What is the first line medical treatment for patients with hypoglycemia?

The overlapping symptoms of hypo- and hyperglycemia (e.g., hunger, sweating, trembling, confusion, irritability, dizziness, blurred vision) make the two conditions difficult to distinguish from one another (Paradalis, 2005). Since the treatment is different for each condition, it is critical to test the patient’s blood glucose when symptoms occur. The risk factors that may have led to the condition, and the recent medical history of the patient also help to determine the cause of symptoms.

Table of Contents Show

Hypoglycemia
Hyperglycemia
Which controls type 2 diabetes best at five years: rosiglitazone, metformin, or glyburide?
What does this article say?
Should we believe this study?
What should the family physician do?

Hypoglycemia

Hypoglycemia is a condition occurring in diabetic patients with a blood glucose of less than 4 mmol/L. If glucose continues to remain low and is not rectified through treatment, a change in the patient’s mental status will result. Patients with hypoglycemia become confused and experience headache. Left untreated, they will progress into semi-consciousness and unconsciousness, leading rapidly to brain damage. Seizures may also occur.

Common initial symptoms of hypoglycemia include:

Cold, clammy skin
Weakness, faintness, tremors
Headache, irritability, dullness
Hunger, nausea
Tachycardia, palpitations

These symptoms will progress to mood or behaviour changes, vision changes, slurred speech, and unsteady gait if the hypoglycemia is not properly managed.

The hospitalized patient with type 1 or type 2 diabetes is at an increased risk for developing hypoglycemia. Potential causes of hypoglycemia in a hospitalized diabetic patient include:

Receiving insulin and some oral antidiabetic medications (e.g., glyburide)
Fasting for tests and surgery
Not following prescribed diabetic diet
New medications or dose adjustments
Missed snacks

Hypoglycemia is a medical emergency that must be treated immediately. An initial blood glucose reading may confirm suspicion of hypoglycemia. If you suspect that your patient is hypoglycemic, obtain a blood glucose level through skin puncture. A 15 g oral dose of glucose should be given to produce an increase in blood glucose of approximately 2.1 mmol/L in 20 minutes (Canadian Diabetes Association, 2013). Table 9.2 outlines an example of a protocol that may be used in the treatment of hypoglycemia.

Table 9.2 Hypoglycemia Treatment


Capillary Blood Gas (CBG)	Able to Swallow	Nil per Mouth with IV Access	Nil per Mouth with No IV Access
≥ 4 mmol/L	No treatment necessary	No treatment necessary	No treatment necessary
2.2-3.9 mmol/L	Give 15 g of glucose in the form of: 3-5 dextrose/glucose tabs (check the label) (best choice), OR 175 ml of juice or soft drink (containing sugar), OR 1 tablespoon of honey, OR 3 tablespoons of table sugar dissolved in water Note: Milk, orange juice, and glucose gels increase blood glucose (BG) levels more slowly and are not the best choice unless the above alternatives are not available. Repeat CBG every 15 to 20 minutes and repeat above if BG remains below 4 mmol/L. Once BG reaches 4 mmol/L, give patient 6 crackers and 2 tablespoons of peanut butter. If meal is less than 30 minutes away, omit snack and give patient meal when it is available.	Notify physician. Give 10-25 g (20-50 ml of D50W — dextrose 50% in water) of glucose intravenously over 1 to 3 minutes, OR as per agency policy. Repeat CBG every 15 to 20 minutes until 4 mmol/L. Continue with BG readings every 30 minutes for 2 hours.	Notify physician. Give glucagon 1 mg subcutaneously (SC) or intramuscularly (IM). Position patient on side. Repeat CBG every 15 to 20 minutes. Give second dose of glucagon 1 mg SC or IM if BG remains below 4 mmol/L.
≤ 2.2 mmol/L	Call lab for STAT BG level. Continue as above.	Call lab for STAT BG level. Continue as above.	Call lab for STAT BG level. Continue as above.
Data source: Canadian Diabetes Association, 2013; Paradalis, 2005; Rowe et al., 2015; VCH 2009

Hyperglycemia

Hyperglycemia occurs when blood glucose values are greater than 7 mmol/L in a fasting state or greater than 10 mmol/L two hours after eating a meal (Pardalis, 2005). Hyperglycemia is a serious complication of diabetes that can result from eating too much food or simple sugar; insufficient insulin dosages; infection, illness, or surgery; and emotional stress. Surgical patients are particularly at risk for developing hyperglycemia due to the surgical stress response (Dagogo-Jack & Alberti, 2002; Mertin, Sawatzky, Diehl-Jones, & Lee, 2007). Classic symptoms of hyperglycemia include the three Ps: polydipsia, polyuria, and polyphagia.

