Out with the old, in with the old and new?
In the not too distant past, patients with diabetes were managed by targeting a specific range of blood glucose values. Like anything else in the medical community, these ranges fluctuated as expert consensus and opinions changed over the years as new findings became available. As proof of this, one needs look no further than the history of the American Diabetes Association’s “Standards of Medical Care in Diabetes,” which is released annually. As an example, in 2014, the ADA changed the range of targeted fasting blood glucose from 70-130 mg/dl to 80-130 mg/dl. While this change does not appear to be overwhelming, it was decided that tight control to 70 mg/dl increased the incidence of hypoglycemia, which is recognized as a dangerous sequela of diabetes treatment. Another example is the discovery by Dr. Samuel Rahbar in 1968 that hemoglobin A1C is elevated in patients with diabetes. It took several years for this idea to take hold, but following the Diabetes Control and Complications Trial in 1993, and the United Kingdom Prospective Diabetes Study in 1998, with established HbA1C as a useful clinical marker in type 1 and type 2 diabetes respectively, the ADA agreed in 2010 that HbA1C be used in the diagnosis and monitoring of diabetes. Since then, it has been widely regarded that HbA1C should be maintained below 7 to achieve “good control,” and, more importantly, to minimize the risk of adverse cardiovascular events and improve overall survival.
In the current issue of the Journal of the American Medical Association, discussion is underway about shifting focus away from HbA1C and glucose monitoring, and more toward cardiovascular outcomes and mortality data. This is evidenced by recent trials where different approaches to glucose control yielded varying degrees of cardiovascular protection. For example, SGLT2 inhibitors (e.g. empagliflozin) and GLP-1 agonists (e.g. liraglutide) both effectively lower blood sugar and HbA1C, and also significantly reduce cardiovascular risk. On the other hand, a different GLP-1 agonist, semaglutide, also lowered glycemic markers, but the imparted degree of cardiovascular protection and reduction in mortality was considerably less than with liraglutide. A trial involving the DDP-4 inhibitor saxagliptin demonstrated that even with good glycemic control, there was a considerable rise in hospitalizations due to heart failure. This divergence of outcomes in spite of achieving control of glucose and HbA1C reinforce the importance of focusing on cardiovascular sequelae.
Another consideration with this approach revolves around the older drugs used in type 2 diabetes, specifically sulfonylureas and metformin. There is a considerable void of data looking at cardiovascular outcomes in sulfonylureas, which were first presented long before newer cardioprotective agents (ACE-inhibitors and statins, for example) were available, and CV protective measures primarily involved lifestyle modifications. CV effects of metformin were studied on a very small scale during initial safety and efficacy trials, which results are too lightly powered to stand up against much larger studies of today. As all drugs in these two groups have long since become unbranded, there is little financial backing from interested manufacturers to support large scale studies. This continues to feed the ongoing divergence in available evidence.
Ultimately, it has been shown that the same glycemic target used across several different patients will yield several different CV outcomes, giving rise to the question: are currently accepted glycemic targets right for everyone? More specific to the question is does the same HbA1C across a continuum of patients correlate to the same blood glucose level? We know the answer to these questions is no. The glucose control requirements for a patient who is newly diagnosed and should try to achieve decreased cardiovascular risks are clearly tighter than for someone who is a long-standing person with diabetes, has a shorter life expectancy, and has irreversible comorbidities, whose primary goal is avoidance of hypoglycemia. In both, it is difficult to assign the same target HbA1C, as variations in coincident glucose are likely to be seen. This gives rise to a patient-centered approach, where each individual has unique glycemic targets independent of all other patients.
It is important to consider the ADA Standards of Care to be guidelines, and that recommendations should be utilized with focus on patient-specific qualities that may require diversion from those guidelines. While some have suggested that insurance companies who require strict adherence to community accepted standards of care may actually impede this mindset, a renewed approach to what constitutes good control must be achieved. Perhaps the primary outcome of reducing cardiovascular risk and mortality should take the forefront, and traditional glycemic targets should be utilized to prevent hypoglycemic events.
- Like all medical practice guidelines, the ADA Standards of Medical Care in Diabetes is dynamic and evolving from year to year.
- Even though older drugs like metformin are considered first line agents, little data exist to show their effectiveness in cardiovascular protection and reduction of mortality.
- Studies of current generation agents are now required by the FDA to provide cardiovascular risk and mortality data in diabetic patients as primary outcome measures
Lipska KJ, Krumholz HM. Is Hemoglobin A1c the Right Outcome for Studies of Diabetes? JAMA. 2017;317(10):1017-8.
Reusch JE, Manson JE. Management of Type 2 Diabetes in 2017:Getting to Goal.JAMA.2017;317(10):1015-6.
Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD