The pharmacist’s role in hypoglycemia in patients with diabetes treated with basal insulin

By Esmond Wong, RPh, CDE, APA

is a drug-induced side effect that is also affected by other factors such as food intake and physical activity.

Drug-induced hypoglycemia is both a barrier to achieving glycemic control in people with diabetes as well as an opportunity for pharmacists to help patients and reduce healthcare costs. Hypoglycemia as defined by the Diabetes Canada clinical practice guidelines is 1) the development of autonomic or neuroglycopenic symptoms; 2) a low plasma glucose level (<4.0 mmol/L for people with diabetes treated with insulin or an insulin secretagogue); and 3) symptoms responding to the administration of carbohydrate.(1) With people who have diabetes, hypoglycemia

The global Hypoglycemia Assessment Tool (HAT) study enrolled 27,000 people with diabetes treated on insulin around the world to study real-world rates of hypoglycemia.(2) The Canadian cohort enrolled 498 Canadians and found that over a four-week prospective period, 95.2% of people with type 1 diabetes and 64.2% of people type 2 diabetes (treated with insulin) experienced an episode of hypoglycemia. The Canadian cohort of the HAT study found hypoglycemia to be associated with higher work absenteeism, higher healthcare utilization and higher self-reported fear of hypoglycemia.

The pathophysiology of hypoglycemia

The brain’s preferred source of energy is glucose. Only four grams of glucose (less than a teaspoon) is dissolved in the blood of an average 70 kg human. Functional β cells are able to respond to fluctuating glucose by secreting or supressing insulin in seconds. This keeps blood glucose in a very tight range which is delicately balanced by functional β cells.(3)

Blood glucose levels dropping below 4.7 mmol/L will result in the suppression of insulin secretion. Below 3.8 mmol/L the body will start secreting counter regulatory hormones such as glucagon and epinephrine that oppose insulin action to raise sugars.(4) Glucagon can cause nausea and vomiting. Epinephrine can cause anxiety, sweating, trembling and palpitations (think fight or flight response). These are classified as autonomic symptoms. Below 2.8 mmol/L the brain starts running low on glucose and neuroglycopenic symptoms occur such as confusion, difficulty concentrating and difficult speaking.(1)

Pseudo-hypoglycemia is when a person experiences symptoms of hypoglycemia, but their blood glucose is above 4 mmol/L. This occurs in people who have had long-standing poor glycemic control so that their body is acclimatized to high blood glucose levels. Once their blood glucose trends to a normal range, their body sometimes interprets the normal blood glucose as hypoglycemia.(5) Hypoglycemia unawareness occurs after frequent episodes of hypoglycemia and the body loses the autonomic symptoms. This results in the first symptoms of hypoglycemia being confusion or unconsciousness.

(1) This is a dangerous situation as the person may not respond (or be unable to respond) appropriately to the hypoglycemia.

Some people are more prone to hypoglycemia than others. Elderly people are at higher risk especially if they have severe cognitive impairment. Hypoglycemia unawareness, long duration of insulin therapy, renal impairment, poor health literacy and food insecurity are also risk factors for hypoglycemia.(1) For adults experiencing hypoglycemia unawareness it is suggested that they are educated to how to avoid further episodes of hypoglycemia, have less stringent glycemic targets for three months if needed, increase the frequency of monitoring, or use a continuous blood glucose monitoring device.(1)

TABLE 1 Types of Hypoglycemia

The Diabetes Canada clinical practice guidelines classifies hypoglycemia into separate categories based on severity of symptoms:(1)

Mild hypoglycemia

Moderate hypoglycemia

When autonomic symptoms are present, and the person can still selftreat

When autonomic and neuroglycopenic symptoms are present, but the person can still self-treat

When the person requires assistance of another person. The person may be unconscious and blood glucose is typically below 2.8 mmol/L. Nocturnal hypoglycemia

Severe hypoglycemia

Hypoglycemia that occurs when the person is sleeping, with symptoms including nightmares, weird dreams and waking up in the middle of the night.

