Megatrials in type 2 diabetes. From excitement to frustration?
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Whether glycaemic control may result in a reduction of cardiovascular (CV) risk has been a matter of continuous discussion and investigation. Epidemiological analyses have extensively suggested a relationship between glycaemic control and CV events; however, the results of intervention trials have been less conclusive. The UKPDS reported a 16% reduction in the risk of myocardial infarction, but this reduction was not statistically significant. The results of the Kumamoto and PROactive studies could not allow any firm conclusions to be drawn either, because of limited size and the defined primary endpoint, respectively. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials and the Veteran Administration Diabetes Trial (VADT) were published in rapid succession over the second half of 2008 and at the beginning of 2009. A total number of almost 25,000 type 2 diabetic patients were recruited in these three trials, which assessed the effect of intensive glycaemic control vs conventional treatment on well-defined CV endpoints. In spite of the achievement and maintenance of strict glycaemic control (HbA1c <7.0%), no beneficial effect of intensive therapy was apparent in any of the studies. At the same time these results were presented, the results of an analysis of the 10 year follow-up of the UKPDS also became available and provided a more optimistic view of the potential benefit of achieving good glycaemic control. The relative risk reductions for myocardial infarction and all-cause mortality were significantly lower in the patients who initially received the intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. Once again the debate on the importance of glycaemic control in preventing macrovascular complications remains unsettled. These results, however, require some reconciliation, and the objective of this commentary is to analyse a series of elements, including the changes in the treatment approach to CV risk factors in type 2 diabetes, the effect of glucose-lowering agents, and the characteristics of the patients included in the different trials, that should be taken into account when interpreting the results of intervention trials in type 2 diabetes.
KeywordsCardiovascular disease Clinical trials Diabetic complications Disease duration Macrovascular complications Microvascular complications Risk of hypoglycaemia Type 2 diabetes Type 2 diabetes treatment
Action to Control Cardiovascular Risk in Diabetes
Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation
American Diabetes Association
Coronary artery calcium
University Group Diabetes Program
Veteran Administration Diabetes Trial
In the beginning...the UKPDS...
The expectations in Barcelona were high 10 years ago when, at the 34th Annual Meeting of the EASD, a large audience anxiously awaited the results of the first large long-term intervention trial in type 2 diabetes following the debacle of the University Group Diabetes Program (UGDP) . The results of the UKPDS were welcomed as they showed that intensive treatment, as opposed to the conventional approach, was associated with a significant reduction in diabetes-related events . This excitement soon translated into official recommendations from the major scientific and professional organisations. The American Diabetes Association (ADA), for instance, emphatically stated that ‘the results of the UKPDS mandate that treatment of type 2 diabetes includes aggressive efforts to lower blood glucose levels as close to normal as possible’ .
Yet, some questions remained unanswered. While the effect of glycaemic control on microvascular complications was fully apparent, its effect on macrovascular disease was less clear. In spite of a sizable 16% reduction in the risk of myocardial infarction, borderline statistical significance was achieved, with a p value of 0.052 . No third decimal place in the history of medicine has stimulated such an amount of discussion and speculation. The publication of the results of the Kumamoto study  did not help much. In this small (n = 110) trial, the administration of intensive insulin treatment to Japanese type 2 diabetic patients was associated with a significant reduction in microvascular complications. After the initial 8 year follow up, the number of cardiovascular (CV) events was ~50% lower in the intensive group than in conventionally treated individuals, but the absolute number of events was too small to allow a formal statistical analysis, and no conclusive results were obtained.
...then, the PROactive...
It was a few years later, in Athens, that thousands of diabetologists eagerly anticipated the announcement of the results of the PROactive study . The addition of pioglitazone to the existing glucose-lowering therapy of type 2 diabetic patients at high CV risk improved HbA1c in a significant manner, but produced controversial results as regards CV events. In spite of significant improvement of glycaemic control, the primary endpoint (a composite of CV events, mortality and procedures) was not affected, while a significant difference was achieved in pre-specified secondary endpoints . To cut a long story short, the question of whether strict glycaemic control could improve CV outcome in type 2 diabetes had still not been answered.
...and now, the Megatrials
Summary of the main features and results of the most recent intervention trials in type 2 diabetic patients
VADT (n = 1,700)
ACCORD (n = 10,250)
ADVANCE (n = 11,140)
8.4 vs 6.9
7.5 vs 6.4
7.3 vs 6.5
MI, stroke, death from CV causes, new or worsening CHF, revascularisationb and inoperable CAD, amputation for ischaemic gangrene
Non-fatal MI, non-fatal stroke, CVD death
Non-fatal MI, non-fatal stroke, CVD death
HR (95% CI) for primary outcome
HR (95% CI) for mortality
Can we draw any conclusions from the results of these intervention trials? Do they undermine the value of good glycaemic control in preventing or slowing progression of diabetic complications? To address these questions a number of issues need to be considered.
Improved care for CV risk in diabetes
The therapeutic approach to type 2 diabetes has greatly changed since the results of the UKPDS were reported in 1998. The use of statins and newly developed agents for hypertension, more liberal use of aspirin and smoking cessation are all increasingly becoming part of the standard approach. This is well reflected in the three most recent trials. More than 86% of the ACCORD  and VADT  study populations were on statins. This percentage (~46%) was lower among the ADVANCE  study participants, but a large proportion of this study population was from Asia, making a direct comparison with ACCORD and VADT difficult. Aspirin was prescribed for ~94%, 76% and 57% of the populations of the three trials, respectively [6, 7, 8]. Average blood pressure was 130/70 mmHg in the ACCORD trial and the VADT, and 130/75 mmHg in the ADVANCE trial. The proportion of smokers at the end of the three trials was ≤10%. None of the trials showed a difference between patients on intensive and conventional treatment, reducing the likelihood of a substantial impact of tight glycaemic control. The multifactorial treatment strategy used in the intervention trials is not simply the result of careful study design, but reflects a positive trend in the general therapeutic approach of type 2 diabetes. The recent analysis of the US National Health and Nutrition Examination Survey 1999–2004  reported that, over the 5 year period, there was an increase in the percentage of type 2 diabetic patients achieving their target for HbA1c (57%; +21%), blood pressure (48%; +12%) and total cholesterol (54%; +6%). Although the proportion of individuals at target for all three variables was low (13.2%), this was a 100% improvement on the percentage 5 years earlier. The picture emerging from these trials and from general practice is in accordance with the steady decline in CV mortality in the diabetic population  and account for the finding of lower mortality rates than predicted in the three trials. In summary, the results of the recent trials provide a clue as to the explanation for the more favourable overall outcome in diabetic patients in recent years. Under these conditions the potential absolute risk reduction attributable to glucose lowering is likely to be difficult to demonstrate, requiring an even larger number of patients or much longer follow-up.
Multifactorial intervention may also exert an effect on microvascular complications. This possibility becomes apparent if we switch for a moment to type 1 diabetes, a condition in which hyperglycaemia is considered the main pathogenetic factor for micro- and macrovascular complications . Data on the Italian cohort of the EURODIAB population gave us the opportunity to analyse the predictive factors for prevalent and incident microvascular complications (retinopathy and nephropathy). Multivariate analysis revealed not only glucose control and disease duration as independent predictors of the development of microvascular complications, but also dyslipidaemia, blood pressure and even a derived estimation of insulin sensitivity. The role of these factors has been indicated by several observations [12, 13] and confirmed in intervention trials. In the UKPDS a significant interaction between HbA1c and blood pressure was been observed with respect to both micro- and macrovascular complications and mortality . The results of the Steno-2 Study are even more suggestive, since multifactorial treatment reduced the risk of CV mortality by 53%, and was also associated with a risk reduction of 61% for nephropathy, 58% for retinopathy and 63% for neuropathy .
Thus, the results of the most recent trials, when analysed together with data from previous studies and with the available epidemiological evidence, rather than stimulating new discussion on the relative role of each risk factor, support the need for a comprehensive treat-to-target approach for all of them.
Different glucose medications, different outcomes?
