Hypoglycemia
Introduction
Hypoglycemia is the rate-limiting factor when treating people with diabetes. Most often hypoglycemia is from diabetes medications. Careful review of the person’s daily schedule (meals and activity) can also assist in figuring out the etiology of hypoglycemia. The primary care clinician should be comfortable assessing for hypoglycemia and be able to help patients prevent these episodes. Further, helping the patient address both symptomatic hypoglycemia and severe hypoglycemia are critical skills for people with diabetes.
Case 1. Reactive Hypoglycemia
“I need to eat, so I do not drop low.”
A 43-year-old woman with no diabetes history presents complaining of low blood sugars. Over the last few months, she has been having episodes of feeling shaky, lightheaded, and sweaty after she eats. At first this was uncommon, happening every few weeks but it is occurring more frequently now. Over the last month she has had them several times per week. Usually, they happen 1 to 2 hours after eating. The spells are more likely to occur when she eats rice or pasta. If she eats something sweet when she feels one coming on, she will feel better. She does not have a glucometer, but her friend checked her glucose once during one of the spells and the reading was 64 mg/dL. She is afraid to drive because she is worried that these spells will cause her to pass out.
Med HX: prediabetes, dyslipidemia
Medications: none and no OTC (over-the-counter) supplements or vitamins
Allergies: none
Family Medical History: mother, brother, and maternal grandmother have type 2 diabetes; dad died from a heart attack
Social History: lives with her spouse and two children; works as an administrator; no tobacco use; drinks wine with dinner most nights per week; walks the dog daily morning and evening
Physical Exam: Ht. 5′4″, Wt. 154 lb, BMI 26.4, P 84, R 14, BP 132/74
GEN: in no distress
HEENT: normal including thyroid exam
CV: normal
RESP: normal
Otherwise: normal exam
Labs: all normal except HbA1c 5.9%
CASE QUESTIONS1. Is she becoming hypoglycemic?
View Answer
1. Hypoglycemia is typically defined in diabetes as a glucose level below 70 mg/dL. The complete definition of hypoglycemia is the triad of (1) signs and symptoms of hypoglycemia; (2) a blood glucose measured to be low; and (3) resolution of those symptoms with treatment.1 Innate counterregulatory physiologic responses start at a glucose level of 70 mg/dL to protect from further drops in blood sugar. Progressive hypoglycemia below this threshold poses an increased health risk for the person.2,3
People without any glucose or insulin abnormalities can have glucose readings in the 60s mg/dL, particularly at night.4 This is because physiologic glucose management during fasting and while asleep is a balance between hepatic glucose release and pancreatic insulin production. Typically, the liver generates just enough glucose to meet the basal metabolic needs of the body (primarily the brain) and pancreatic insulin production is just enough to assist in the cellular uptake of available glucose.
Symptomatic hypoglycemia is defined by Whipple triad: a measured glucose less than 55 mg/dL, typical signs and symptoms of hypoglycemia, and resolution of symptoms with normalization of glucose.1 Hypoglycemia is relatively uncommon in people who are not taking antidiabetic medications, as the body possesses multiple physiologic layers of defense to prevent hypoglycemia from occurring (Table 5.1). Ironically, the body has fewer defenses to prevent hyperglycemia. Symptomatic hypoglycemia, while very distressing for the patient, is rarely dangerous to someone who does not have diabetes. However, hypoglycemia can be immediately life-threatening.
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The patient presenting in this scenario has typical symptoms; however, it is necessary to confirm that she is indeed becoming hypoglycemic and identify a cause if possible.
2. How can we confirm that her episodes are as a result of hypoglycemia?
View Answer
2. There are many things other than hypoglycemia that could cause this patient’s symptoms (dysrhythmias, hypotension, seizures, etc). This patient’s fingerstick glucose helps to narrow our differential. Now we need to focus on her diagnosis.
These can be determined in several ways. Perhaps the simplest option would be to provide the patient with a glucometer and instructions to check glucose levels upon the occurrence of each “spell.” Another option is to have the patient use a CGM and maintain a log of when she is symptomatic. There are professional versions of CGM systems available that will allow the patient to continuously record 7 to 14 days of glucose readings that can either be downloaded or accessed remotely. This is particularly useful as it allows the physician to see if symptoms correspond in time with hypoglycemia. Alternatively, the patient could be asked to complete a glucose tolerance test.
If hypoglycemic episodes are found, the next step is to understand their relationship to eating. One way to further define hypoglycemia is by the time it occurs. Postprandial hypoglycemia is most likely to occur within 4 hours of ingestion of food. Postabsorptive hypoglycemia is hypoglycemia that occurs in the fasting state and is more likely to present while the person is sleeping (Figure 5.1).
