Despite guidelines, hypoglycemia can largely be avoided without shortchanging tight glucose control.
By Stanley S. Schwartz, MD and Mary E Herman, PhD
ACP’s new 2018 recommendation for blood glucose targets for A1C “from 7 to 8 percent” (Qaseem et al. 2018) has created an uproar in the medical community. The ACP’s relaxed A1c targets are a striking departure from the learnings of seminal studies – a body of evidence that informed the recommendations of the American Diabetes Association (ADA), the American Association for Clinical Endocrinologists (AACE), the American Association of Diabetes Educators (AADE) and the Endocrine Society. A joint statement from those societies was issued shortly after release of the ACP guidelines with the following pronouncement, “…strongly disagree with the American College of Physicians’ (ACP’s) proposed new guidance that suggests higher blood glucose targets for people with type 2 diabetes” (American Diabetes Association, 2018). They argue that deviating from tight glucose control sacrifices well-documented ‘legacy effects’ of intensive blood glucose. Diabetes in Control’s Steve Freed, R.Ph., CDE adeptly outlines this and other chief concerns with the ACP glucose target in his review of the controversy. (http://www.diabetesincontrol.com/american-college-of-physicians-recommending-controversial-increase-in-a1c-of-7-to-8/)
We would like to add to this discussion. We ask: Why should we be going backwards, forfeiting optimal care? Is it for the benefit of healthcare providers? For want of time or training to avoid hypoglycemic episodes? A slackening of A1C targets fails to factor the vastly improved approaches that take the work out of avoiding hypoglycemia. Newer classes, such as SGLT2 inhibitors and GLP-1 receptor agonists, are associated with low risk for hypoglycemia. These classes are noted in the March 9, 2018 joint statement, wherein the societies stress that patients deserve ”individualized care that can improve their lives and reduce their risk of complications.” These classes can also significantly improve morbidity and mortality.
While new agents such as these are revolutionizing care, older agents deserve to be revisited. We would do well to perform a wholesale replacement of sulphonylureas in standard care. Sulphonylureas have an abysmal proclivity to drift into the hypoglycemic zone. Sulphonylureas are also highly suspect for overextending beta cells, making them work harder and possibly hastening their demise (Schwartz, Jellinger and Herman, 2016). Until we can experimentally prove otherwise, it is imprudent to take chances with the most important ‘tool’ for managing hyperglycemia – the beta cells.
Injected insulin continues to enjoy a rather privileged position in diabetes treatment, extending to liberal use in non-insulin-dependent diabetes. Newer insulin formulations reduce – but do not eliminate – risk of hypoglycemia. Moreover, insulin therapy does not compare to some newer agents in reducing the risk of diabetes-related complications and mortality. In fact, several long-term outcome studies suggest the opposite: that exogenous insulin may be associated with poorer outcomes as compared to newer agents, or even metformin, in some settings (reviewed by Herman et al. 2017). Any increased risks of diabetes-related complications could be incurred both directly and indirectly. Even mild hyperinsulinemia has been shown to exert of range of deleterious effects on vasculature and other tissues, including potentially, the beta cells, thereby compromising endogenous glucose control over the longer term (Schwartz, Jellinger and Herman, 2016).
Our current antihyperglycemic know-how extends beyond treatment of choice. We can do one better than targeting A1C level as a sole endpoint. Instead, we should identify the various pathways through which hyperglycemia arises in a given patient’s disease, and therapeutically address each (Schwartz et al 2016). At least eleven pathways now appear to contribute to elevated blood sugar – the Ominous Octet (Defronzo 2009) plus three more recently proposed mediating pathways of hyperglycemia: stomach/small intestine (via reduced amylin), immune dysregulation/inflammation (Subauste et al. 2014), and, gut biome (Tai et al. 2015). Most of these pathways have targeted interventions (Miller et al. manuscript submitted). As example, metformin counters hepatic gluconeogenesis, pioglitazone offsets insulin resistance, bromocriptine-QR (or GLP-1 RAs) helps reset elevated hypothalamic drive for increased plasma glucose and fuel, SGLT inhibitors reduce kidney-derived glucose, DPP-4 inhibitors (among others) control incretin levels, and, pramlintide retunes gut glucose regulation. Those contributing to hyperglycemia in a given patient can be largely discerned by clinical presentation, diagnostics, or, plasma glucose levels on the next check-up. Any combination of these may be at play in a given patient, and, fluctuate over the course of the disease. This approach allows for ‘true’ precision medicine for the first time for our patients.
