Pharmacologic Prevention of Microvascular and Macrovascular Complications in Diabetes Mellitus

Implications of the Results of Recent Clinical Trials in Type 2 Diabetes

Nikhil Tandon; Mohammed K. Ali; K.M. Venkat Narayan


Am J Cardiovasc Drugs. 2012;12(1):7-22. 

In This Article

6. Conclusions

Attempts to reduce HbA1c to euglycemic levels in patients with long-standing type 2 diabetes and co-morbidities result in marginal benefits in non-fatal coronary episodes, but not in survival benefits (reduced all-cause mortality and CV mortality) or stroke reduction. A recent retrospective cohort study of patients with type 2 diabetes, analyzing the relationship between glycemic control and survival, showed a U-shaped association, with the lowest hazard ratio for mortality being seen at a median HbA1c of 7.5%.[68] There may in fact be a 'basement' level of glycemia, below which the balance between benefit and excess risk becomes more tenuous.[69] It also becomes apparent that in absolute terms, glycemia is a weaker risk factor for CV outcomes than BP and cholesterol levels, a point that becomes critical when we compare the impact of isolated glucose control with that of multiple risk-factor intervention.[70] Truly determining whether intensive glucose control to HbA1c values <7% is beneficial for CV outcomes and survival when applied early in the course of disease would require enormous resources, a massive patient population, and/or a minimum of 10 years of follow-up. It is not clear that the incremental benefits outweigh the costs given how much is known already.[34] Also, a major limitation of intensive therapy has been the heightened risk of hypoglycemia, which indicates that an improved pharmacotherapeutic strategy, including new agents with lower hypoglycemic risk and established long-term safety, should be aimed at achieving aggressive intensification of glucose control.

Intensive glucose control clearly prevents microvascular complications, although again, the effect may become apparent only after prolonged follow-up.[15,16] The difference in impact of tight glycemic control on macro- and microvascular endpoints suggests that there may be a difference in responsiveness of different organs to prevailing glycemia. A similar difference in end-organ responsiveness has also been suggested for BP, with the kidney and brain continuing to show benefits at BP levels at which the impact on the heart plateaus off.[71]

The benefits of multiple risk-factor control, however, remain indisputable, even in people with diabetes with high CV risk. Such a strategy is also being tested in younger patients with recent onset of diabetes in ADDITION (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care), and sufficient follow-up of these participants may provide data that have major implications for early clinical management in people with type 2 diabetes.[72]

In conclusion, these findings clearly indicate that neither the 'one size fit all' nor the 'fixed target(s)' approach are beneficial when it comes to glucose and BP control in people with diabetes. In older patients with co-morbidities, in particular, caution should outweigh aggression, while there is definite scope to consider aggressive glucose, BP-, and lipid-lowering therapy in younger individuals with new-onset diabetes while aiming to preserve quality of life for the remaining several decades they have to contend with these diseases. These targets can be varied at different time points, even in the same individual, depending on the burden of treatment, side effects, concurrent illness, and personal preference. While aspiring for 'lower' values, one must not forget that in an era where 'personalized medicine' is the emerging 'mantra', we cannot lose sight of the individual as a whole before deciding on targets for control.


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