Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement From the American Diabetes Association and the European Association for the Study of Diabetes

Response to Nathan et al.

  1. Philip E. Cryer, MD
  1. From the Division of Endocrinology, Metabolism and Lipid Research, the General Clinical Research Center, and the Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri
  1. Address correspondence to Philip E. Cryer, MD, Campus Box 8127, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: pcryer{at}wustl.edu

The consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes published in both Diabetologia (1) and Diabetes Care (2) included the following statement concerning the incidence of hypoglycemia in insulin-treated type 2 diabetes: “In clinical trials aimed at normoglycemia and achieving a mean A1C of ∼7%, severe hypoglycemic episodes (defined as requiring help from another person to treat) occurred at a rate of between 1 and 3 per 100 patient-years.” This is not a balanced description of the published literature.

The authors cited five publications to support the statement quoted (37). However, two of those do not include event rates for severe hypoglycemia as defined in the statement (5,6), and one was a review with no original data (7). Notably, however, the latter review cited studies reporting severe hypoglycemia event rates of 28 and 35 per 100 patient-years in insulin-treated type 2 diabetes (7), event rates well in excess of “between 1 and 3 per 100 patient-years” (1,2). Thus, only two (3,4) of the five publications cited, involving 127 patients with insulin-treated type 2 diabetes, support the authors’ statement (Table 1).

The authors did not cite original publications reporting severe hypoglycemia event rates of 10 (8), 28 (9), 35 (10), 44 (11), and 73 (12) per 100 patient-years, involving 907 patients with insulin-treated type 2 diabetes (Table 1). (Admittedly, one [11] was published at about the same time as the consensus statement.) These five reports included a prospective study of a population-based random sample of patients with insulin-treated type 2 diabetes that found a severe hypoglycemia event rate of 35 per 100 patient-years (10). These severe hypoglycemia event rates, which ranged from 10 to 73 per 100 patient-years in insulin-treated type 2 diabetes (8,9,10,11,12), approach those ranging from 62 to 170 per 100 patient-years in type 1 diabetes (10,1214) (Table 1).

Furthermore, the authors did not cite additional population-based data in which the event rates for severe hypoglycemia requiring emergency medical treatment in insulin-treated type 2 diabetes ranged from 40 (15) to 100% (16) of those in type 1 diabetes.

The barrier of hypoglycemia precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the now well-established vascular benefits of glycemic control (17). In contrast to type 1 diabetes, hypoglycemia is relatively infrequent early in the course of type 2 diabetes when glucose counterregulatory defenses against falling plasma glucose concentrations are intact (17,18). However, as discussed here and summarized in Table 1, there is a body of evidence, including prospective, population-based data, that indicates that hypoglycemia becomes progressively more frequent, approaching its incidence in type 1 diabetes, as patients approach the insulin-deficient end of the spectrum of type 2 diabetes, when physiological and behavioral defenses against falling glucose levels become compromised (17,18).

I agree with the authors of the consensus statement that “[i]nsulin is the most effective of diabetes medications in lowering glycemia” (1,2). In my opinion, insulin should be introduced earlier, rather than later, in inadequately controlled type 2 diabetes. However, our associations should provide a balanced view of the downside of that effective therapy: hypoglycemia.

Table 1—

Event rates for severe hypoglycemia (that require the assistance of another person) in insulin-treated type 2 diabetes and in type 1 diabetes

Acknowledgments

This work was supported, in part, by U.S. National Institutes of Health Grants R37 DK27085, M01 RR00036, P60 DK20579, and T32 DK07120 and a fellowship award from the American Diabetes Association.

Janet Dedeke assisted in the preparation of this manuscript.

Footnotes

  • P.E.C. has served on advisory boards for Novo Nordisk, Takeda Pharmaceuticals North America, MannKind Corporation, and Merck & Co.

References

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