In summary, perhaps the most important learning from years of diabetes research is the need for tight glycemic control. Drug development and ‘intelligently designed’ strategies mean we no longer need to compromise low A1C levels. Hypoglycemic episodes can be largely avoided in the short term. For the long haul in managing type 2 diabetes, tight glycemic control by targeting the specific pathways to hyperglycemia refines care, reduces need for exogenous insulin, and, minimizes the workload and detrimental exposure of beta cells. Common sense should prevail in incorporating newer agents and strategies, dodging older more dubious agents, and not compromising our ‘target’ for a long, healthy life for patients with diabetes.
- A1C target is the lowest that can be attained without hypoglycemia.
- A1C targets of the ADA and other leading societies (but NOT ACP) are achievable with monotherapy, or more commonly, combination therapy, with newer agents that have low risk of hypoglycemia, and especially those that have been demonstrated to reduce risk of long-term outcomes.
- Replace sulfonylureas/glinides with better alternatives (with lower risk of hypoglycemia and other attendant side effects). Reduce reliance on exogenous insulin in patients with T2DM; a patient well-managed throughout the course of their disease is far less likely to eventually need insulin.
- Adopt a new strategy for managing hyperglycemia: identify the pathways at work in each patient in contributing to the elevated plasma glucose, and use targeted treatments for each source of excess glucose.
American Diabetes Association, March 9, 2018. The American Diabetes Association®, the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators and the Endocrine Society Strongly Disagree with the American College of Physicians’ Guidance for Higher Blood Glucose Targets for People with Type 2 Diabetes (Press release]. Retrieved from http://www.diabetes.org/newsroom/press-releases/2018/joint-acp-guidance-response.html
DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795
Freed S. American College of Physicians Recommending Controversial Increase in A1c of 7% to 8%. Diabetes in Control. March 10, 2018. Retrieved from http://www.diabetesincontrol.com/american-college-of-physicians-recommending-controversial-increase-in-a1c-of-7-to-8/).
Herman ME, O’Keefe JH, Bell DSH, Schwartz SS. Insulin Therapy Increases Cardiovascular Risk in Type 2 Diabetes. Prog Cardiovasc Dis. 2017 Nov – Dec;60(3):422-434. doi: 10.1016/j.pcad.2017.09.001. Epub 2017 Sep 25.
Miller E, Aguilar RB, Schwartz SS. Update on the Management of Diabetes Mellitus. The Core Defects of Hyperglycemia Refined, Precision Medicine Realized: A Review. Manuscript submitted.
Qaseem A, Wilt TJ, Kansagara D, et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians. Ann Intern Med. 2018;Epub ahead of print.
Schwartz S; Epstein S; Corkey B, Grant SF, Gavin JR, 3rd, Aguilar RB. The Time is Right for New Classification System for Diabetes Mellitus: Rationale and Implications of the β-Cell Centric Classification Schema;, Diabetes Care. 2016 Feb;39(2):179-86.
Schwartz, S., Jellinger, P. Herman, M.; Obviating Much of the Need for Insulin Therapy in Type 2 Diabetes Mellitus (T2DM): A Re-Assessment of Insulin Therapy’s Safety Profile., Postgraduate Medicine. 2016 Aug;128(6):609-19.
Schwartz SS. Do Many People with Type 2 Diabetes Really Need Insulin? In, Diabetes Case Studies. Draznin B, Low Wang CC, Rubin DJ, Eds. Alexandria, VA, American Diabetes Association, 2015, p. 247-249.
Subauste A, Gianani R, Chang AM et al. Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes. PLoS One. 2014 Sep 16;9(9):e106537.
Tai N, Wong FS, Wen L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord. 2015 Mar;16(1):55-65. doi: 10.1007/s11154-015-9309-0