Hipoglucemia en DM2 2019

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Curr Diab Rep. Author manuscript; available in PMC 2019 June 21.
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Published in final edited form as:

Curr Diab Rep. ; 18(8): 53. doi:10.1007/s11892-018-1018-0.
Hypoglycemia among Patients with Type 2 Diabetes:

Epidemiology, Risk Factors, and Prevention Strategies
Richard Silbert, MD1, Alejandro Salcido-Montenegro, MD2,3, Rene Rodriguez-Gutierrez, MD,
MSc2,3,4, Abdulrahman Katabi, MBBCh5, and Rozalina G. McCoy, MD MS6,7
1. Department of Medicine Residency Program, Mayo Clinic, Rochester, MN 55905
2.
Endocrinology Division, Department of Internal Medicine, University Hospital “Dr. José E.
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González”, Universidad Autonoma de Nuevo Leon, Monterrey, 64460, México

3.
Plataforma INVEST-Medicina UANL KER Unit, Universidad Autónoma de Nuevo León,
Monterrey, 64460, México
4.Knowledge and Evaluation Research Unit in Endocrinology, Mayo Clinic, Rochester, MN,
55905, USA
5. Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, 55905, USA.
6.Division of Community Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN
55905
7.Division of Health Care Policy & Research, Department of Health Sciences Research, Mayo
Clinic, Rochester, MN 55905
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Abstract
Purpose of the review: Hypoglycemia is the most common and often treatment-limiting
serious adverse effect of diabetes therapy. Despite being potentially preventable, hypoglycemia in
type 2 diabetes incurs substantial personal and societal burden. We review the epidemiology of
Corresponding author: Rozalina G. McCoy, MD MS. Division of Community Internal Medicine, Department of Medicine, Mayo
Clinic. 200 First Street SW. Rochester, MN 55905. Phone (507) 284-5160, fax (507) 266-0036, [email protected].
Richard Silbert, MD, Department of Medicine Residency Program, Mayo Clinic, 200 First Street SW, Rochester, MN 55905,
[email protected]
Alejandro Salcido-Montenegro MD, Endocrinology Division, Department of Internal Medicine, University Hospital “Dr. José E.
Author Manuscript
González”, Universidad Autónoma de Nuevo León, Av. Francisco I. Madero y Av. Gonzalitos s/n, Mitras centro, Monterrey, Nuevo
León, México. CP 64460. Phone: +52 (81) 8348-3220, [email protected]
Rene Rodriguez-Gutierrez, MD, MSc, Endocrinology Division, Department of Internal Medicine, University Hospital “Dr. José E.
González”, Universidad Autónoma de Nuevo León, Av. Francisco I. Madero y Av. Gonzalitos s/n, Mitras centro, Monterrey, Nuevo
León, México. CP 64460. Phone: +52 (81) 1474-9146, [email protected]
Abdulrahman Katabi, MBBCh, Evidence-Based Practice Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905,
[email protected]
Rozalina G. McCoy, MD MS, Division of Community Internal Medicine, Department of Medicine, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, Phone: (507) 284-5160, Fax: (507) 266-0036, [email protected]
Conflict of Interest
Richard Silbert, Alejandro Salcido-Montenegro, Rene Rodriguez-Gutierrez, and Abdulrahman Katabi declare that they have no
conflict of interest.
Rozalina G. McCoy reports a consulting fee from Dexcom paid to her institution (2016).
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Silbert et al. Page 2
hypoglycemia in type 2 diabetes, discuss key risk factors, and introduce potential prevention
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strategies.
Recent findings: Reported rates of hypoglycemia in type 2 diabetes vary widely as there is
marked heterogeneity in how hypoglycemia is defined, measured, and reported. In randomized
controlled trials, rates of severe hypoglycemia ranged from 0.7 to 12 per 100 person-years. In
observational studies, hospitalizations or emergency department visits for hypoglycemia were
experienced by 0.2 (patients treated without insulin or sulfonylurea) to 2.0 per 100 person-years
(insulin- or sulfonylurea-users). Patient-reported hypoglycemia is much more common. Over the
course of 6 months, 1-4% non-insulin users reported need for medical attention for hypoglycemia;
1-17%, need for any assistance; and 46-58%, any hypoglycemia symptoms. Similarly, over a 12-
months period, 4-17% of insulin-treated patients reported needing assistance and 37-64%
experienced any hypoglycemic symptoms. Hypoglycemia is most common among older patients
with multiple or advanced comorbidities, patients with long diabetes duration, or patients with a
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prior history of hypoglycemia. Insulin and sulfonylurea use, food insecurity, and fasting also
increase hypoglycemia risk. Clinical decision support tools may help identify at-risk patients.
Prospective trials of efforts to reduce hypoglycemia risk are needed, and there is emerging
evidence supporting multidisciplinary interventions including treatment deintensification, diabetes
self-management, and social support.
Summary: Hypoglycemia among patients with type 2 diabetes is common. Patient-centered

multidisciplinary care may help proactively identify at-risk patients and address the multiplicity of
factors contributing to hypoglycemia occurrence.
Keywords
Type 2 diabetes mellitus; hypoglycemia; epidemiology; patient-reported outcome; patient-centered
care
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Introduction
Diabetes mellitus is one of the most common and increasing chronic health conditions in the
U.S. and around the world, affecting an estimated 30.2 million (12.2%) U.S. adults [1] and
422 million (8.4%) adults worldwide.[2, 3] Most, approximately 95%, have type 2 diabetes.
[1] Diabetes is a major cause of blindness, kidney failure, heart attacks, strokes, and lower
extremity amputations and is the seventh leading cause of death in the U.S.[1] To reduce
these risks, diabetes management has prioritized lowering blood glucose levels through
lifestyle modifications and glucose-lowering medications. In the U.S., 83% of the 23 million
adults who have been diagnosed with diabetes (9.3% of the total U.S. adult population) are
treated with glucose-lowering medications [1]. However, glucose-lowering pharmacotherapy
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can lead to iatrogenic hypoglycemia, the most common and often treatment-limiting adverse
effect of diabetes therapy [4]. While commonly accepted by patients and their healthcare
providers as an inevitable consequence of preventing long-term diabetes complications,
hypoglycemia is increasingly recognized an important and potentially preventable cause of
morbidity, mortality, high costs, diminished productivity, and impaired quality of life. [5–14]
Real-world data on hypoglycemia rates and risk factors are necessary to inform patients and
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healthcare providers about the benefits and potential harms of glucose-lowering therapies,
facilitate shared decision making, and guide clinical practice. In this review, we discuss the
epidemiology of hypoglycemia among adults with type 2 diabetes as revealed by studies
conducted in diverse clinical settings and patient populations. We focus specifically on type
2 diabetes because the risk of hypoglycemia in this population is more heterogeneous,
treatment-dependent, and ultimately less inevitable than in type 1 diabetes. We conclude by
offering insights into some of the risk factors for hypoglycemia and introducing potential
prevention strategies.
Defining Hypoglycemia
An important barrier to quantifying and understanding the burden of hypoglycemia is the
marked heterogeneity in how it is defined, documented, and ascertained. Since 2005, the
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American Diabetes Association (ADA) has defined confirmed hypoglycemia as