This CGM download appears to show that this person is dropping low most often after eating. The hypoglycemic spells are relatively short-lived.
3. What causes these spells?
View Answer
3. People with prediabetes typically have insulin resistance and hyperinsulinemia. For many, the initial defect of glucose regulation is a blunted first-phase insulin response. The first-phase response is a rapid, short-duration release of insulin in response to an increase in serum glucose concentration. Subsequently, the initial blunted first-phase insulin release is followed by an exaggerated second phase of insulin release. The second-phase insulin response starts concurrently with first-phase response and typically reaches a plateau 2 hours after the initial rise in glucose. When this second phase of insulin release lasts longer than the glucose rise itself, the person is at risk for “reactive hypoglycemia.”
 FIGURE 5.1. CGM for postprandial hypoglycemia. |
4. How can the spells be prevented?
View Answer
4. In general, it is recommended that people with reactive hypoglycemia do the following:
Eat 3 to 5 small meals per day
Make sure each meal consists of mixed nutrients (carbohydrate/fat/protein) to allow for longer absorption times
Avoid simple carbohydrate ingestion alone, as carbohydrate-only meals induce significant insulin spikes leading to rapid glucose uptake followed by second-phase mismatches
Avoid intake of alcohol for similar reasons
While it is antidotal and off label, the use of DPP-4 inhibitors can help reduce the frequency and severity of these spells.
Finally, if the person has prediabetes, physical activity and weight loss (at least 5%) improve insulin sensitivity and reduce progression to type 2 diabetes and reduce risk of reactive hypoglycemia.7
ANSWERS AND EXPLANATIONS1. Hypoglycemia is typically defined in diabetes as a glucose level below 70 mg/dL. The complete definition of hypoglycemia is the triad of (1) signs and symptoms of hypoglycemia; (2) a blood glucose measured to be low; and (3) resolution of those symptoms with treatment.1 Innate counterregulatory physiologic responses start at a glucose level of 70 mg/dL to protect from further drops in blood sugar. Progressive hypoglycemia below this threshold poses an increased health risk for the person.2,3
People without any glucose or insulin abnormalities can have glucose readings in the 60s mg/dL, particularly at night.4 This is because physiologic glucose management during fasting and while asleep is a balance between hepatic glucose release and pancreatic insulin production. Typically, the liver generates just enough glucose to meet the basal metabolic needs of the body (primarily the brain) and pancreatic insulin production is just enough to assist in the cellular uptake of available glucose.
Symptomatic hypoglycemia is defined by Whipple triad: a measured glucose less than 55 mg/dL, typical signs and symptoms of hypoglycemia, and resolution of symptoms with normalization of glucose.1 Hypoglycemia is relatively uncommon in people who are not taking antidiabetic medications, as the body possesses multiple physiologic layers of defense to prevent hypoglycemia from occurring (Table 5.1). Ironically, the body has fewer defenses to prevent hyperglycemia. Symptomatic hypoglycemia, while very distressing for the patient, is rarely
dangerous to someone who does not have diabetes. However, hypoglycemia can be immediately life-threatening.
dangerous to someone who does not have diabetes. However, hypoglycemia can be immediately life-threatening.
|
The patient presenting in this scenario has typical symptoms; however, it is necessary to confirm that she is indeed becoming hypoglycemic and identify a cause if possible.
2. There are many things other than hypoglycemia that could cause this patient’s symptoms (dysrhythmias, hypotension, seizures, etc). This patient’s fingerstick glucose helps to narrow our differential. Now we need to focus on her diagnosis.
These can be determined in several ways. Perhaps the simplest option would be to provide the patient with a glucometer and instructions to check glucose levels upon the occurrence of each “spell.” Another option is to have the patient use a CGM and maintain a log of when she is symptomatic. There are professional versions of CGM systems available that will allow the patient to continuously record 7 to 14 days of glucose readings that can either be downloaded or accessed remotely. This is particularly useful as it allows the physician to see if symptoms correspond in time with hypoglycemia. Alternatively, the patient could be asked to complete a glucose tolerance test.
If hypoglycemic episodes are found, the next step is to understand their relationship to eating. One way to further define hypoglycemia is by the time it occurs. Postprandial hypoglycemia is most likely to occur within 4 hours of ingestion of food. Postabsorptive hypoglycemia is hypoglycemia that occurs in the fasting state and is more likely to present while the person is sleeping (Figure 5.1).
This CGM download appears to show that this person is dropping low most often after eating. The hypoglycemic spells are relatively short-lived.
