Iatrogenic hypoglycaemia is the limiting factor in the glycaemic management of diabetes, particularly with insulin. That hypoglycaemia can kill experimental animals has been known since the discovery of insulin. There are now numerous reports of deaths of patients with diabetes associated with hypoglycaemia. Since hypoglycaemia can kill, and hypoglycaemia at the time of death has been documented by continuous glucose monitoring in a patient with diabetes, it is reasonable to conclude that these are causal associations. That conclusion is supported by hypoglycaemia mortality rates of 7% to 10% or more in series of patients with diabetes. Given the lack of convincing evidence of clinically important outcomes that require intensive glycaemic control, it is difficult to justify tight glycaemic control in patients with diabetes who are at risk of harm from hypoglycaemia or who have no likelihood of benefit.
Iatrogenic hypoglycaemia is the limiting factor in the glycaemic management of diabetes with insulin, a sulfonylurea or a glinide (1). Hypoglycaemia is particularly common in patients whose diabetes is treated with insulin (2). Serious, clinically important hypoglycaemia (3) occurs frequently. For example, continuous glucose monitoring detected glucose concentrations less than 3.0 mmol/L (54 mg/dL) were found to occur every three or four days in a study of patients with type 1 diabetes mellitus (T1DM) using multiple daily injections of insulin (4).
That hypoglycaemia can kill has been known since the discovery of insulin in 1921. Collip and colleagues found that decrements in the blood glucose concentrations following injection of the pancreatic insulin extract into rabbits could be fatal and documented that death of the animals could be prevented by administration of glucose (5). Clinical colleagues of Banting and Best had patients with diabetes die from “hypoglycaemic reactions” (5).
There are now numerous reports of deaths associated with hypoglycaemia in patients with diabetes (e.g., 5-13). In addition to clinical hypoglycaemic death (5), the findings included: Increased mortality with severe (requiring the assistance of another person), symptomatic hypoglycaemia in type 2 diabetes mellitus (T2DM) (6), increased mortality with severe hypoglycaemia in patients with T2DM (7-9), increased cardiovascular and arrhythmic mortality with severe hypoglycaemia in insulin-treated patients with T2DM or impaired glucose tolerance (10), increased mortality with severe hypoglycaemia and seizure, coma, or both in type 1 diabetes mellitus (T1DM) (11), increased mortality in intensive care unit (ICU) patients with hypoglycaemia of less than 70 mg/dL (3.9 mmol/L) (12) and increased mortality in ICU patients and in hospital inpatients with hypoglycaemia of less than 70 mg/dL (3.9 mmol/L) (13). Given the fact that it is known that hypoglycaemia can kill experimental animals (5) and that hypoglycaemia was documented by continuous glucose monitoring at the time of death of a patient with T1DM (14), it is reasonable to conclude that these are causal associations.
Where reported (8,9) the risk of hypoglycaemia associated with death was stronger with shorter intervals between the detected episode of hypoglycaemia and death, consistent with a causal connection between hypoglycaemia and death. Obviously, the last detected episode of hypoglycaemia was not the cause of death since, in the absence of a continuous glucose monitoring record (14), the patient had to survive to report it. But, previous hypoglycaemia is a potent risk factor for subsequent, potentially fatal hypoglycaemia (1). The culprit is not the last detected episode of hypoglycaemia but rather a subsequent episode predicted by that last episode. The interval is not critical, although a shorter interval between the last detected episode and death suggests more frequent hypoglycaemia.
The conclusion that these are causal associations is supported by reports of hypoglycaemic mortality rates in series of patients with diabetes (11,15-19). Early reports indicated that 2% to 4% of deaths of patients with T1DM were the result of hypoglycaemia (15-17). However, more recent reports include hypoglycaemic mortality rates of 7% (18), 8% (11), and 10% (19) in childhood-onset (largely T1DM) diabetes. Indeed, the estimate of Skrivarhaug and colleagues (19) that 10% of deaths of Norwegian patients with childhood-onset T1DM were the result of hypoglycaemia may well have been an under estimate since another 15% of the deaths were listed as “sudden death” or “unexpected death,” categories in which the cause of death was ill-defined and might have been the result of hypoglycaemia and cardiac dysrhythmias as the authors suggested. One wonders if the higher hypoglycaemic mortality rates in the more recent reports (11,18,19) might be a clue to overtreatment of diabetes in recent years.
Primary brain death sometimes occurs in patients with diabetes who suffer prolonged, profound iatrogenic hypoglycaemia, but most hypoglycaemia mortality is probably the result of a fatal cardiac arrhythmia with secondary brain death. There is increasing evidence that hypoglycaemia is pro-arrhythmogenic (20-22). Holter monitoring during continuous glucose monitoring detected episodes of hypoglycaemia has documented runs of cardiac arrhythmias ranging from ventricular tachycardia (20) to bradycardia (21) and repolarization abnormalities have been identified in diabetes (22).