Adapted from the Diabetes Canada 2018 Guidelines(1)

Next (second)-generation basal insulins and their role in hypoglycemia prevention

Insulin is a protein that is active in its monomer form. An insulin monomer can quickly interact with an insulin receptor to facilitate glucose uptake from the blood into the cell. Monomers are quicky degraded in minutes by enzymes in the blood into amino acids which do not interact with the insulin receptor. However, an insulin monomer can combine with five other insulin monomers to form a hexamer. Hexamers are resistant to degradation by enzymes and are not as easily absorbed by cells. An ideal basal insulin will form stable hexamers which dissociate back into monomers at a regular rate with little variation and without a peak in activity over at least a 24-hour period.(6,7)

Second-generation basal insulins which include insulin degludec and insulin glargine U300 use novel mechanisms to create a longer duration of action that results in lower incidence of hypoglycemia than first generation basal insulin analogues such as insulin glargine U100 and insulin detemir. Insulin degludec uses a novel mechanism of protraction with phenol, zinc and an insulin analogue structure that forms hexamer chains. These hexamer chains are stable and disassociate back into monomers at a regular rate leading to less day-to-day variation and flatter action profile. Degludec has a duration of action of 42 hours.(5,6) Insulin glargine U300 utilizes a different mechanism of action than insulin degludec. By concentrating glargine, compact conglomerates of insulin are formed. Absorption is slowed because the surface area of the conglomerates on which absorption can occur is reduced and there is a greater distance from the conglomerate surface to capillaries.(8)

Studies have demonstrated the value of second-generation versus the first-generation basal insulins. A study compared glargine U300 vs glargine U100 in people with type 2 diabetes using oral antihyperglycemic drugs over a 12-month period. The researchers found that the people treated with glargine U300 had a 37% relative risk reduction in experiencing nocturnal hypoglycemia or severe hypoglycemia compared to glargine U100.(9)

The DEVOTE trial compared insulin degludec to insulin glargine U100 with a primary outcome of major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and a secondary outcome of severe hypoglycemia. The study found insulin degludec and insulin glargine U100 had similar rates of major cardiovascular events. However, the rate of severe hypoglycemia was significantly lower in the insulin degludec group. The rate of severe hypoglycemia was 3.70 events per patient-years in the insulin degludec group and 6.2 events per 100 patient-years in the insulin glargine U100 group. This is despite the reduction in A1c being similar in both groups.(10)

The BRIGHT study was a head-tohead trial comparing insulin degludec with insulin glargine U300 in 929 patients with type 2 diabetes who were insulin naïve. The primary end point was A1c change with rates of hypoglycemia as a safety endpoint. Participants were randomized 1 to 1 to receive either degludec or insulin glargine U300 which was self-administered by the patient. The primary end point showed comparable reductions in A1c. The mean A1c of the group assigned to insulin degludec was 8.7% which came down to 7% by the end of the study. The mean A1c of the group assigned to insulin glargine U300 was 8.6% which came down to 7% by the end of the study. The researchers concluded that the A1c reduction was comparable for both of the insulins. The incidence of confirmed hypoglycemia (at any time of day [24 h]) was comparable for both insulins, 66.5% for insulin glargine U300 and 69% for insulin degludec. The incidence of nocturnal hypoglycemia was also comparable for both insulins, 28.6% for insulin glargine U300 and 28.8 for insulin degludec.(11)

The pharmacist’s role in screening hypoglycemia

There are several interventions that pharmacists can perform to reduce the burden of hypoglycemia for patients. Most important is to ask patients with diabetes if they have experienced symptoms of hypoglycemia, especially if they are using sulfonylureas (SU) and/ or insulin. The question can be as simple as: “Hello Mr. Smith, I notice you are on the insulin A and/or pill B (sulfonylurea), these medications can cause low blood sugars which can present as dizziness, weakness, trembling or sweating. Have you experienced any of those symptoms?” An alternative could be: “Hello Mr. Smith, I notice you are on the insulin X and/or pill Z (sulfonylurea), these medications can cause low blood sugars. Have you noticed any of your blood glucose readings dipping below 4 mmol/L lately?”