3. People with prediabetes typically have insulin resistance and hyperinsulinemia. For many, the initial defect of glucose regulation is a blunted first-phase insulin response. The first-phase response is a rapid, short-duration release of insulin in response to an increase in serum glucose concentration. Subsequently, the initial blunted first-phase insulin release is followed by an exaggerated second phase of insulin release. The second-phase insulin response starts concurrently with first-phase response and typically reaches a plateau 2 hours after the initial rise in glucose. When this second phase of insulin release lasts longer than the glucose rise itself, the person is at risk for “reactive hypoglycemia.”
 FIGURE 5.1. CGM for postprandial hypoglycemia. |
4. In general, it is recommended that people with reactive hypoglycemia do the following:
Eat 3 to 5 small meals per day
Make sure each meal consists of mixed nutrients (carbohydrate/fat/protein) to allow for longer absorption times
Avoid simple carbohydrate ingestion alone, as carbohydrate-only meals induce significant insulin spikes leading to rapid glucose uptake followed by second-phase mismatches
Avoid intake of alcohol for similar reasons
While it is antidotal and off label, the use of DPP-4 inhibitors can help reduce the frequency and severity of these spells.
Finally, if the person has prediabetes, physical activity and weight loss (at least 5%) improve insulin sensitivity and reduce progression to type 2 diabetes and reduce risk of reactive hypoglycemia.7
Case Summary and Closing Points
In this case a person with prediabetes was experiencing postprandial hypoglycemia because of a mismatch between glucose absorption and insulin secretion. These types of episodes are often mild, but the symptom severity does not always match the level of the glucose. Assuming that there are no competing etiologies, this patient can be managed with lifestyle changes.
References
1. Whipple’s triad. Found in Melmed, S. Williams Text Book of Endocrinology. 13th ed. Elsevier; 2016:1582-1607. ISBN 978-0-323-29738-7.
2. 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(1):155-157. doi:10.2337/dc16-2215
3. Agiostratidou G, Anhalt H, Ball D, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a consensus report of the American association of clinical endocrinologists, the American association of diabetes educators, the American diabetes association, the endocrine society, JDRF International, the Leona M. and Harry B. Helmsley charitable trust, the pediatric endocrine society, and the T1D exchange. Diabetes Care. 2017;40(12):1622-1630. doi:10.2337/dc17-1624
4. Service FJ. Hypoglycemic disorders. NEJM. 1995;332(17):1114-1152.
5. Cryer PE. Hypoglycemia-associated autonomic failure in Diabetes. Am J Physiol Endocrinol Metab. 2001;281(6):E1115-E1121.
6. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902-1912. doi:10.2337/diacare.26.6.1902
7. The Diabetes Prevention Program (DPP) Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
Case 2. Defensive Eating
“I have to eat a snack between meals or I get shaky.”
A 67-year-old man is being seen for a diabetes recheck. He tells you he thinks things are going well. He has had diabetes for 6 years and has learned what he
must do to keep his readings in control. It is very important that he follows a strict daily schedule. For example, if he golfs longer than usual, or if he gets to lunch late, he can get shaky spells. He checks his glucose every morning; it is usually below 100 mg/dL. Recently he has had to increase from eating four to five meals per day to prevent these shaky spells.
must do to keep his readings in control. It is very important that he follows a strict daily schedule. For example, if he golfs longer than usual, or if he gets to lunch late, he can get shaky spells. He checks his glucose every morning; it is usually below 100 mg/dL. Recently he has had to increase from eating four to five meals per day to prevent these shaky spells.
Med HX: type 2 diabetes, dyslipidemia (6 years), hypertension (6 years)
Medications: metformin 1000 mg bid, glipizide 10 mg bid, basal insulin degludec 80 units in the evening
Allergies: none
Family Medical History: mother and sister with type 2 diabetes; dad with dyslipidemia and coronary artery disease
Social History: no tobacco, no alcohol, and no recreational drug use; lives with his spouse; likes to golf 3 to 4 times per week.
Physical Exam: Ht. 5′8″, Wt. 194 lb, BMI 29.5, P 84, R 14, BP 132/74
GEN: in no distress
HEENT: normal including thyroid exam
CV: normal
RESP: normal
Diabetes foot exam: pulses +2/2 bilateral, sensation decreased to first and second toes by monofilament, bunions noted to both great metatarsophalangeal joints.
Otherwise: normal exam
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HbA1c: 5.9%, no evidence of anemia or hemoglobinopathy.
CASE QUESTIONS1. Is he dropping low?
