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

Disclosures

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

In This Article

5. Combined Risk Factor Reduction

5.1 Steno-2 Study

The benefit of intensive control of multiple risk factors was demonstrated in the Steno-2 study.[62] This study randomized 80 patients with type 2 diabetes and microalbuminuria to receive conventional treatment consistent with the Guidelines of the Danish Medical Association, while a similar number of subjects in the intensive therapy arm had the following targets: HbA1c <6.5%, BP <130/80 mmHg, total cholesterol level <175 mg/dL, and serum triglyceride level <150 mg/dL. In addition all subjects received ACE inhibitors and aspirin. After a mean follow-up of 7.8 years, the mean values of HbA1c, systolic BP and LDL cholesterol in the intensive and standard therapy arms, respectively, were as follows: 7.9% versus 9.0%; 131 mmHg versus 146 mmHg; and 83 mg/dL versus 126 mg/dL. During this period, patients in the intensive therapy arm had a significantly lower risk of CV disease (HR 0.47; 95% CI 0.24, 0.73), nephropathy (HR 0.39; 95% CI 0.17, 0.87), and retinopathy (HR 0.42; 95% CI 0.21, 0.86). An absolute 20% reduction in risk of CV events was higher than that reported in any study employing single risk factor (glucose, BP, cholesterol) control interventions.

Similar to the UKPDS and DCCT follow-up studies, all participants surviving at the end of the Steno-2 study were followed up observationally for an additional 5.5 years.[63] At the end of the combined 13.3 years of follow-up, intensive therapy arm participants had sustained beneficial effects: a lower risk of death (HR 0.54; 95% CI 0.32, 0.89), CV death (HR 0.43; 95% CI 0.19, 0.64), CV events (HR 0.41; 95% CI 0.25, 0.67), and need for retinal photocoagulation (HR 0.45; 95% CI 0.23, 0.86). These data support a sustained benefit of intensive multiple-factor interventions.

5.2 UKPDS Combination Intervention Analysis

Epidemiologic data from the UKPDS also suggest an additive effect of hyperglycemia and high BP exposure on the risk of complications.[64] Glucose and BP control were divided into four quartiles each based on mean HbA1c (<6, 6.0–6.9, 7.0–7.9, and ≥8%) and systolic BP (<130, 130–139, 140–149, and ≥150 mmHg) values. The incidence of 'any diabetes-related endpoint' was 15 per 1000 person years in those achieving the lowest glucose and BP levels (HbA1c <6%; systolic BP <130 mmHg) as opposed to 82 per 1000 person-years in those who had the highest glucose (HbA1c ≥8%) and BP (≥150 mmHg) levels. Analysis also revealed that those allocated to both tight glucose and BP control had significantly fewer events than those randomized to either intervention alone or to neither (p = 0.024).

5.3 ADVANCE: Combined Glucose and BP Lowering

A more recent analysis from the ADVANCE study also confirms that the effects of tight glucose and BP control are additive with regard to renal outcomes and death, and that the effect of each intervention was not altered by the other therapy.[65] Risk reduction due to combined therapy was most apparent in situations where intensive glucose and BP control had separate significant beneficial effects.

5.4 Implications for Clinical Practice

Data from the Steno-2 study and from analysis of combined glucose and BP control strategies in UKPDS and ADVANCE clearly underscore the importance of concurrent multiple risk-factor intervention in contrast to a 'glucocentric' approach. Cost-effectiveness analysis also supports such an approach as exemplified by the analysis presented for the Steno study.[66] This analysis revealed that the intensive multifactorial risk reduction strategy was associated with increased life expectancy (1.1 year benefit in discounted life expectancy), quality-adjusted life expectancy (1.66 years benefit in quality-adjusted life-year [QALY]), and lifetime direct medical costs. The incremental cost-effectiveness ratio was €2538 per QALY gained (expressed in year 2005 values). These data indicated that there was a 74% probability that this intensive therapy would be considered cost effective compared with conventional treatment in the context of Denmark's healthcare system and economy. In a similar analysis of UKPDS data, incremental cost for intensive glucose control as an isolated intervention was £6028 (in year 2004 UK prices).[67] In the same study, since the incremental cost per QALY of BP control is not high (£369) in comparison to that of glucose control, and one could hypothesize much greater synergistic benefits of combined glucose and BP control, it is conceivable that the cost per QALY of combination therapy would be very favorable.[67] This economic analysis further underscores the benefit of multiple risk-factor intervention.

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