In the absence of large, long duration, prospective randomized trials it is not possible to establish causation definitively and severe hypoglycaemia clearly cannot be induced deliberately, in one arm, for both ethical and practical reasons. It has been argued that “confounding” may explain the association between mortality and hypoglycaemia, i.e., that a comorbidity (such as renal or liver disease, weight loss or cognitive impairment) confers both an increased risk of mortality and hypoglycaemia. Zoungas and colleagues (7) have speculated that confounding contributed to the association between mortality and severe hypoglycaemia in the ADVANCE trial. That was based on the association they observed between non-cardiovascular mortality (as well as cardiovascular mortality) and severe hypoglycaemia; they reasoned that death from respiratory, gastrointestinal or skin disorders was unlikely to be caused by hypoglycaemia. However, the conclusion that the associations between mortality and hypoglycaemia are causal is further supported by a systematic review, meta-analysis and bias analysis of studies involving 903,510 participants with T2DM, which concluded that comorbid severe illness alone may not explain these associations since comorbid illnesses would have had to be extremely strongly associated with both cardiovascular disease and severe hypoglycaemia (23).
Given that glycaemic goals in diabetes are a trade-off between glycaemic control and iatrogenic hypoglycaemia, it has been suggested that a reasonable individualized glycaemic goal is the lowest hemoglobin A1C that does not cause severe hypoglycaemia and preserves awareness of hypoglycaemia, preferably with little or no symptomatic or even asymptomatic hypoglycaemia at a given stage in the evolution of the individual’s diabetes (24). Parenthetically, the substantial relationship between a lower A1C level and a higher incidence of severe hypoglycaemia has been consistently documented in randomized controlled clinical trials in both T1DM (25,26) and T2DM (27-29). In these trials when patients with diabetes were randomly assigned to intensive glycaemic therapy and shown to have lower A1C levels or to more conventional glycaemic goals and shown to have higher A1C levels, the incidence of severe hypoglycaemia was 2- to 3-fold higher in each of the groups with the lower A1C levels. The frequency of hypoglycaemia was inversely related to the A1C level in both the original DCCT and the follow-up EDIC phase (25,26), although the slope was less steep in the EDIC phase. The extent to which the latter is the result of insulin analogues, improved insulin delivery, glucose monitoring, patient education, patient or caregiver skill or some other factor is not known.
In an extensive review, with the exception of a 15% reduction of non-fatal myocardial infarction, Rodriguez-Gutierrez and Montori (30) found no significant impact of tight glycaemic control of T2DM on outcomes important to patients—end stage renal disease/dialysis, renal death, blindness, clinical neuropathy, cardiovascular or all-cause mortality, stroke or amputation or peripheral vascular disease. They did find a 2- to 3-fold increase in severe hypoglycaemia during intensive therapy. The authors concluded that the overwhelming consensus in favour of tight glycaemic control to prevent complications needs to recalibrated. That tight glycaemic control did not reduce mortality in T2DM was also reported in an earlier meta-analysis (31). Some of these reservations could also be applied to T1DM. But, there is an association between mortality and substantial elevations in A1C levels in T1DM (32,33). In a 27-year follow-up of DCCT patients a rise in mortality above that of the general U. S. population began only with an A1C level greater than 9% (75 mmol/mol) (32). An analysis of a much larger data set, disclosed a similar finding (33). At 30 years of follow-up previous intensive glycaemic therapy (i.e., during the DCCT) did not reduce major cardiovascular events significantly, although the trend was in that direction (34). Given these data (32-34) one might conclude that the overwhelming consensus for intensive glycaemic therapy for the prevention of macrovascular complications (35), like that for microvascular complications (30), is stronger than the evidence to support it.
Clearly, we must carefully match therapeutic benefit and harm when we select a glycaemic goal in a patient with diabetes. Therapy with insulin is life-saving and prevents symptomatic hyperglycaemia in T1DM and many with advanced T2DM, but these benefits, like the prevention of macrovascular complications (32-34), do not require intensive glycaemic control. If we cannot convincingly document clinically important benefits of intensive glycaemic control we can advocate intensive glycaemic therapy only if the treatment is free from harm. But, many patients with diabetes are at risk for therapeutic harm. For example, those with hypoglycaemia-associated autonomic failure (including both defective glucose counterregulation and impaired awareness of hypoglycaemia), a history of severe hypoglycaemia, a long duration of diabetes, chronic kidney disease or malnutrition are at risk for hypoglycaemia (1). Exclusion of such patients would eliminate many patients with insulin-treated diabetes, perhaps most with T1DM (1,2), from intensive glycaemic therapy. Furthermore, since potential cardiovascular benefits develop over decades (34) one cannot anticipate benefit in patients with chronic vascular complications or other comorbidities with a short life expectancy. In these groups a less stringent glycaemic goal is indicated (36), perhaps an A1C level less than 8.5% (69 mmol/mol) (37) rather than less than 7% (53 mmol/mol) (35). In short, it is difficult to justify attempts to maintain A1C levels less than 7% (53 mmol/mol) in patients at high risk of harm or with no likelihood of benefit. Diabetes could be considered over-treated in such patients. At the very least, the risks and benefits should be explained to patients and their family before embarking on such an approach.