View Answer
1. A normal fasting blood sugar for someone with diabetes is 80 to 130 mg/dL (4.4-7.2 mmol/L).1 Based on his fasting fingerstick readings, he is hypoglycemic most mornings. It is important to recognize his symptoms are result of his current medication regimen.
2. What is causing the drops?
View Answer
2. This person is taking too much medication and is experiencing hypoglycemic episodes. Both glipizide (sulfonylurea) and degludec (basal insulin) can cause hypoglycemia. In fact, his basal insulin dose is quite high (>0.7 U/kg/d). We could consider him “overbasalized.” It is generally ill-advised to utilize sulfonylureas when patients are taking large insulin doses. It is important to note that some of the sulfonylureas are considered Beers list medications and should be avoided in elderly patients.2 While some of his glucose readings in the morning are ideal, it is highly likely that he is dropping low overnight, which in turn is leading to glucose variability in the morning. He is also experiencing what sounds like hypoglycemia during the day based on his reported “shaky spells.”
3. What are the common signs and symptoms of hypoglycemia?
View Answer
3. Hypoglycemia signs and symptoms can vary considerably between people and even within the same person. Therefore, it is important to ask patients and their family what signs and symptoms they notice with hypoglycemic episodes. Sometimes the patient’s family members will notice changes before the patient experiences symptoms. For this reason, if possible, it is important to obtain information from both the patient and their family (Table 5.2).
For most people, a combination of adrenergic and cholinergic symptoms will present first. Then, if the glucose continues to drop to the point that the brain does not have enough glucose to function, the person will develop neuroglycopenic symptoms. Neuroglycopenia refers to alteration of neuronal function in the brain because of a shortage of available glucose. Many people need assistance once the neuroglycopenic symptoms start.
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It is a good practice to ask patients about hypoglycemia at every visit and make sure that they:
know how to recognize it
know how to treat it
have the appropriate supplies
4. What can be done to prevent hypoglycemia in this patient?
View Answer
4. This patient needs both a reduction in medication and education about his own
safe glucose range. There are a couple of options to reduce his medication. Option one is to start withdrawing the sulfonylurea. This should be accomplished by stopping the nighttime dose first, as nocturnal hypoglycemia can be more dangerous. Then, if needed, we can stop the daytime dose as well. The second option is to reduce his basal insulin. We should reduce his dose at a minimum by 10%. However, considering how high his basal dose is, a 20% reduction is reasonable.
Patients are empowered when they participate in the decision-making process. Work with the patient by asking him which medication change he prefers. The main objectives are to help the patient himself become successful while safely managing his diabetes. This is a great opportunity to let the person know that sometimes it is better to reduce medication to enable flexibility in his schedule rather than forcing him to do “defensive eating” to prevent hypoglycemia.
ANSWERS AND EXPLANATIONS1. A normal fasting blood sugar for someone with diabetes is 80 to 130 mg/dL (4.4-7.2 mmol/L).1 Based on his fasting fingerstick readings, he is hypoglycemic most mornings. It is important to recognize his symptoms are result of his current medication regimen.
2. This person is taking too much medication and is experiencing hypoglycemic episodes. Both glipizide (sulfonylurea) and degludec (basal insulin) can cause hypoglycemia. In fact, his basal insulin dose is quite high (>0.7 U/kg/d). We could consider him “overbasalized.” It is generally ill-advised to utilize sulfonylureas when patients are taking large insulin doses. It is important to note that some of the sulfonylureas are considered Beers list medications and should be avoided in elderly patients.2 While some of his glucose readings in the morning are ideal, it is highly likely that he is dropping low overnight, which in turn is leading to glucose variability in the morning. He is also experiencing what sounds like hypoglycemia during the day based on his reported “shaky spells.”
3. Hypoglycemia signs and symptoms can vary considerably between people and even within the same person. Therefore, it is important to ask patients and their family what signs and symptoms they notice with hypoglycemic episodes. Sometimes the patient’s family members will notice changes before the patient experiences symptoms. For this reason, if possible, it is important to obtain information from both the patient and their family (Table 5.2).
For most people, a combination of adrenergic and cholinergic symptoms will present first. Then, if the glucose continues to drop to the point that the brain does
not have enough glucose to function, the person will develop neuroglycopenic symptoms. Neuroglycopenia refers to alteration of neuronal function in the brain because of a shortage of available glucose. Many people need assistance once the neuroglycopenic symptoms start.
not have enough glucose to function, the person will develop neuroglycopenic symptoms. Neuroglycopenia refers to alteration of neuronal function in the brain because of a shortage of available glucose. Many people need assistance once the neuroglycopenic symptoms start.
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