The possibility that, irrespective of the extent of glycaemic control they can provide, the different pharmacological agents have varying effects on CV outcome has been repeatedly suggested, but there is currently no conclusive evidence of this. The UGDP  was stopped because of an apparent increased mortality rate with sulfonylureas and the results were dismissed because of statistical biases . No harm was observed with sulfonylureas in the UKPDS , although metformin treatment was associated with better CV outcome , a benefit lost with the combination of the two medications . These results are in agreement with large retrospective analyses. In the survey of Evans et al. , in spite of similar glycaemic control (HbA1c ~8%), the mortality rate was lower for metformin than for sulfonylureas, with the combination of the two producing an intermediate rate. Among the older adults of the Cardiovascular Health Study , a greater mortality rate was observed for those treated with insulin compared with those on oral hypoglycaemic agents, even though there was no apparent difference between these two subgroups in terms of fasting plasma glucose (~10 mmol/l). In the Euro Heart Survey, in diabetic patients with coronary artery disease, insulin was related to a more serious prognosis than were oral glucose-lowering medications . Interestingly, in the VADT, insulin therapy at baseline was an independent predictor of subsequent CV mortality . Whether this association reflects a true medication-related risk, or, rather, different severity of the disease condition remains a matter of debate, but it is intriguing that agents that may cause hypoglycaemia are more often associated with increased CV risk.
Hypoglycaemia: a trigger for CV events?
A similar picture emerges from the ACCORD study, in which intensive treatment was associated with a significantly greater rate of severe hypoglycaemic events . In both the ACCORD study  and the VADT a clear association between severe hypoglycaemia and CV events was found, although no clear-cut cause–effect relationship could be proven .
It should be noted that the absolute rate of severe hypoglycaemia remains lower than the rates reported in trials performed in type 1 diabetic patients [2, 6, 7, 8, 11], but hypoglycaemia may still be a matter of concern in older type 2 diabetic patients, particularly in those with previous CV events. Hypoglycaemia can be associated with (1) activation of adrenergic response , (2) impaired flexibility in substrate shift in the diabetic myocardium , (3) QTc prolongation and cardiac rate/rhythm disturbances , and (4) excessive glucose fluctuations with marked activation of oxidative stress . A further potential indicator of patient vulnerability is represented by diabetic autonomic neuropathy. In the VADT , 43% of the patients had diabetic neuropathy at study entry. Although not specified, such a high prevalence probably includes patients with autonomic neuropathy, a condition associated, in an independent manner, with a greater rate of CV mortality .
Glucose control—the longer the disease duration, the smaller the benefit?
Together, these results suggest that, at least within the timeframe of the intensive treatment period of the most recent trials, there is less opportunity to influence the development and/or progression of complications in individuals with longstanding diabetes. Conversely, in both type 1 [28, 29] and type 2  diabetic patients, early strict glycaemic control generates a legacy that may confer protection against, or delay, long-term diabetic complications. Data in support of this view can also be derived from the ACCORD trial . In spite of an increased risk of mortality in intensively treated patients, per group analysis indicates a significant HR reduction with respect to primary CV endpoint in diabetic patients with no previous CV events (p = 0.04) and in those with a HbA1c level of ≤8% (p = 0.03). Moreover, the VADT investigators reported that the HR for CV disease owing to intensive glycaemic control varies as a function of disease duration: it is much reduced in diabetic patients with short disease duration, and this reduction becomes smaller with longer disease duration, to actually worsen in individuals with longstanding diabetes .
Micro- and macrovascular complications—a common soil?