About the Authors
Acknowledgements: This manuscript was prepared without external support or assistance. Dr. Cryer has served as a consultant to Novo Nordisk in recent years. Dr. Heller has undertaken consultancy and worked on advisory boards on behalf of Eli Lilly, Novo Nordisk, Takeda and Boeringher Ingelheim for which his institution has received fees and he has received personal fees from Novo Nordisk, Astra Zeneca, Roche for work on speaker panels.
Philip E. Cryer, MD
Division of Endocrinology, Metabolism and Lipid Research (Campus Box 8127)
Washington University School of Medicine
660 South Euclid Avenue
St. Louis, Missouri 63110 U. S. A.
Simon R. Heller, DM, FRCP
Department of Oncology and Metabolism
University of Sheffield School of Medicine
Beech Hill Road
Sheffield S10 1UK
- Cryer PE. Hypoglycemia in Diabetes, 3rd Edition. American Diabetes Association, Alexandria, VA, 2016.
- Khunti K, Alsifri S, Aronson R, et al. Rates and predictors of hypoglycaemia in 27,585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study. Diabetes Obes Metab 2016;18:907-915.
- International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017;40:155-157.
- Riddlesworth T, Price D, Cohen N, Beck RW. Hypoglycemic event frequency and the effect of continuous glucose monitoring in adults with type 1 diabetes using multiple daily insulin injections. Diabetes Ther 2017;8:947-951.
- Bliss M. The Discovery of Insulin. University of Chicago Press, Chicago, IL, 1982, p 109 and p 158 respectively.
- Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ2010;340:b4909.
- Zoungas S, Patel A, Chalmers J, et al., ADVANCE Collaborative Group. Severe hypoglycemia and risk of vascular events and death. N Engl J Med 2010;363:1410-1418.
- Pieber TR, Marso SP, McGuire B, et al. Temporal relationships between severe hypoglycemia, cardiovascular outcomes and mortality. Diabetologia 2017: in press
- Zinman B, Marso SP, Christiansen E, et al. Severe hypoglycemia, cardiovascular outcomes and death. Diabetes2017;66(Suppl 1):A95.
- ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013;34:3137-3144.
- Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313:45-53.
- Finfer S, Liu B, Chittock DR, et al., NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108-1118.
- Krinsley JS, Maurer P, Holewinski S, et al. Glucose control, diabetes status, and mortality in critically ill patients: the continuum from intensive care unit admission to hospital discharge. Mayo Clinic Proc 2017;92:1019-1029.
- Tanenberg RJ, Newton CA, Drake AT III. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 2010;16:244-248.
- Deckert T, Poulsen JE, Larsen M. Prognosis of diabetics with diabetes onset before the age of thirtyone. I. Survival, cause of death and complications. Diabetologia 1978;14:363-370.
- Liang SP, Swerdlow AJ, Slater SD, et al. The British Diabetic Association Cohort Study. I. All-cause mortality in patients with insulin-treated diabetes mellitus. Diabet Med 1999;16:459-465.
- Patterson CC, Dahlquist G, Harjutsalo V, et al. Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989. Diabetologia 2007;50:2439-2442.
- Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes. Diabetes Care 2008;31:922-926.
- Skrivarhaug T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49:298-305.
- Pistrosch F, Ganz X, Bornstein SR, et al. Risks of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acta Diabetol 2015;52:889-895.
- Novodvorsky P, Bernjak A, Chow E, et al. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Diabetes Care 2017;40:655-662.
- Chow E, Bernjak A, Walkinghaw E, et al. Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in type 2 diabetes. Diabetes 2017;66:1322-1333.
- Goto A, Arah OA, Goto M, et al. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013;347:f4533.
- Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes2014;63:2188-2195.
- The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271-286.
- Gubitosi-Klug RA, Braffett BH, White NH, et al., and the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Risk of severe hypoglycemia in type 1 diabetes over 30 years of follow-up in the DCCT/EDIC study. Diabetes Care2017;40:1010-1016.
- Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.
- ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.
- Duckworth W, Abraira C, Moritz T, et al., VADT Investigators. Intensive glucose control and complications in American veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.C
- Rodríguez-Gutiérrez R, Montori VM. Glycemic control for patients with type 2 diabetes mellitus: our evolving faith in the face of evidence. Circ Cardiovasc Qual Outcomes 2016;9:504-512.
- Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288-2298.
- The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Mortality in type 1 diabetes in the DCCT/EDIC versus the general population.Diabetes Care 2016;39:1378-1383.
- Palta P, Huang ES, Kalyani RR, Golden SH, Yeh HC. Hemoglobin A1C and mortality in older adults with and without diabetes: results from the National Health and Nutrition Examination Surveys (1988-2011). Diabetes Care 2017;40:453-460.
- Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: The DCCT/EDIC Study 30-year follow-up. Diabetes Care 2016;39:686-693.
- Nathan DM. Diabetes: advances in diagnosis and treatment. JAMA 2015;314:1052-1062.
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149.
- Chiang JL, Kirkman MS, Laffel LM, Peters AL, and the Type 1 Diabetes Sourcebook Authors. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 2014;37:2034-2054.