symptomatic or asymptomatic blood glucose ≤70 mg/dL (3.9 mmol/L), probable
hypoglycemia as symptoms typical of hypoglycemia in the absence of blood glucose
measurements, and relative hypoglycemia as typical symptoms accompanied by blood
glucose >70 mg/dL (3.9 mmol/L).[15] Severe hypoglycemia was defined as hypoglycemia
requiring assistance of another person for management and symptom recovery after
treatment.[15] In 2013, the ADA began to explicitly recommend that providers routinely ask
at-risk patients about symptomatic and asymptomatic hypoglycemia,[16] thereby
acknowledging the importance of patient-reported events. In 2017, the ADA reclassified
blood glucose ≤70 mg/dL (3.9 mmol/L) as a hypoglycemia alert value warranting treatment
with fast-acting carbohydrate and adjustment of glucose-lowering therapy; added the
category of clinically significant hypoglycemia with blood glucose <54 mg/dL (3.0
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mmol/L); and reaffirmed severe hypoglycemia as the presence of severe cognitive

impairment requiring external assistance for recovery irrespective of the glucose level.[17,
18] However, these definitions are difficult to operationalize in population-based and clinical
research. Most hypoglycemic events occur outside the confines of the healthcare system
[19–21] and we lack efficient mechanisms to detect and document such events. Indeed,
while low blood glucose values are captured by self-monitoring of blood glucose and
continuous glucose monitors as part of routine or symptom-responsive testing, this data is
not routinely incorporated into the electronic health record. As a result, hypoglycemic events
occurring in the real-world setting and outside of prospectively defined research studies or
registries cannot be easily or consistently detected.
Research studies generally focus on either documented hypoglycemia (confirmed by a

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laboratory result, a patient-measured glucose value that is directly visible to the research or
clinical team, or a clinical encounter with the diagnosis of hypoglycemia) or patient-reported
hypoglycemia (reported by the patient without explicit confirmation by laboratory data).
Often, hypoglycemia is reported without a clear definition of how it was measured or
defined. The type of hypoglycemia reported is typically contingent on study design and data
source. Cross-sectional (e.g. survey or interview) studies commonly assess patient-reported
events, whereas retrospective studies using administrative or electronic health record data
focus on healthcare utilization events with the diagnosis codes of hypoglycemia. While there
are validated claims-based algorithms to identify hypoglycemic encounters using ICD-9[22]

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and ICD-10[23] codes, studies vary widely in their choice of diagnosis codes and types of
encounters (e.g. ambulatory visits, emergency department visits, hospitalizations) used to
capture events. Some retrospective and many prospective studies also report hypoglycemic
events confirmed by laboratory results, which can be patient-reported or documented in the
electronic health record, with qualifying glucose values ranging between 36 mg/dL (2.0
mmol/L) and 70 mg/dL (3.9 mmol/L).
All of these approaches to identifying hypoglycemic events have limitations. Self-report of

hypoglycemia is affected by accuracy of patient recall, which can be poor, particularly for
non-severe events.[24] It is further contingent on the patient’s ability to recognize
hypoglycemia when it occurs, which is limited by impaired hypoglycemia awareness, and to
correctly differentiate them from symptoms unrelated to hypoglycemia. On the other hand,
exclusive reliance on documented low blood glucose values will fail to identify events
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during which patients did not, or could not, measure their blood glucose. Furthermore,
approximately 95% of hypoglycemic events are managed outside the healthcare system,
either by the patient, caregivers, or emergency medical services.[19–21] These events do not
precipitate a clinical encounter or billing claim and as are therefore missed by methods that
rely on administrative or electronic health record data. The probability that a hypoglycemic
event is brought to medical attention is confounded by multiple factors including patient
access to healthcare, availability of resources (e.g. food, medications, and third party
assistance) to manage hypoglycemia, and the ability to recognize and effectively treat
hypoglycemic events when they occur. For example, in a study of ambulance calls for
hypoglycemia, 13.5% of patients with hypoglycemia (blood glucose <60 mg/dL [3.3
mmol/L]) were managed on the scene without transport to the emergency department.[25]
Patients brought to the emergency department were more likely to be older, residents of
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skilled nursing or assisted living facilities, or have altered consciousness or weakness (both
potential signs of frailty).[25] Thus, all reports of hypoglycemia need to be considered in the
context of the methodology used to identify and measure these events.
Frequency of Hypoglycemia in Randomized Controlled Trials

Severe hypoglycemia occurred rarely in the two landmark randomized controlled trials
conducted among patients with newly diagnosed type 2 diabetes or prediabetes. The UK
Prospective Diabetes Study (UKPDS) of intensive glucose-lowering therapy in type 2
diabetes enrolled adults with newly diagnosed type 2 diabetes who had no significant
microvascular or macrovascular disease between 1977 and 1991. Participants were treated
with metformin, sulfonylurea, or insulin to maintain fasting plasma glucose <108 mg/dL (6
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mmol/L), or received standard treatment of diet alone as long as fasting plasma glucose
remained <270 mg/dL (15 mmol/L) and participants were asymptomatic.[26, 27] Severe
hypoglycemia, defined by need for third party assistance, occurred each year, on average, in
0.1/100 patients treated with diet, 0.4-0.6/100 of patients treated with sulfonylurea, 2.3/100
of patients treated with insulin.[27] Non-severe hypoglycemia was more common, with at
least one hypoglycemic event per year experienced by 0.8/100 persons treated with diet,
1.7/100 persons treated with metformin, 7.9/100 persons treated with sulfonylurea, 21.2/100
persons treated with basal insulin, and 32.6/100 persons treated with basal plus prandial
insulin.[28] More recently, the Outcome Reduction with an Initial Glargine Intervention
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(ORIGIN) trial compared intensive glucose-lowering therapy with insulin glargine (targeting
fasting plasma glucose ≤95 mg/dL [5.3 mmol/L]) vs. standard treatment among older
patients with cardiovascular disease risk factors and either prediabetes or early type 2
diabetes.[29] The incidence rates of severe hypoglycemia requiring third party assistance
were 1.00/100 person-years in the insulin glargine group and 0.31/100 person-years in the
standard treatment group.[29]
The paradigm of type 2 diabetes management began to shift a decade ago after three large
randomized controlled trials of intensive glycemic control conducted among adults with
long-standing type 2 diabetes at high cardiovascular disease risk did not demonstrate
meaningful improvements in cardiovascular events or mortality, yet had much higher rates of
hypoglycemia than both UKPDS and ORIGIN trials.[30–33] In the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial, intensive treatment also resulted in higher
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cardiovascular and all-cause mortality,[31] thereby raising awareness of potential risks