There is no official way to screen for hypoglycemia mentioned in the Diabetes Canada clinical practice guidelines, so pharmacists are encouraged to personalize their approach and be consistent about asking patients using insulin and/or SU. The Canadian cohort of the HAT study found that the majority of patients using insulin did experience hypoglycemia in a four-week period so the majority of your patient’s using insulin and/or SU are also likely experiencing hypoglycemia.(2)

Newer Technologies

New technology in blood glucose monitoring can help patients and pharmacists detect hypoglycemia. In 2021 there was an update to the blood glucose monitoring section of the Diabetes Canada clinical practice guidelines with new definitions. See Table 2.

There are now ways for pharmacists to remotely track their patients’ blood glucose levels to provide timely feedback on blood glucose excursions. Pharmacists can create a healthcare professional account on websites like LibreView (https://www.libreview.com/), Dexcom Clarity (https://clarity.dexcom.com/ professional/) or Guardian CareLink (https://carelink.medtronic.com/login). Once this account is set up, patients who use an app on a smartphone can upload their data to the healthcare professional in real time. The pharmacist can then review the patient’s data online. They can look for days where the patient had glucose excursions and review what happened that day with the patient to determine the reasons for the excursions.

Pharmacists can encourage patients to record physical activity, food, illness, missed insulin/medications or unexpected events in the app so that they can see how these events influence their sugars. It’s important for patients to understand 1) why these events increase or decrease their sugars and 2) that sugars will normally fluctuate by themselves at times. By getting patients to understand what causes their fluctuations, pharmacists can empower them to take control of their sugars instead of being a helpless bystander. The professional website will also allow the sorting of patients to determine which patients are experiencing hypoglycemia.

One study randomized adults with poorly controlled type 2 diabetes treated with basal insulin, to either real time continuous glucose monitoring or capillary blood glucose monitoring. They found the real time continuous glucose monitoring arm had significantly lower A1c levels at eight months. Also, there was less time spent in blood glucose levels below 3.9 mmol/L.(13)

The pharmacist’s role in treating hypoglycemia

Once you have identified that the patient is experiencing hypoglycemia, it’s important to discuss why it is happening and how to treat hypoglycemia. Keep the language simple. For example, you could start by explaining that the brain needs glucose like a computer needs electricity. Just as a computer operates sub-optimally when it doesn’t get enough electricity, your brain may experience confusion, difficulty with speaking or concentrating when it doesn’t receive enough glucose from the blood. To treat hypoglycemia the Diabetes Canada clinical practice guidelines, suggests that 15 g glucose (or a similar fast-acting carbohydrate) is required. This produces an increase in blood glucose of approximately 2.1 mmol/L within 20 minutes, providing adequate symptom relief for most people. Some examples of fast acting carbohydrate include a tablespoon (15g) of sugar, a tablespoon of honey, 4 Dex-4 glucose tablets, 6 Lifesaver candies or 150 ml of juice or pop.(1)

Remember that the carbohydrate must be easily digested to be “fast-acting.” Things like chocolate cake, ice cream and fruit may taste sweet but contain significant amounts of fat or fibre which slow down the digestion of the carbohydrate.(14) During a hypoglycemic event quick treatment is a priority. For patients experiencing severe hypoglycemia who are unconscious, glucagon is the preferred treatment.(1) There are now two different methods of administering glucagon available in Canada. Injectable glucagon requires reconstitution by mixing the powdered glucagon with a diluent before subcutaneous injection.(15) Nasal glucagon can be administered intranasally with no mixing required.(16) One study showed that participants using subcutaneous vs nasal glucagon found that nasal glucagon was easier to use, easier to prepare, had more confidence in using glucagon and overall was more satisfied than subcutaneous glucagon.(17) Some practical tips include counselling patients on the expiry date of glucagon, ensuring that they have refills left on file and that they are storing the glucagon properly.

