tight diabetes control and cardiovasc disease-- followup of the VA study

The Veterans Affairs Diabetes Trial (VADT) was one of the triumvirate published around 2009, along with the ACCORD and ADVANCE trials, which looked at intensive glycemic control and cardiovascular outcomes. These trials basically found that intensive control did not help and perhaps hurt: the ACCORD trial achieved an A1c of 6.4% in the intensive group vs 7.5% in the standard group, but had no benefit overall for nonfatal MI, nonfatal stroke and cardiovascular disease (CVD) deaths and actually had a 22% increased mortality after 3.5 years; the ADVANCE trial achieved an A1c separation of 6.3% vs 7.0% and found no macrovascular or mortality benefit after 5 years; and the VADT achieved an A1c separation of 6.9% vs 8.5% and found no CVD or mortality benefit after 5.6 years.  The current study looked at VADT outcomes in the 1791 military veterans after 11.8 years of followup, up to 5 years after the study ended (see dm tight control VADT followup nejm 2015 in dropbox, or N Engl J Med 2015;372:2197-206). findings:

--followup data available for 92.4% of the participants, with 77.7% agreeing to additional data collection: annual surveys and periodic chart reviews

--participants in the followup study: mean age 61, 97% male, 63% white/15% hispanic/16% black, diabetes for 12 years, 43% with prior cardiac event, 73% hypertensive, BMI 31, BP 132/76, LDL 106 mg/dl, HDL 36 mg/dl, 15% current smokers

--the A1c separation between the groups decreased from 1.5 percentage points (6.9% vs 8.5%) during the trial, to 0.2-0.3 percentage points (8.0% vs 8.3%) by 3 years after the trial ended .

--results:

        --intensive group had lower risk of primary outcome (time to first CVD event: heart attack, stroke, new or worsening heart failure, amputation for ischemic gangrene,CVD death) with HR 0.83 (0.70-0.99), p=0.04, after median followup of 9.8 years.   Absolute risk reduction of 8.6 major CVD events per 1000 person-years, though no reduction in CVD mortality

        ​--no reduction in total mortality, with HR 1.05 (0.89-1.25) after median followup of 11.8 years

conclusion: no evidence of any mortality benefit (similar results in long-term followup of the ADVANCE trial). And, the benefit (significant 17% decrease in major CVD events with intensive therapy) did come at some expense (increased severe hypoglycemic events in 21.2% vs 9.9% in the standard therapy arm, and likely increased medicalization in the intensive arm). Of note, posthoc analysis of the ACCORD trial (see dm ACCORD posthoc analysis diabcare 2010 in dropbox, or Diabetes Care 33:983–990, 2010) did find that the achieved A1c still had the strongest relationship with mortality, with a 1% increase in A1c being associated with a 20% increase in mortality.  But they found that higher mortality  was largely explained by which group the patients were assigned to, and not by the achieved A1c -- specifically, those patients in the intensive control arm who could not achieve an A1c<7% had the highest mortality. This analysis suggested that the issue was flogging those in the intensive group who had hard-to-control diabetes with more meds (and, they happened to use a lot of rosiglitazone...).

so, how does one piece this all together?  My sense is that the data do support aggressive (even very aggressive) control for younger people who have easy-to-control diabetes. Those with harder-to-control diabetes don't seem to do so well. This may be because of the long-term sequelae of diabetes and the attendant vascular changes, etc. Or the agents we use to improve the A1c (metformin is really great, but as we keep adding other agents, there seems to be less cardioprotection). Or because of an interplay of other comorbidities (eg a 5-year Italian study found that those with increasing numbers of comorbidities such as CAD, lung disease, GI problems, heart failure.... had no improvement in cardiovascular events with an A1C < 7 vs <6.5; those without comorbidities did better with the lower A1C threshold. -- see Ann Intern Med. 2009; 151(12):854-860​). Therefore, my bottom line: treat those with long life-expectancy and easy-to-control diabetes as aggressively as I can do safely (as always, as a joint decision with the patient, and largely relying on life-style changes/nonphamacological management), but avoid just adding on more and more meds in those with difficult-to-treat diabetes to lower the A1c below 7.5-8% or so. My caveat on the last point: there are no good intervention trials looking at higher A1c levels than 8% (ie, is a target of 9% or 10% really worse than 8% in difficult-to-treat patients with longstanding diabetes and lots of comorbidities??), and I certainly have many patients who cannot achieve close to a level of 8% (the goal of diabetes management, to me, is not to treat the A1c level, but the patient with diabetes. Although it is important to lower the A1c as much as we can, I have several patients with blood sugars that range from 45-450 with a very high A1c despite many mutual attempts to improve diet and exercise, and where adding more insulin or other agents is in fact dangerous for them).