associated with intensive glucose-lowering therapy, polypharmacy, and overtreatment. These
trials sought to lower HbA1c much more aggressively than either UKPDS or ORIGIN, with
the intensive treatment arms targeting HbA1c levels below 6%[31, 32] or 6.5%,[30] often
using multiple glucose-lowering medications. As a result, intensive treatment more than
doubled the risk of hypoglycemia compared to standard treatment.[30–32] While
hypoglycemia itself was not the immediate cause of excess death in these trials, it was
associated with a 2-3-fold increase in major macrovascular and microvascular events and all-
cause mortality irrespective of the treatment arm.[5, 8]
The absolute rates of severe hypoglycemia observed in these trials varied widely,
demonstrating how much hypoglycemia risk is contingent on patient characteristics,
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treatment modality, and approach to ascertainment and monitoring during the trial. In the
intensive vs. standard treatment arms, rates of severe hypoglycemia were 0.7 vs. 0.4/100
patient-years in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
Controlled Evaluation (ADVANCE) trial (defined by symptoms or blood glucose <50 mg/dL
[2.8 mmol/L] resulting in transient central nervous system dysfunction and need for any
third party assistance);[30] 3.1 vs. 1.0/100 patient-years in ACCORD (defined by requiring
medical assistance);[31] and 12 vs. 4/100 patient-years in the Veterans Affairs Diabetes Trial
(VADT; defined by impaired or complete loss of consciousness).[32] Non-severe
hypoglycemia was much more common with 120 vs. 90 events/100 patient-years in
ADVANCE,[30] while rates of any hypoglycemia in VADT were 1,566 vs. 432/100 patient-
years, in the intensive vs. standard treatment arms, respectively.[32]
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More recent large randomized controlled trials of glucose-lowering therapies have focused
primarily on the cardiovascular safety of newly approved glucose-lowering medications
rather than intensive glycemic control. These trials include EMPA-REG OUTCOME
(empagliflozin),[34] CANVAS (canagliflozin),[35] LEADER (liraglutide),[36] SAVOR-
TIMI 53 (saxagliptin),[37] TECOS (sitagliptin),[38] EXAMINE (alogliptin),[39] ELIXA
(lixisenatide),[40] SUSTAIN-6 (semaglutide),[41] and DEVOTE (insulin degludec).[42]
Most patients had baseline HbA1c above 8% (except TECOS and ELIXA, where baseline
HbA1c was 7.2%[38] and 7.6%,[40] respectively) and patients were treated to “standard”
HbA1c targets in all treatment arms; differences in HbA1c levels achieved with study drugs
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vs. placebo were less than 0.5%. Hypoglycemia was infrequent in these trials, though there
was variability in how hypoglycemia was reported (e.g. the percent of patients with at least
one hypoglycemic event during the study period vs. annualized event rates). Severe
hypoglycemia requiring third-party assistance occurred in 1.3% of empaglifozin-treated
patients (vs. 1.5% in placebo group; median 3.1 years of observation), [34] 2.4% of
liraglutide-treated patients (vs. 3.3% in placebo group; median 3.8 years of observation),
[36] 2.1% of saxagliptin-treated patients (vs. 1.7% in placebo group; median 2.1 years of
observation), [37] and 0.7% of alogliptin-treated patients (vs. 0.6% in placebo group;
median 1.5 years of observation).[39] In the TECOS trial, severe hypoglycemia occurred at
the rate of 0.8/100 person-years in the sitagliptin group and 0.7/100 person-years in the
placebo group.[38] Non-severe hypoglycemia with blood glucose ≤54 mg/dL (3.0 mmol/L)
occurred in 14.2% of saxagliptin-treated patients (vs. 12.5% in placebo group) [37] and <70
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mg/dL (3.9 mmol/L) in 27.9% of empaglifozin-treated patients (vs. 27.8% in placebo

group).[34] Any hypoglycemia occurred in 6.7% of alogliptin-treated patients (vs. 6.5% in
placebo group) [39] and 21.7%-23.1% of semaglutide-treated patients (vs. 21-21.5% in
placebo group; median 2.1 years of observation).[41] In the CANVAS trial, rates of any
hypoglycemia were 5.0/100 person-years in the canagliflozin group and 4.6/100 person-
years in the placebo group.[35] Finally, the in the DEVOTE trial (the only cardiovascular
outcome trial of an insulin agent), rates of severe hypoglycemia were 3.7/100 person-years
in the insulin degludec group and 6.3/100 person-years in the insulin glargine group.[42]
Results from trials may not immediately generalize to real-world practice. Large,
randomized trials often select motivated patients who are adherent to their recommended
treatments, are less likely to experience socioeconomic barriers to care, are closely
monitored, and may have their treatment regimens promptly adjusted in the event of adverse
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events. None of the studies discussed above included patients with history of severe
hypoglycemia, poor health status, or with major non-cardiovascular comorbidities. As a
result, the rates and nature of hypoglycemia reported in trials likely differ substantially from
real-world practice.[43]
Frequency of Hypoglycemia in Real-World Studies

Iatrogenic hypoglycemia is one of the most common adverse drug events requiring
emergency department care or hospitalization.[44] The Centers for Disease Control and
Prevention estimates that there were 245,000 emergency department visits for hypoglycemia
in 2014, or 1.12 visits/100 person-years, exceeding the number of hyperglycemic crises
managed in the emergency department (0.95 events/100 person-years).[1] Between 2007 and
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2009, insulin and oral glucose-lowering medications were implicated in nearly 14% and
10.7% of emergent hospitalizations among diabetes patients ≥65 years, respectively,[44]
though hypoglycemia was not necessarily the primary reason for admission. In a claims-
based study of commercially-insured and Medicare Advantage beneficiaries across the U.S.,
hypoglycemia was the primary reason for hospitalization among 1.2% of 594,146
hospitalized adults with diabetes between 2009 and 2014.[45] However, these estimates,
which include patients with type 1 and type 2 diabetes, likely represent a small fraction of
hypoglycemic events, as hypoglycemia rarely necessitates emergency care and even less
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often culminates in hospital admission.[19–21]
When patients were asked about their experience of severe hypoglycemia, the rate of self-
reported events varied widely. Multiple studies have assessed the rates of self-reported
hypoglycemia, most often during the preceding 6-months period, among non-insulin treated
patients with type 2 diabetes. Rates of severe hypoglycemia, defined by requiring third party
assistance, were highly variable, ranging from 1% (questionnaire completed by 412 patients
in Sweden; mean age 69 years, 71% with diabetes duration >7 years, mean HbA1c 6.3%, all
on metformin/sulfonylurea combination therapy),[46] 9% (questionnaire completed by 392
patients in Germany; mean age 62.7 years, 60.3% with diabetes duration >7 years, HbA1c
7.2%, all on metformin/sulfonylurea combination therapy),[47] 12% (questionnaire
completed by 2,257 patients in China, Korea, Taiwan, Malaysia, and Thailand; mean age
58.7 years, HbA1c 7.5%, 13.9% on metformin monotherapy and 46% using sulfonylureas),
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[48] 13% (internet survey completed by 1984 non-insulin-treated patients in the U.S.; mean
age 58.1 years, diabetes duration 7.3 years, 50% treated with sulfonylurea),[49] and 17%
(postal survey completed by 326 patients with type 2 diabetes in the U.S.; mean age 69.3
years, diabetes duration 15.7 years, HbA1c 7.4%, 66% insulin-treated)[14]. In the same
studies, severe hypoglycemia requiring medical assistance was reported by 1%,[46] 6%,[47]
8%,[48] and 4%[49] of respondents. Non-severe events were much more frequent. Mild
events, defined by symptoms causing little disruption to patients’ activities, were reported by
51%,[47] 58%,[48] and 46% [49] of participants. Similarly, moderate severity events,
defined by symptoms causing disruption but self-managed, were reported by 17%,[46] 46%,
[47] 22%,[48] and 37%.[49]
Patients treated with insulin have higher self-reported rates of hypoglycemia. Studies
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conducted in this population commonly asked patients treated with insulin for ≥1 year about
hypoglycemic events in the preceding 12 months. Self-reported severe hypoglycemia,
defined by requiring third party assistance, was reported by 4% (interview of 1667 patients
in the Netherlands; mean age 67.2 years, diabetes duration 11.5 years, using insulin for 4.6
years),[50] 15% (interview of 215 patients in Scotland; mean age 68 years, HbAlc 8.6%,
diabetes duration 13 years, using insulin for 4 years),[51] and 17% (survey completed by
401 patients in Denmark; mean age 66 years, HbA1c 8.3%, diabetes duration 15 years, using
insulin for 7 years) [52] of patients. Once again, non-severe hypoglycemic events were more
common, reported by 37% [50] and 64% of patients [51] in these studies.
More recently, the InHypo-DM Study of patient-reported hypoglycemia examined

