I wouldn’t dismiss the Accord study too quickly. It was a massive survey of more than 10,000 patients, in which the negative outcomes in the strict control group were so dramatic that it was deemed unethical not to stop the study early. This is far from confirming that strict control actually has any benefit for all the burden it involves. Of course, as soon as it came out, there were efforts to escape its implications, since it threatened the established explanatory paradigm of the development of complications, and philosophers of science from Kuhn to Lakatos have described how scientific theories fight against departures from their established views. It also endangered the profits of the huge diabetes control industry, as well as challenging the reputation of the medical community.
But the scientific evidence hardly indicates that the study is simply worthless. The Accord study, the Action in Diabetes and Vascular Disease study (Advance), and the Veterans Affairs Diabetes trial (Vadt) all came to the same result, “that intensive control to near normoglycemia had either no, or potentially even a detrimental, effect on cardiovascular outcomes” in type 2 diabetes. (1) In 2012, it was evident that a “five-year follow-up study confirmed the earlier observation of an increased mortality signal in the intensive treatment group.” (2) Again in 2012, another review still concluded that “intensive glycemic therapy is rarely, if ever, justified in Accord type patients.” (3) The American Diabetes Association recommendation of less stringent A1c targets for type 2 patients “who do not achieve an A1c less than 7% in the face of ongoing diabetes self-management education and effective doses of insulin in combination with, for instance, with metformin,” was again confirmed. (4) One of the most extensive reviews of the research found in 2011 that “sufficient evidence exists for an absence of a 10% relative risk reduction in all cause mortality with intensive glycaemic control in patients with type 2 diabetes,” as well as insufficient evidence “for a 10% relative risk reduction in cardiovascular mortality” in this group. Further, it found “insufficient evidence to support the conclusion that intensive glycaemic control prevents the occurrence of microvascular disease assessed on a composite outcome, retinopathy, or nephropathy,” but it did find that intensive control caused a 30% increase in severe hypoglycemia in type 2 patients. (5) The Clinical Practice Guidelines of Diabetes Canada, updated in 2016, carried forward the Accord conclusions, noting that “less stringent A1c targets … may be appropriate in patients with type 1 or type 2 diabetes with any of the following … : a) limited life expectancy, … d) multiple comorbidities, e) history of recurrent severe hypoglycemia, … longstanding diabetes for which it is difficult to achieve an A1c less than or equal to 7.0% despite effective doses of multiple anti-hyperglycemia agents … .” So, in effect, they are saying that for some patients at least, the potential negative interaction with various background factors of intensive blood sugar control may well outweigh the benefits.
Of course the Accord study data has been mined to try to find what factors correlate with those patients who are most likely to be harmed by strict control. Generally, it seems that strict control may help newly-diagnosed patients, but may do more harm than good in those who have had the disease for a long time. (6) If there are already other health problems present, this increases the odds of a negative outcome for strict control measures, as does more frequent hypoglycemia. One intriguing study has suggested that those patients for whom strict control may be particularly bad share a genetic trait which makes intensive glucose normalization efforts harmful, and that was published in 2016. (7)
Generally, there is some disconnect between better blood sugar control and a reduction in the incidence and intensity of diabetic complications. For example, in the DCCT study, 40% of type 1 patients with an A1c greater than 9. had no retinopathy after ten years of follow-up. (8) One study of type 1 diabetics surviving more than 50 years with the disease found an average A1c among them of more than 10! (9) The strongest predictive factor for type 1 diabetics developing coronary artery disease is not A1c but the magnitude of their insulin requirement. (10) So even in type 1 patients, strict and poor control don’t exactly match the expected results.
- A. Brown, “Intensive Glycemic Control and Cardiovascular Disease: An Update,” Nature Reviews Cardiology, 7, 369 (2010).
- Andrew Krentz, “Drug Therapy for Type 2 Diabetes,” London: Springer, 2012, p. 13.
- S. Genuth and F. Ismail-Beigl, “Clinical Implications of the Accord Trial,” The Journal of Clinical Endocrinology and Metabolism, 97 (1) 41 (2012).
- J. Buse, “Glycemic Targets in Diabetes Care: Emerging Clarity after Accord,” Transactions of the American Clinical and Climatological Association, 126, 62 (2015).
- B. Hemmingsen, et al., “Intensive Control for Patients with Type 2 Diabetes: Systemic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials,” British Medical Journal, 343, 24 November, 2011.
- H. Shah, et al., “Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes,” Diabetes Care, 39 (11) 1915 (2016).
- J. Estenes, “Absence of Diabetic Retinopathy in a Patient who had Diabetes Mellitus for 69 Years and Inadequate Glycemic Control,” Diabetology and Metabolic Syndrome, 1 (13) (October 5, 2009)
- G. Gill, et al., “Insulin Dependent Diabetes of over 50 Years Duration,” Partical Diabetes International, 10 (2) 60 (2005); cf. J. Sun, et al., “Protection from Retinopathy and Other Complications in Patients with Type 1 Diabetes of Extreme Duration,” Diabetes Care, 34 (4) 968 (2011).
- B. Conway, et al., “Is Glycemia or Insulin Dose the Stronger Risk Factor?” Diabetic Vascular Disease Resarch, 6 (4) 223 (2009).