypertensives. Side effects were rare, mild, and mostly expected (eg, cough was slightly more frequent in the intensive arm). The results confirm and extend some of the UKPDS findings and help to explain the epidemiological data,17 with a marked reduction in the prevalence of microvascular and CV risk in T2D and significant improvements in renal prognosis, CV mortality, and all-cause mortality (Figure 1).

In the BG arm, the benefits achieved with intensive gliclazide MR therapy are particularly instructive for T2D patient care. Again, they confirm and extend the UKPDS data by showing that reducing HbA1c by 0.67% compared with the conventional strategy (and effectively achieving the 6.5% objective) reduced the composite primary end point by 10%, with a 21% reduction in the relative risk of new or worsening nephropathy and a nonsignificant trend for reductions in CV events, CV mortality, and all-cause mortality.28 Again, there was no subgroup heterogeneity in the results: the data were valid across both sexes, all ages, presence or absence of previous micro- or macrovascular disease, diabetes duration, previous HbA1c level, lipid profile, and use/nonuse of cardioprotective drugs.28 A gradual trend in the reduction of HbA1c was observed over 2 years and was maintained up to the end of the study, showing that intensive BG reduction is feasible in routine T2D patient care.

Figure 2
Figure 2. Results of the ADVANCE blood pressure reduction arm: comparison with UKPDS. Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; UKPDS, United Kingdom Prospective Diabetes Study. Modified from reference 30: Adler AI, Stratton IM, Neil HA, et al. BMJ. 2000;321:412-419. Copyright © 2000, BMJ Publishing Group Ltd.

These data are extremely reassuring for T2D patients and their carers in providing a firm basis for key opinion leader recommendations to reduce BG to near-normal levels (HbA1c <6.5%).8,9 They contradict those of the Action to Control CardiOvascular Risk in Diabetes (ACCORD) study which was terminated due to excess mortality in the intensive BG arm.29 The ADVANCE data show that BG can be safely reduced to near-normal levels in both the primary and secondary intervention settings provided the therapeutic strategy is based on algorithms and drugs that are tried and tested, rather than on experimental algorithms and relatively new drugs such as TZDs. ADVANCE benefits came at little cost: the absolute increase in the risk of severe hypoglycemia (the traditional fear of both patients and carers with sulfonylureas or insulin) was extremely small (4 extra episodes per 1000 patients per year compared to the control group); there were no sequelae of hypoglycemia attributable to the intensive strategy; and weight gain was nonsignificant, with an intergroup difference <1 kg and a temporal trend towards weight loss in the control group versus weight maintenance in the intensive group.28 By comparison, in ACCORD, the severe hypoglycemia rate was several times higher and mean weight gain was 3 kg, with one third of participants gaining more than 10 kg over 3.5 years.29 Intergroup CV and all-cause mortality did not differ significantly in ADVANCE (although P values of 0.28 and 0.12 mean that the probabilities of the intensive strategy is better than conventional strategy hypotheses being untrue are only 28% and 12%). However, results for these end points were similarly nonsignificant at the end of UKPDS, but the intensive BG-lowering strategy proved beneficial after a further 10 years had elapsed.21 Thus, follow-up of the ADVANCE participants may show a similar mortality benefit several years hence. Overall, the results of the BG arm of ADVANCE confirm and extend the UKPDS evidence (Figure 2).30 Although the study design offered no method of apportioning the benefit specifically attributable to gliclazide MR, the ADVANCE results strongly support the preferential use of this long-acting sulfonylurea in an intensive BG-lowering strategy. How generalizable are the ADVANCE results? This was a multicontinental study conducted under day-to-day conditions similar to those in the routine practice of diabetologists and primary care physicians worldwide, whether in the public or private sector. With the noticeable exception of black Africans, the ADVANCE results can be generalized to most of the world’s patients with T2D. Baseline characteristics in the ADVANCE population closely resembled those of T2D patients in many countries, eg, the T2D patient profile in a typicalWestern country, such as France.31

Recommendations for the use of ADVANCE results in everyday diabetic care: summary and conclusions

Current T2D care rests on two broad strategies: the glycemic and nonglycemic. Glycemic strategies are subject to debate over the intensity of glycemic control required and how best to achieve it. Nonglycemic strategies are based on the early intensified control of all other CV risk factors, in particular BP. How can the ADVANCE results help to improve the guidelines in these respects?

Glycemic strategies

The ADVANCE results have shown, for the first time, that reducing HbA1c below 6.5% (ie, a level approximating the normal range) using established drugs in the routine care setting is feasible, beneficial, and safe.

It is feasible in that it was achieved in all participating study centers worldwide (no intersite heterogeneity), and it was sustained for as long as the study lasted. In fact, BG control improved over time, in contrast to the observations made just 3 years after inclusion in UKPDS.32 Note also that weight gain, which the UKPDS data suggested was inevitable over time, was not observed in ADVANCE. It is beneficial in terms of microvascular prognosis, with particular respect to the kidney. Renal benefit was of the same magnitude (21% reduction in relative risk of the composite of new proteinuria, doubling of serum creatinine, and end-stage renal failure) as that reported with the angiotensin II subtype 1 receptor antagonists losartan and irbesartan in T2D.33-35 That reducing the risk of renal involvement in T2D improves the overall prognosis has already been established.36 The presently nonsignificant CV benefit may become significant in the long term, based on the UKPDS 10 year follow-up data.21 It is safe in that there was no deterioration in participants’ clinical status and no premature CV or all-cause mortality, in contrast to the ACCORD study29 (despite identical HbA1c follow-up values in the intensive arms of each study). There was no weight gain. The risk of severe hypoglycemia admittedly increased, but caused no sequelae. No cases of dementia could be attributed to treatment group allocation in ADVANCE.28 As for the BG-lowering drugs used in ADVANCE, international guidelines recommend metformin as a first-line drug in newly diagnosed T2D, combined with life-style changes. Tier 2 therapy includes TZDs, GLP-1 agonists, and other drugs.15 Sulfonylureas are recommended as second-line therapy, on a par with insulin. The algorithm used in the intensive arm of ADVANCE involved the use of gliclazide MR, an established evidence-based sulfonylurea, as a first-line intensification strategy in combination with intensified general lifestyle measures.26,28 Nevertheless, metformin was also very widely used, as was insulin.

Nonglycemic strategies

ADVANCE validates current guidelines regarding the use of antihypertensive drugs to reduce BP below 130/80 mm Hg. It was the first time that this threshold was achieved in a group of T2D subjects.37 Moreover, ADVANCE validates the concept that BP should be lowered in T2D, whatever its baseline level, if vascular risk is high (as is the case in most T2D patients). BP-lowering benefit was achieved using a fixed combination of indapamide and perindopril that had already been documented as effective38,39 and safe.27 ADVANCE confirmed the suitability of this easy-to-use drug combination for protecting T2D patients from micro- and macrovascular disease, via early BP intervention.
Both intensified strategies in ADVANCE were tested during an era of general improvement in T2D care. Event rates were, for this reason, lower than expected. Indicators of proper patient care improved considerably during the study, irrespective of allocated treatment group. Thus, the proportion of current smokers halved during the study, falling to 8% by the study end.27,28 These figures confirm the need for multifactorial intervention in T2D patients at risk.40,41


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Keywords: type 2 diabetes; blood glucose control; blood pressure control; gliclazide; perindopril; indapamide; ADVANCE; UKPDS