hypoglycemia rates among patients treated with insulin and/or insulin secretagogues. An
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online survey was completed by 458 patients with self-identified type 2 diabetes (mean age
53.4 years, diabetes duration 10.0 years, HbA1c 7.1%) who reported taking insulin (34.7%),
insulin secretagogues (47.4%), or both (17.9%); it included questions about non-severe
(symptoms of hypoglycemia managed by the patient) and severe (symptoms requiring any
third party assistance) hypoglycemic events in the preceding 30 days and 12 months,
respectively. Non-severe hypoglycemia was reported by 54% of patients (12.1 events per
person year) and severe hypoglycemia was reported by 38% (2.5 events per person year).
[53]
Reliability of self-reported measures of hypoglycemia is contingent on confidence in

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patients’ hypoglycemia awareness, willingness to report events, and ability to differentiate

true hypoglycemia from pseudo-hypoglycemia. In a study of 6,273 insulin-treated adults
with type 2 diabetes (median age 58 years, diabetes duration 12 years, HbA1c 8.6%, using
insulin for 5 years) 48.1% of patients blood glucose <3.1 mmol/L (56 mg/dL) over a 4-week
period (1.6 events/patient/month). However, analysis of continuous glucose monitor data
revealed that in fact 95.3% had experienced episodes of hypoglycemia (2.4 events/patient/
month). Furthermore, just 1.7% were hospitalized for hypoglycemia during the 4-week
period (0.026 events/patient/month),[54] reinforcing the small fraction of hypoglycemic
events captured by hospitalization encounters.
Continuous glucose monitoring detects substantially more hypoglycemic events than

identified and reported by patients. This was demonstrated in the continuous glucose
monitor sub-study of the Treating to Target in Type 2 Diabetes Trial (4-T), where 106
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patients with insulin-dependent type 2 diabetes (mean age 61.8 years, diabetes duration 8.9
years, HbA1c 8.5%) underwent continuous glucose monitoring. During the 3-day study
period, 10% reported hypoglycemia with glucometer glucose <3.1 mmol/L (56 mg/dL), yet
continuous glucose monitor data showed that 42% had glucose ≤3.0 mmol/L (54 mg/dL) and
18% had glucose ≤2.2 mmol/L (40 mg/dL).[55] In another study of 108 patients with type 2
diabetes (both insulin and non-insulin treated), continuous glucose monitoring detected
glucose <70 mg/dL [3.9 mmol/L] in 49.1% of participants over 5 days (1.74 episodes/patient
per 5 days); 75% of those with hypoglycemia had at least one asymptomatic event.[56]
Despite its incompleteness, glucometer data is still informative, particularly as continuous
glucose monitors are used infrequently by patients with type 2 diabetes. In a study of 165
insulin-treated adults with type 2 diabetes (mean age 67, diabetes duration 18 years, HbA1c
7.6%) an electronic diabetes management system was retrospectively used to capture
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patients’ home glucometer data at the time of clinical encounters. Over a 3-months period,
19% of patients had episodes with glucose ≤45 mg/dL (2.5 mmol/L) and 82% with glucose
≤70 mg/dL (3.9 mmol/L), corresponding to annualized rates of 2.9 and 37 events/person-
year, respectively.[57]
Clinicians are often unaware of their patients’ hypoglycemic events, potentially due to
patient reluctance to report events and lack of direct questioning about hypoglycemia in
between and during clinical encounters. Patients may underreport report hypoglycemia due
to fear of repercussions such as loss of driving privileges.[58] In a Japanese web survey of
230 insulin-treated adults with type 2 diabetes (mean age 55 years, diabetes duration 15
years), 90% of respondents reported at least one episode of non-severe daytime
hypoglycemia and 34% reported at least one episode of non-severe nighttime hypoglycemia
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over the prior 3 months. However, only 60% of patients experiencing daytime hypoglycemia
and 42% experiencing nighttime hypoglycemia had notified their healthcare provider.[59] In
another online survey of 3,042 insulin-adults with type 2 diabetes (mean age 61 years,
diabetes duration 11 years, using insulin for 5 years) in the U.S., Canada, Japan, Germany,
UK, and Denmark, 36% endorsed non-severe (i.e. self-treated) hypoglycemia during the
preceding 30 days (3.1 events/person/30 days), but only 2% of those with hypoglycemia
were seen by their healthcare provider for it, 1% emailed their healthcare provider, 1% saw a
diabetes specialist, and fewer than 1% were evaluated in the emergency department.[60]
This has important research and clinical implications, because if patients do not report or
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discuss their hypoglycemic events with their healthcare providers, precipitating factors
cannot be identified, treatment is unlikely to be modified, and future hypoglycemic events
are less likely to be prevented.
Hypoglycemic events requiring emergency department care or hospitalization are, by