Although the results of the UKPDS post-trial results were felt reassuring, the recent published results of the VADT , ACCORD , and ADVANCE  have left a feeling of uneasiness on the light of limited effect not just on CV event, a very debated issue, but also because of poor microvascular complication outcome. These findings, however, may be less striking if we avoid looking at micro- and macrovascular complications as two separate entities. Literature is now available to show that retinopathy predicts CV mortality in type 2 diabetes . A cross-sectional association between coronary artery calcium (CAC) and proliferative diabetic retinopathy has been reported in a VADT subsample of diabetic patients . Of note, the association remained statistically significant even after adjustment for multiple CV risk factors. Individuals with proliferative diabetic retinopathy had a sixfold higher risk of having a CAC score of >400. This sort of association is not surprising given the many common pathophysiological mechanisms, including inflammation, hypercoagulability state and endothelial dysfunction . The possible contribution of both traditional and non-traditional CV risk factors to the development and progression of microvascular complications has already been mentioned above. Finally, hyperglycaemia and associated metabolic alterations may well represent a single unifying process producing diabetic complications through activation of oxidative stress . It is therefore not surprising that in patients with longstanding diabetes and consolidated micro- and macrovascular damage, 6 years of intensive glycaemic control may not result in any apparent beneficial effect.
Conclusion and perspectives
At the press conference that followed the presentation of the VADT on the occasion of the 68th Scientific Sessions of the ADA, William C. Duckworth, the VADT principal investigator, commented: ‘If you go into a population that already has multiple risk factors—or prior cardiovascular disease—and longstanding poor glucose control, you cannot expect benefits from glucose control in the short term. You can’t expect miracles.’ . But it is not a miracle that we look for, but, rather, rational approaches for effective treatment and prevention of diabetic complications.
A large number of diabetic patients still have poor glycaemic control . Their HbA1c must be lowered but we should be very careful in deciding how low the target should be and how to reach it. Individualisation of the glycaemic target is definitely needed in people with existing micro- and macrovascular complications. Reduction of the risk of severe hypoglycaemia is desirable given the association with CV events. Risk-to-benefit assessment of available glucose-lowering agents should be performed so that an appropriate treatment strategy is selected. An improvement in HbA1c may be attained with slow but progressive decline. In both the VADT  and ACCORD  trials, HbA1c declined very quickly, and such a rapid improvement has been associated, in controlled studies, with initial worsening of existing diabetic complications [38, 39]. Interestingly, a much smoother reduction in HbA1c was obtained in the ADVANCE trial . Although the real implications of a rapid achievement of glycaemic control may not be fully apparent, the risk of hypoglycaemia is likely to be greater if a more aggressive approach is used. The use of statins and effective anti-hypertensive treatment should be initiated irrespective of previous CV events in all diabetic patients. However, a true shift in treatment strategy for type 2 diabetes will require the implementation of appropriate treatment at the time of the diagnosis , if not earlier on. The probability of there being existing diabetic complications is lower at diagnosis, allowing effective protection. The ‘metabolic legacy’ is short in duration and hence easier to be modified. In these patients, therefore, targeting normoglycaemia is not just feasible but mandatory. One possible strategy would be to avoid agents that may expose the patient to an unnecessary risk of hypoglycaemia. From this point of view, taking into consideration the pathophysiological basis of hyperglycaemia may provide guidance for the selection of medications. In all cases, however, an uncompromised therapeutic insistence should be adopted , including the treatment of all CV risk factors.
Ideally, diabetes prevention should be desirable, but while we wait for effective and feasible preventative procedures, efforts should be made to treat-to-target all newly diagnosed diabetic patients. Finally, we should all remember and emphasise to the entire medical community that no form of mild diabetes exists, and no excuse exists to postpone appropriate and effective treatment.
I would like to thank R. Miccoli and G. Penno at the University of Pisa (Pisa, Italy) for continuous support and critical suggestions during the preparation of my commentary to the VADT on the occasion of the 44th Annual Meeting of the European Association for the Study of Diabetes, Rome, 8–11 September 2008, as well as during the preparation of this manuscript. A special thank you to R. Bonadonna (University of Verona, Verona, Italy), who provided useful suggestions following critical reading of the manuscript.
Duality of interest
The author declares the following potential duality of interest: participation in advisory panels for Novartis Pharmaceuticals, Merck, Roche Pharmaceuticals, Roche Diagnostics, Pfizer, Eli Lilly, Amylin Pharmaceuticals, Mannkind, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, GlaxoSmithKline, sanofi-aventis and Takeda Pharmaceuticals; research support received from Merck, sanofi-aventis and Takeda Pharmaceuticals.
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