For debateEffects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal
Section snippets
Acronyms of clinical trials
- ACCORD
Action to Control Cardiovascular Risk in Diabetes
- ADVANCE
Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation
- BARI 2D
Bypass Angioplasty Revascularization Investigation 2 Diabetes
- DCCT
Diabetes Control and Complications Trial
- EDIC
Epidemiology of Diabetes Interventions and Complications
- EXAMINE
Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome
- Look AHEAD
Action for
Reasons for failure to demonstrate clinical benefit on cardiovascular outcomes
There are several reasons why it is difficult to demonstrate a beneficial effect of glucose-lowering agents on vascular complications of T2DM patients in randomized controlled trials as required by evidence-based medicine. What follows is a brief discussion of the reasons related to the pathophysiology of T2DM, the pharmacological properties of the medications used, the characteristics of the populations recruited into clinical trials and the particularities of the study protocols (Table 1).
Impact of glucose-lowering agents on microvascular complications
Besides macrovascular complications, microangiopathy represents a major burden that may be more strongly linked to chronic hyperglycaemia than macroangiopathy in both T1DM [57] and T2DM [6] patients. It has a major impact on quality of life, and it also reduces life expectancy, especially when diabetic nephropathy is present [58]. All diabetic retinopathy end points (including proliferative retinopathy, macular oedema and vision-threatening retinopathy) increase with diabetes duration and poor
Discussion
Evidence-based medicine requires demonstration of the efficacy and safety of addressing a risk factor/marker or using a specific drug in randomized controlled trials (RCTs). These trials are generally performed by academic bodies for risk factors (UKPDS, ACCORD) and by pharmaceutical companies for drugs (PROactive, SAVOR-TIMI 53, EXAMINE). A major driving force behind the planning of such trials is the commercialization of novel drugs and their implementation in clinical practice. This strategy
Conclusion
As pointed out by Boussageon et al., most RCTs have failed to demonstrate the efficacy of glucose-lowering agents in reducing cardiovascular complications in patients with T2DM. Given the natural history and complexity of the disease, such a demonstration in RCTs would be difficult to obtain. However, subgroup analysis has provided evidence suggesting that the potential beneficial effect may largely depend on patients’ characteristics, including age, diabetes duration, previous glucose control,
Disclosure of interest
No sources of funding were used to assist in the preparation of this manuscript. No conflicts of interest are directly relevant to the content of this manuscript.
A.J. Scheen has received lecturer/advisor fees from Abbott, AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi-Aventis and Takeda.
B. Charbonnel has received fees for consultancy and speaking, and travel and accommodation, from Merck-Serono,
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