definition, most severe, as they represent the need for the highest level of medical assistance.
In a UK study of 17,604 sulfonylurea-treated patients (mean age 68 years, diabetes duration
1.6 years), there were 0.42/100 person-years hospitalizations for hypoglycemia.[61] In a
more recent U.S. study of 206,435 adults with type 2 diabetes (mean age 64; 35% treated
with sulfonylurea and 20% treated with insulin), the rate of emergency department visits or
hospitalizations for hypoglycemia was 0.49/100 person-years.[62] And in a German study of
29,485 sulfonylurea-treated patients (median age 71 years, diabetes duration 8.2 years),
which defined severe hypoglycemia more broadly as requiring external help, causing altered
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mental status or seizure, and/or requiring hospitalization, there were 3.9 severe
hypoglycemic events/100 patient-years.[63] In this study, severe hypoglycemia rates by
treatment regimen were, per 100 patient-years, 6.7 (sulfonylurea plus insulin), 4.9
(sulfonylurea plus insulin plus other non-insulin drug), 3.1 (sulfonylurea plus other non-
insulin drug) and 3.8 (sulfonylurea only).[63]
Despite the recent availability and use of new classes of glucose-lowering medications that
have a lower risk of hypoglycemia (e.g. glucagon-like peptide 1 (GLP-1) receptor agonists,
dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2)
inhibitors),[64] rates of severe hypoglycemia do not appear to be decreasing. In a claims-
based study of 1.66 million U.S. commercially-insured and Medicare Advantage
beneficiaries with type 2 diabetes, emergency department visits and hospitalizations for
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hypoglycemia remained stable at 1.3 events/100 person-years between 2006 and 2013.[65]
There was, however, marked variation in hypoglycemia rate as a function of patient age,
medications used, and comorbidity status. In 2016, patients aged ≥75 years experienced 2.3
events/100 person-years, compared to 1.3 events/100 person-years among patients aged
65-74 years, and 0.9 events/100 person-years among patients aged 45-64 years and 18-44
years. Patients with ≥2 comorbidities experienced 3.5 events/100 person-years, while
patients with one and no comorbid conditions had 1.1 and 0.4 events/100 person-years,
respectively. Patients treated with insulin or sulfonylurea experienced 2.0 events/100 person-
years, compared to 0.2 events/100 person-years among patients treated with other glucose-
lowering drugs. [65] Comparable rates were observed in a longitudinal study conducted in a
different patient population in the U.S., though that study included patients with both type 1
and type 2 diabetes.[66]
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There is limited data regarding diabetes management and hypoglycemia among people
living in long-term care facilities, despite their high clinical complexity and, presumably,
hypoglycemia risk. Approximately one third of nursing home residents in the U.S. have
diabetes[67]. In a cohort study of 200 patients ≥65 years (mean age 80 years) in two U.S.
skilled nursing facilities, the majority of patients were treated with hypoglycemia-prone
drugs: 71% were treated with insulin, 15.5% with insulin and non-insulin drugs, and 13.5%
with only non-insulin drugs; 78% of the non-insulin drugs were sulfonylureas. During up to
30 days of observation, 38% of patients in the study experienced events with glucose <70
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mg/dL (3.9 mmol/L; 3.4% of patient-days) and 3.5% with glucose <40 mg/dL (2.2 mmol/L;
0.1% of patient-days).[68] Hypoglycemia rates were similar among patients treated with
insulin and non-insulin mediations. Two other studies that focused on nursing home
residents in the U.S. [69] and India [70] demonstrated comparable rates of hypoglycemia.
Risk Factors for Hypoglycemia

Precipitating events for hypoglycemia are rarely ascertained, documented, and reported in
the literature. In a UK online survey of 1,329 adults with type 2 diabetes (mean age 58.8
years, diabetes duration 9.6 years, HbA1c 7.3%, 76.2% treated only with non-insulin
medications) most hypoglycemic events were ascribed to dietary factors: delayed meals
(29%), irregular or inadequate carbohydrates (25%), or skipped meals or snacks (20%).[71]
Other commonly cited factors were excessive physical activity (16%) and stress (13%).
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Medication misadventures were implicated less often; 10% of patients blamed a

miscalculated insulin dose and 5% a newly started glucose-lowering medication. [71]
Similar factors were cited by participants in the ACCORD trial, including delayed or missed
meals (31% of patients in the intensive treatment arm and 44% of patients in the standard
treatment arm), eating fewer carbohydrates than usual (26% and 25%, respectively), more or
unplanned exercise (15% and 12%, respectively), use of more insulin than prescribed or
usually administered (5% and 7%, respectively), and illness (4% and 3%, respectively).[72]
In the SAVOR-TIMI 53 trial of saxagliptin therapy, there was an identifiable precipitant in
47.3% of hypoglycemic events in the saxagliptin arm and 48.4%in the placebo arm,
including illness (2.5 % and 3.1%, respectively), overdose of hypoglycemic agent (9.8% and
7.8%, respectively), and missed meals (50.7% and 48.7%, respectively).[73]
The risk of hypoglycemia in type 2 diabetes is influenced by many patient- and treatment-
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related factors (Figure 1). One of the strongest predictors of future hypoglycemia is history
of prior hypoglycemia, both severe and non-severe.[74, 45, 62, 75] A large U.S. claims-
based case control study of adults with type 2 diabetes found that an emergency department
visit for hypoglycemia within prior 180 days increased the risk of subsequent hospitalization
for hypoglycemia by 9.5-fold.[76] In a U.S. claims-based cohort study, history of an
ambulatory visit for hypoglycemia increased the risk of subsequent hypoglycemia requiring
emergency department or hospital care by 3-fold.[77] Similarly, in the prospective Fremantle
Diabetes Study, the risk of ambulance use, emergency department care, or hospitalization for
hypoglycemia during 6.4 years of follow-up increased more than 6-fold with prior history of
severe hypoglycemic events.[78]
A strong and potentially modifiable risk factor for hypoglycemia is the choice of
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glucoselowering therapy, with insulin or insulin secretagogues (e.g. sulfonylureas and

meglitinides) posing the highest risk.[44, 65, 66, 79, 74, 80] In the ORIGIN trial, the risk of
severe hypoglycemia increased 2-fold with sulfonylureas and 4.5-fold with insulin.[81] In
observational studies, the risk of severe hypoglycemia was increased 2- to 3-fold with
sulfonylureas [76–78] and 3- to 4-fold with insulin [77, 78]. The risk of hypoglycemia is
highest with prolonged insulin use, as demonstrated by a UK study that prospectively
quantified rates of hypoglycemia (glucose <54 mg/dL [3.0 mmol/L]) in sulfonylurea- and
insulin-treated adults over a 9-12 months observation period.[82] Rates of severe

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hypoglycemia requiring third party assistance were 10/100 person-years among

sulfonylurea-treated patients (mean age 60.8 years, diabetes duration 6 years, HbA1c 7.5%)
and patients treated with insulin for <2 years (mean age 59.7 years, diabetes duration 7
years, HbA1c 7.4%), and 70/100 person-years among patients treated with insulin >5 years
(mean age 62.4 years, diabetes duration 14.2 years, HbA1c 7.7%). Non-severe events were
more common: 192/100 person-years, 408/100 person-years, and 1020/100 person-years
among patients treated with sulfonylurea, insulin <2 years, and insulin >5 years,
respectively. At the same time, 7-day CGM detected interstitial glucose <40 mg/dL (2.2
mmol/L) in 14% of sulfonylurea-treated patients (0.25 event/person/week), 13% of patients
treated with insulin for <2 years (0.29 event/person/week), and 26% of patients treated with
insulin for >5 years (0.73 event/person/week)[82]. In the Fremantle Diabetes Study, the risk
of severe hypoglycemia requiring ambulance, emergency department, and hospital care
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increased by 42% with each additional year of insulin therapy.[78] Still, glucose-lowering
polypharmacy in high risk patients (e.g. the elderly or those with multiple comorbidities) can
lead to hypoglycemia even without the use of sulfonylurea or insulin.[5, 77, 78, 83]
Importantly, while sulfonylurea and insulin medications do carry the highest risk of
hypoglycemia, they can be used safely and should not be avoided if clinically necessary.
Indeed, patients may be limited to using insulin or sulfonylurea drugs for a variety of clinical
and non-clinical reasons, including intolerance or contraindication to other medications or
cost considerations. Metformin is the only generic medication at low risk for hypoglycemia
that is part of the World Health Organization list of essential medicines and available
through low cost generic drug programs in the U.S.[84], together with human insulin and
sulfonylureas. If patients do not tolerate metformin, have contraindications for its use, or
metformin monotherapy is not sufficient, sulfonylureas and insulin may be the only
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affordable treatment options.
Other commonly cited risk factors for hypoglycemia in type 2 diabetes include older age, [5,
57, 65, 66, 79, 83, 85, 86] longer duration of diabetes, frailty, and multimorbidity. The
chronic health conditions most often implicated in increasing hypoglycemia risk are kidney
disease,[5, 66, 74, 76, 78, 85] cognitive impairment, [81, 87–89] cardiovascular disease,[66,
77] depression,[66, 79] and heart failure.[66, 77, 79] Post-hoc analyses of both ACCORD
and ADVANCE found a direct association between hypoglycemia risk and rising serum
creatinine.[5, 85] Furthermore, in the ADVANCE trial, history of microvascular disease was
the strongest predictor of hypoglycemia (HR 2.62), with greater impact on hypoglycemia
than allocation to the intensive treatment arm (HR 1.86) or use of ≥2 glucose-lowering
medications (HR 1.79)[5], Impaired hypoglycemia awareness, which affects up to 10% of
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insulin-treated patients with type 2 diabetes, further increases the risk of hypoglycemia by
nearly five-fold.[90]
Social determinants of health also contribute to hypoglycemia risk, including food

