Elsevier

Diabetes & Metabolism

Volume 40, Issue 3, June 2014, Pages 176-185
Diabetes & Metabolism

For debate
Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal

https://doi.org/10.1016/j.diabet.2014.03.004Get rights and content

Abstract

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM.

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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