Reducing CV Risk in Diabetes: 'When' and 'How' Matter

Gregory A. Nichols, PhD


July 19, 2017

Does Early Aggressive Therapy Reduce Risk?

It is common knowledge that cardiovascular disease (CVD) is the single largest cause of morbidity and mortality in people with type 2 diabetes; it is also the largest contributor to the medical costs of diabetes.[1]

Although lower A1c levels have long been associated with reduced CVD and mortality risk,[2] it isn't clear from recent major clinical trials that the act of lowering A1c is what reduces that risk.[3,4,5] Two new studies suggest that the keys to reducing CVD risk might be when and how A1c levels are lowered.

An observational cohort study[6] from Denmark sought to determine the association between A1c levels achieved early in therapy, the magnitude of A1c reduction, and CVD events or death in patients with type 2 diabetes treated with metformin. All patients were aged 30 years or older and had initiated metformin monotherapy as their first-ever glucose-lowering treatment between 2000 and 2012, and had at least one A1c measurement within 12 months before therapy initiation and another within 2-6 months after therapy initiation (N = 24,752).

The key analysis variables were the A1c levels after metformin initiation and the difference between the pre- and postinitiation A1c levels. Using Cox regression analyses, the researchers estimated the risk for myocardial infarction (MI), stroke, or all-cause mortality across strata of the key variables, adjusting for baseline demographic and clinical characteristics that could be associated with these outcomes.

Lower Is Better

About 75% of the patients achieved A1c levels < 7%, and about half (54%) experienced an A1c change of at least 1%. After adjusting for confounders, the risk for the composite outcome increased with rising A1c levels (Table).

Table. HbA1c and Risk for Composite Outcome

HbA1ca Hazard Ratiob
6.5%-6.9% 1.18
7%-7.4% 1.23
7.5%-7.9% 1.34
≥ 8% 1.59

a Reference category: < 6.5%
b All hazard ratios statistically significant

The magnitude of A1c change suggested an association between larger reductions and lower risk, but statistical significance was lacking.

After Metformin, What Next?

In another study, researchers from the United Kingdom used the Clinical Practice Research Datalink (CPRD) to study 10,484 patients aged 65 years or older with type 2 diabetes, who had been treated with metformin monotherapy and who required escalation (addition or switch) to a second-line oral regimen from 2008 to 2014.[7]

Three second-line therapies were considered: a sulfonylurea (SU), a dipeptidyl peptidase-4 (DPP-4) inhibitor, and a thiazolidinedione (TZD). The primary outcomes included time to first event and total event rate for any event (any diabetes-related complication), MI, stroke, or a composite of MI/stroke (major adverse cardiac event; MACE). The cost-effectiveness ratios for each therapy were also evaluated with a simulation model.

Not All Treatments Are Equal

The mean age of the participants was 73 years, and 56% were men. After metformin monotherapy failure, most patients (42%) had an SU added or were switched to SU monotherapy (28%). The proportions adding or switching to a DPP-4 inhibitor or to a TZD were 20% and 9%, respectively.

In multivariate-adjusted analyses, total MACE event rates per 1000 person-years for metformin plus a DPP-4 inhibitor were 39% lower compared with metformin plus a SU, a result driven by a 42% lower rate of MI. No other mono- or combination therapies were statistically significantly different from metformin plus a SU. The reduced risk associated with metformin plus DPP-4 inhibitor therapy came at a cost of approximately $24,000 per quality-adjusted life-year (QALY) gained compared with metformin plus a SU.


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