insecurity,[91–93] socioeconomic deprivation, and poor health literacy.[19] A population-
based study in California, which included all adults with diabetes as it could not subset
patients by diabetes type, found that hospitalizations for hypoglycemia were much more
common among lower income adults (0.27 events/100 person-years) compared to higher
income adults (0.20 events/100 person-years). Furthermore, lower-income, but not higher-
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income, adults experienced a 27% increase in hypoglycemia admissions in the last week of
the month (period of greater food insecurity and financial hardship) compared to the first.
[91] Even among commercially-insured adults, patients with diabetes (once again, not subset
by diabetes type) earning less than the median household income had a significantly higher
rate of emergency department visits and hospitalizations for hypoglycemia than higher
income patients (0.20 events/100 person-years vs. 0.15 events/100 person-years), with
greatest probability of events during the last week of the month.[94] There have been no
studies of food insecurity exclusively in type 2 diabetes. Several studies also found increased
risk of hypoglycemia among racial/ethnic minorities, particularly African Americans,[77,
85, 86, 95, 96] though this may be confounded by differences in access to healthcare, food
insecurity, and financial burden –factors that are known to increase hypoglycemia risk yet
are poorly ascertained in many research studies.
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An often overlooked hypoglycemia risk factor is fasting, whether planned or unplanned.

Continuing to take glucose-lowering medications while fasting for medical tests or
procedures can lead to hypoglycemia.[97] Patients who observe Ramadan are at increased
risk for hypoglycemia while fasting, particularly when treated with insulin or sulfonylurea
drugs.[98–100]
The association between HbA1c and hypoglycemia risk is complex, partly because HbA1c
reflects the average glycemic control over a 3 month period and does not convey glycemic
variability and excursions. Recent studies have suggested that low HbA1c may predict
hypoglycemia risk in type 1 but not type 2 diabetes.[101] While hypoglycemia rates were
higher among patients with type 2 diabetes achieving low HbA1c targets with intensive
glucose-lowering therapy in the ADVANCE,[30] ACCORD,[31] and VADT[32] trials, these
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episodes may be the result of intensive treatment and polypharmacy rather than low
glycemic levels themselves.[5] In a survey of patients with diabetes, the relationship
between HbA1c and severe hypoglycemia was U-shaped, and the association became less
significant once other key patient- and treatment-related factors were taken into
consideration (specifically: patient age, sex, comorbidities, polypharmacy, diabetes
medications used, history of prior hypoglycemia).[20] In the UKPDS trial, hypoglycemia
was more common at lower HbA1c levels among patients treated with metformin or
sulfonylureas, and at higher HbA1c levels among patients treated with insulin.[28] In most
studies, however, the risk of hypoglycemia increased progressively with higher, not lower,
HbA1c.[5, 78, 85]
Preventing Hypoglycemia
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Preventing hypoglycemia is a priority for patients, healthcare providers, and policy makers.
[102] Diabetes agents and iatrogenic hypoglycemia are part of the U.S. Department of
Health and Human Services Adverse Drug Event Action Plan. These initiatives may provide
counterbalance to existing incentives and performance metrics rewarding intensive glycemic
control and low HbA1c targets. Incorporation of patient-reported outcomes into diabetes
management and use of individualized glycemic targets can further raise awareness about
hypoglycemia and align financial incentives with patient safety.[103]
The first step in preventing hypoglycemia is identifying patients at highest risk for these
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events, engaging them in conversation about contributing and/or exacerbating factors, and
identifying strategies to mitigate these risks (Figure 2). Through shared decision-making,
patients and clinicians can apply scientific evidence regarding the benefits and risks of
glucose-lowering therapy to each patient’s unique circumstance, context, and preferences for
care.[104] Clinical decision support tools can facilitate this process by integrating a variety
of data sources to compute an individualized hypoglycemia risk and alert providers when an
intervention may be necessary.[105, 106] Ideally, clinical decision support tools would also
guide interventions, signaling need to change or de-escalate glucose-lowering therapy,
and/or make appropriate referrals.[107]
Two recently published hypoglycemia prediction models can help identify at-risk patients.
[62, 108] Developed and validated in different populations, these models were reliable,
accurate, and efficient. The model proposed by Karter and colleagues stratifies patients with
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type 2 diabetes on the basis of their 12-months risk for hypoglycemia-related utilization
(emergency department use, hospitalization) and is predicated on 6 variables: total number
of prior hypoglycemia-related emergency department visits or hospitalizations, number of
emergency department visits for any cause in the prior year, insulin use, sulfonylurea use,
presence of stage 4 or 5 chronic kidney disease, and age ≥77 years.[62] Schroeder and
colleagues developed two models, a marginally more accurate 16 variable model and a
parsimonious 6 variable model, to predict emergency department use or hospitalization for
hypoglycemia over 6 months among adults with type 1 or type 2 diabetes. The 6-variable
model includes patient age (U-shaped relationship), diabetes type (nearly doubled risk with
type 1 diabetes), HbA1c (U-shaped relationship), creatinine clearance (small increase in risk
with worse renal function), severe hypoglycemia within the prior year (4-fold higher risk),
and insulin use (2.3-fold higher risk).[108]
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While clinical practice guidelines recommend raising glycemic targets for patients at high
risk for hypoglycemia,[17] this strategy alone may not be sufficient.[109, 110] A more
effective approach may be to proactively de-intensify treatment regimens of overtreated
patients.[111, 112] Potential overtreatment of adults with type 2 diabetes is common,
including among older adults, patients with advanced kidney disease and dementia, and
patients with high clinical complexity.[83, 113–115] These patients are at highest risk for
hypoglycemia, yet because of their multi-morbidity and limited life expectancy they also
derive less benefit from intensive glycemic control. De-escalation of glucose-lowering
therapy, simplification of treatment regimens, and preferential use of medications with lower
risk of hypoglycemia may moderate their risk of hypoglycemia, reduce polypharmacy and
burden of treatment, and improve quality of life.[111, 112]
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Indeed, change of glucose-lowering therapy, if clinically and logistically feasible, may be the
simplest way to lower hypoglycemia risk. For example, patients with chronic kidney disease
are at high risk for hypoglycemia,[5, 66, 74, 76, 78, 85] yet are often treated with insulin or
sulfonylureas as both are approved for use with estimated glomerular filtration rate (eGFR)
<15 mL/min/1.73m2. However, other glucose-lowering medications may also be considered
in the setting of renal impairment, which may lower the patients’ hypoglycemia risk.
Metformin may be used, at reduced doses, as long as eGFR is above 30 mL/min/1.73m2.
DPP-4 inhibitors may be used at reduced doses with eGFR <30 mL/min/1.73m2 and GLP-1
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receptor agonists can be used without dose reduction as long as eGFR is above 15 mL/min/
1.73 m2 (except for liraglutide and dulaglutide, where there is limited evidence for use at
lower eGFR, and lixisenatide, which may be considered even with eGFR 15-29 mL/min/
1.73m2). SGLT-2 inhibitors are contraindicated in patients with eGFR<30 mL/min/1.73m2
and caution is advised during use in patients with moderate kidney disease (eGFR 30-45
mL/min/1.73m2) due to limited data supporting safety and efficacy in this population.[116]
Still, in clinical practice, access to these medications may be limited by financial
considerations and formulary restrictions, which would need to be addressed as part of a
systems-wide effort to promote safe, effective, and equitable diabetes care.
Engagement and coordination of multi-disciplinary clinical teams may also improve diabetes
management and reduce hypoglycemia risk (Figure 2). Patients experiencing or at risk for
hypoglycemia may benefit from diabetes self-management education focused on glucose
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monitoring, medication management, recognition of precipitating events, and treatment of