The pharmacist’s role in preventing hypoglycemia

To manage and prevent hypoglycemia it is useful to see if there is a pattern. If the hypoglycemic event was a one-time event that occurred after a patient skipped a meal or after some unexpected exercise, reinforce the importance of regular meals and suggest carrying glucose tablets (a common mistake patients make is taking only a single Dex-4 tablet for treatment which is about 4 grams of carbohydrate; remind them it’s Dex 4 because 4 tablets is a dose of 15 grams of fast-acting carbohydrate). They can also carry glucagon with them or a diabetes-specific meal replacement, such

The pharmacist’s role in hypoglycemia in patients with diabetes treated with basal insulin as Glucerna or Boost Diabetic. For more information with great visuals, you could refer them to the Diabetes Canada patient handout which can be found at: https://guidelines.diabetes.ca/docs/ patient-resources/hypoglycemia-lowblood-sugar-in-adults.pdf

If there is a pattern of lows, appendix 5 of the 2018 Diabetes Canada clinical practice guidelines has an excellent overview of which insulins to adjust depending on the pattern of lows. Certain sulfonylureas and insulins have a lower incidence of hypoglycemia than others. Glyburide has a moderate risk of hypoglycemia, while gliclazide has a minimal/moderate risk of hypoglycemia. As per the guidelines, gliclazide is preferred over glyburide due to lower risk of hypoglycemia, cardiovascular events, and mortality. If you have prescribing privileges in your province this is a change that is justifiable and easy to explain to patients. If you need to fax a prescriber to make the change, then including the suggestion from the guidelines is worthwhile to show your rationale. As discussed before, newer generation basal insulin analogues (insulin degludec and insulin glargine U300) have a lower incidence of hypoglycemia than first-generation insulin analogues.(18)

In the past, detecting nocturnal hypoglycemia was more cumbersome. Asking patients to set up an alarm to wake themselves over several nights to poke their fingers was sometimes a difficult conversation. Patients would be unwilling or forget to test in the middle of the night to detect nocturnal hypoglycemia. Intermittently scanned and real-time continuous blood glucose monitoring offer an excellent alternative to capillary blood glucose monitoring at night. While these sensors can be expensive, you could contact a company representative to provide a sample or suggest contacting their insurance plan to check for coverage. The sensors will detect and record any instances of nocturnal hypoglycemia that happens overnight. Some of the sensors allow the patient to set alarms if their blood glucose fall below a certain level. If your patient is experiencing nocturnal hypoglycemia, you could reduce their basal insulin, switch to a newer generation basal insulin analogue which is associated with lower frequency of overnight hypoglycemia or switch their sulfonylurea.

Pharmacists have a major role in screening, education, prevention and treatment of hypoglycemia in patients with diabetes. In doing so, they can make a positive impact in the lives of these patients. One study done at the University of Alberta, showed pharmacists’ intervention in poorly controlled adults with type 2 diabetes within community pharmacies around Alberta, showed a significant A1c reduction of 1.8%.(19) Pharmacists are encouraged to look at managing hypoglycemia as a way to improve patient outcomes, demonstrate pharmacists’ value and encourage their own professional growth.

References are online at eCortex.ca.

FACULTY The pharmacist’s role in hypoglycemia in patients with diabetes treated with basal insulin

ABOUT THE AUTHOR

Esmond Wong is a clinical pharmacist working in the area of diabetes. He has a Bachelor of Science in Pharmacy from the University of Alberta (2006) and became a Certified Diabetes Educator and gained additional prescribing authorization in 2011. At his practice he prescribes/adjusts/refills medications and insulin, does foot screening, sends patients for lab work, and helps set lifestyle goals with patients. His website www.cdestudycourse.com has helped more than 1,500 healthcare professionals across Canada become certified diabetes educators.

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