hypoglycemia. Training in hypoglycemia awareness, though studied primarily in patients
with type 1 diabetes,[117] may benefit patients with type 2 diabetes and hypoglycemia
unawareness. While continuous glucose monitoring can help patients identify asymptomatic
or undetected hypoglycemic events, and they are approved for patients with type 2 diabetes
on the basis of lowering HbA1c,[118] evidence for hypoglycemia reduction with continuous
glucose monitoring in type 2 diabetes (in contrast to type 1 diabetes) is inconsistent.[118–
122] Dieticians can help address hypoglycemia related to dietary miscalculations, while
mental health professionals can focus on diabetes distress, fear of hypoglycemia, and
treatment burden. Patients with complex treatment regimens may benefit from pharmacist
engagement to identify safer, simpler, or more affordable treatment options. While
pharmacist-led interventions have not been studied in relation to hypoglycemia, there is
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evidence for improved HbAlc, medication adherence, and access to care[123]. Finally, real-
time integration of patient-generated glycemic data and self-reported events into the
electronic health record for clinical review, followed by bidirectional flow of information
between the clinical setting and the patient’s home, may help identify, treat, and ultimately
prevent hypoglycemic events. In a pilot study, real-time evaluation of blood glucose data
obtained using a connected glucometer by a diabetes educator lowered the probability of
hypoglycemia (glucose <70 mg/dL [3.9 mmol/L]) by 18%.[124]
Provider awareness of the patient’s situation is also necessary to gauge hypoglycemia risk
and identify strategies to reduce it. This includes cultural practices, eating and physical
activity habits, and socioeconomic realities. For instance, fasting increases the risk for
hypoglycemia during a predefined time period, and proactive focused patient education and
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treatment modification may reduce this risk ahead of medical tests or procedures [97] and
during Ramadan.[125] Community health workers show promise in improving diabetes
management in immigrant groups,[126, 127] though their impact on hypoglycemia has not
been assessed. Similarly, enhancing financial and social support may help lower
hypoglycemia risk in vulnerable patients. In a study of commercially-insured people with
diabetes, the end-of-month increase in emergency department visits and hospitalizations for
hypoglycemia that was likely driven by food insecurity was lessened by an increase in
Supplemental Nutrition Assistance Program benefits,[94] reinforcing access to food as an
important component of diabetes management. Enhancing caregiver support and supervision

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can also help, particularly if patients need assistance with food preparation, medication
administration, and treatment of hypoglycemia before it becomes very severe. Identifying
these non-clinical factors, engaging patients and social support networks, and
acknowledging the realities of each patient’s situation are important aspects of patient-
centered diabetes care that need to be evaluated in prospective studies and, if successful,
implemented into practice.
CONCLUSIONS
Many patients with type 2 diabetes experience hypoglycemia, increasing their risk of
adverse health outcomes including death, high costs, and impaired quality of life. Yet, few
events are brought to medical attention or elicited by healthcare providers, which hinders
identification of precipitating and contributing causes and, ultimately, prevention of future
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hypoglycemic events. Understanding, managing, and preventing hypoglycemia is

particularly important for patients with type 2 diabetes, whose risk may be lessened through
use of safer treatment regimens. Furthermore, evidence demonstrating benefits of intensive
glucose-lowering therapy is weaker and less consistent for type 2 diabetes compared to type
1 diabetes, whereas the risk of hypoglycemia is often increased due to older age and higher
comorbidity burden.
Prospective clinical trials focused specifically on reducing hypoglycemia among high risk
patients with type 2 diabetes are needed. There are several barriers to such trials, including
heterogeneity of hypoglycemia risk and risk factors, need for different interventions at
varying points in time and contexts, and lack of consensus about how hypoglycemia is
defined, measured, and recorded. Both interventional and non-interventional studies should
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be encouraged to use standard definitions of hypoglycemia and to ascertain/report

hypoglycemia in all trials that enroll patients with diabetes. Healthcare providers should ask
patients about their experience of hypoglycemia, how this hypoglycemia is detected and
managed, and what events predated or precipitated its occurrence. This information, and
glycemic data from patient devices and diabetes technologies, can then be incorporated into
the electronic health record to facilitate hypoglycemia detection, management, and
prevention strategies. Finally, both clinical guidelines and quality/accountability measures
need to reflect the importance of hypoglycemia in the management of diabetes and to
consider patients’ treatment goals and anticipated benefits and harms of treatment.[103]
Patient-centered diabetes care is predicated on identifying and promoting safe and effecting
treatment strategies that minimize patient burden, improve quality of life, and reduce risks of
both immediate and long-term complications. Addressing hypoglycemia by leveraging
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advances in diabetes technologies, patient engagement, multi-disciplinary team-based care,

and alignment of reimbursement and policy decisions is an essential part of this effort.
ACKNOWLEDGMENTS
We sincerely appreciate the valuable contributions of Nataly R. Espinoza Suarez, MD for her work on study
screening and review. We further extend a sincere thank-you to Patricia J. Erwin, MLS (Mayo Clinic Library) for
assisting with the comprehensive literature search and to Bryce Bergene (Mayo Clinic Brand Strategy and Creative
Studio) for assisting with creation of the figure graphics.
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Funding
Dr. McCoy is supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care
Delivery and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of
Health under Award Number K23DK114497. The content is the solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes of Health.
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2017) two risk models predicting the 6-months risk of hospitalization or emergency department
visit for hypoglycemia for adults with diabetes (did not differentiate by diabetes type). The full
model, which included 16 variables, slightly outperformed the simplified model with six
variables. The full model was comprised of patient age, race/ethnicity, diabetes type (type 1 or 2),
body mass index, HbA1c, estimated glomerular filtration rate (eGFR), any hospitalization in past
year, any emergency department visit in past year, severe hypoglycemic event in past year,
retinopathy, cardiovascular disease, depression, heart failure, insulin, metformin, number of
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classes of glucose lowering medications. The simplified model was comprised of patient age,
diabetes type, HbA1c, eGFR, history of a hypoglycemic event in the prior year, and insulin use
109*. Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Liberating A1C goals in older
adults may not protect against the risk of hypoglycemia. J Diabetes Complications. 2017;31(7):
1197–9. doi:10.1016/j.jdiacomp.2017.02.014. [PubMed: 28343792] While diabetes management
guidelines and expert consensus recommend that glycemic targets of patients at high risk for
hypoglycemia be relaxed in order to prevent future hypoglycemic events, this study demonstrates
that such an approach may not be sufficient. In this prospective study, the frequency of
hypoglycemic events was monitored by continuous glucose monitoring (CGM) among older
adults treated with multiple daily insulin injections or basal insulin with non-insulin agents who
had different HbA1c treatment targets. The duration of hypoglycemia was not different between
the HbA1c groups, regardless of treatment intensity, demonstrating that higher HbA1c goals may
not protect against hypoglycemia
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111**. Sussman JB, Kerr EA, Saini SD, Holleman RG, Klamerus ML, Min LC et al. Rates of
Deintensification of Blood Pressure and Glycemic Medication Treatment Based on Levels of
Control and Life Expectancy in Older Patients With Diabetes Mellitus. JAMA Intern Med.
2015:1–8. doi:10.1001/jamainternmed.2015.5110.This study demonstrates that deintensification
of potentially overtreated older adults with diabetes does not occur often in routine clinical
practice (this study was conducted in the US Veterans Health Administration), but when it does,
treatment deintensification is safe as it does not result in a clinically significant or concerning rise
in HbA1c. Glucose-lowering therapy was deintensified among 27% of patients with HbA1c
<6.0%, 21% of patients with HbA1c 6.0-6.4%, and 18% of patients with HbA1c ≥6.5%,
demonstrating the remaining opportunities for individualizing and improving the diabetes care
among older adults at risk for hypoglycemia
112*. Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Simplification of Insulin
Regimen in Older Adults and Risk of Hypoglycemia. JAMA Intern Med. 2016;176(7):1023–5.
doi:10.1001/jamainternmed.2016.2288. [PubMed: 27273335] In this single-arm intervention
study, Munshi and colleagues simplified insulin regimens of 65 older adults with type 2 diabetes
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who, at baseline, were treated with ≥2 insulin injections per day or with any hypoglycemia on
baseline 5-day continuous glucose monitor assessment. Simplification to basal insulin with or
without noninsulin agents resulted in reduction in hypoglycemia, reduction in diabetes distress
symptoms, reduction of HbA1c among patients with baseline HbA1c ≥8%, and slight increase in
HbA1c among patients with baseline HbA1c <7.0%. This demonstrates the importance of
treatment simplification and deintensification among older adults not only to reduce
hypoglycemia, but also improve quality of life and attain safe glycemic targets appropriate for
patient age
113. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes
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Figure 1. Risk factors for hypoglycemia among patients with type 2 diabetes.
DSME, diabetes self-management education. EHR, electronic health records. HbA1c,
hemoglobin A1c. PROs, patient-reported outcomes.
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Figure 2. Strategies to reduce hypoglycemia risk among patients with type 2 diabetes.
DSME, diabetes self-management education. EHR, electronic health records. HbA1c,
hemoglobin A1c. PHR, patient health records. PROs, patient-reported outcomes.
Author Manuscript

Hipoglucemia en DM2 2019

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Hypoglycemia among Patients with Type 2 Diabetes:

González”, Universidad Autonoma de Nuevo Leon, Monterrey, 64460, México

Summary: Hypoglycemia among patients with type 2 diabetes is common. Patient-centered

American Diabetes Association (ADA) has defined confirmed hypoglycemia as

mmol/L); and reaffirmed severe hypoglycemia as the presence of severe cognitive

Research studies generally focus on either documented hypoglycemia (confirmed by a

are validated claims-based algorithms to identify hypoglycemic encounters using ICD-9[22]

All of these approaches to identifying hypoglycemic events have limitations. Self-report of

Frequency of Hypoglycemia in Randomized Controlled Trials

cardiovascular and all-cause mortality,[31] thereby raising awareness of potential risks

mg/dL (3.9 mmol/L) in 27.9% of empaglifozin-treated patients (vs. 27.8% in placebo

Frequency of Hypoglycemia in Real-World Studies

often culminates in hospital admission.[19–21]

More recently, the InHypo-DM Study of patient-reported hypoglycemia examined

Reliability of self-reported measures of hypoglycemia is contingent on confidence in

patients’ hypoglycemia awareness, willingness to report events, and ability to differentiate

Continuous glucose monitoring detects substantially more hypoglycemic events than

Hypoglycemic events requiring emergency department care or hospitalization are, by

Risk Factors for Hypoglycemia

Medication misadventures were implicated less often; 10% of patients blamed a

glucoselowering therapy, with insulin or insulin secretagogues (e.g. sulfonylureas and

insulin-treated adults over a 9-12 months observation period.[82] Rates of severe

hypoglycemia requiring third party assistance were 10/100 person-years among

affordable treatment options.

Social determinants of health also contribute to hypoglycemia risk, including food

An often overlooked hypoglycemia risk factor is fasting, whether planned or unplanned.

monitoring, medication management, recognition of precipitating events, and treatment of

important component of diabetes management. Enhancing caregiver support and supervision

hypoglycemic events. Understanding, managing, and preventing hypoglycemia is

be encouraged to use standard definitions of hypoglycemia and to ascertain/report

advances in diabetes technologies, patient engagement, multi-disciplinary team-based care,

1897–901. doi:10.2337/dc11-2054. [PubMed: 22699297] This study demonstrated that patient

1998;352(9131):854–65. [PubMed: 9742977]

10.1056/NEJMoa1509225. [PubMed: 26630143]

10.1016/j.diabres.2017.01.022. [PubMed: 28750219]

2017;31(6):1047–52. doi:10.1016/j.jdiacomp.2016.12.014. [PubMed: 28389158]

Intern Med. 2016 7 1;176(7):969–78. doi: 10.1001/jamainternmed.2016.2275. [PubMed:

0000000000000728. [PubMed: 28481762] In this nationwide US study, conducted among

jamainternmed.2016.5046. [PubMed: 27653613]

Intern Med. 2017;167(6):365–74. doi:10.7326/M16-2855. [PubMed: 28828487]

Therapy. 2017;8(1):55–73. doi:10.1007/s13300-016-0223-6. [PubMed: 28000140]

127. Perez-Escamilla R, Damio G, Chhabra J, Fernandez ML, Segura-Perez S, Vega-Lopez S et al.

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