The common symptoms of hyperglycemia are:

Increased urination/output (polyuria)
Excessive thirst (polydipsia)
Increased appetite (polyphagia), followed by lack of appetite
Weakness, fatigue
Headache

Other symptoms include glycosuria, nausea and vomiting, abdominal cramps, and progression to diabetic ketoacidosis (DKA).

Potential causes of hyperglycemia in a hospitalized patient include:

Infection
Stress
Increased intake of calories (IV or diet)
Decreased exercise
New medications or dose adjustments

Note that testing blood glucose levels too soon after eating will result in higher blood glucose readings. Blood glucose levels should be taken one to two hours after eating.

If hyperglycemia is not treated, the patient is at risk for developing DKA. This is a life-threatening condition in which the body produces acids, called ketones, as a result of breaking down fat for energy. DKA occurs when insulin is extremely low and blood sugar is extremely high.

DKA presents clinically with symptoms of hyperglycemia as above, Kussmaul respiration (deep, rapid, and laboured breathing that is the result of the body attempting to blow off excess carbon dioxide to compensate for the metabolic acidosis), acetone-odoured breath, nausea, vomiting, and abdominal pain (Canadian Diabetes Association, 2013). Patients in DKA also undergo osmotic diuresis. They pass large amounts of urine because of the high solute concentration of the blood and the body’s attempts to get rid of excess sugar.

DKA is treated with the administration of fluids and electrolytes such as sodium, potassium, and chloride, as well as insulin. Be alert for vomiting and monitor cardiac rhythm. Untreated DKA can be fatal.

Patients with hyperglycemia may also exhibit a non-ketotic hyperosmolar state, also known as hyperglycemic hyperosmolar syndrome (HHS). This is a serious diabetic emergency that carries a mortality rate of 10% to 50%. Hyperosmolarity is a condition in which the blood has a high sodium and glucose concentration, causing water to move out of the cells into the bloodstream.

Further information on the treatment of DKA and HHS can be found on the Canadian Diabetes Association clinical guidelines website.

At 0930 hours, your diabetic patient complains of feeling faint. You check his blood sugar and get a reading of 2.8 mmol/L. What actions will you take?
What blood glucose level range do you expect immediately post-operatively from your patient who has type 2 diabetes? Why?

Each month, three presenters will review an interesting journal article in a conversational manner. These articles will involve “hot topics” that affect family physicians or will “bust” commonly held medical myths. The presenters will give their opinions about the clinical value of the studies discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.

Kahn SE, Haffner SM, Heise MA, et al., for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy [published correction appears in N Engl J Med. 2007;356(13):1387–1388]. N Engl J Med. 2006;355(23):2427–2443.

Which controls type 2 diabetes best at five years: rosiglitazone, metformin, or glyburide?

Mark: For the estimated 20 million Americans with type 2 diabetes, this is a very important question. This article is an excellent demonstration of why reading just the abstract could lead you to the wrong conclusion.

What does this article say?

Mark: This study randomized 4,360 patients to monotherapy with rosiglitazone (Avandia), metformin (Glucophage), or glyburide (Micronase). The end point was fasting blood glucose over 180 mg per dL. The authors concluded that, at five years, only 15 percent of patients taking rosiglitazone failed mono-therapy versus 21 percent of those taking metformin and 34 percent taking glyburide. Although the abstract trumpets rosiglitazone as “the winner,” this is exactly the wrong conclusion to draw from this study.

Should we believe this study?

Mark: How did the authors come to the incorrect conclusion? First, fasting blood glucose was the wrong end point to measure. This is a surrogate marker of disease that does not correlate with clinical outcomes. Using such surrogate markers as end points is known as “DOE” or “disease-oriented evidence.” What we care about are patient out-comes, such as adverse cardiovascular events; these are known as “POEMs” or “patient-oriented evidence that matters.” Fasting blood glucose is a surrogate marker that is, perhaps, just as dependent on the half-life of the drug and when the drug was administered as anything else.

What about the more accepted gold standard A1C values (itself a DOE)? There was a negligible difference of 0.13 percent favoring the rosiglitazone group over the metformin group. This miniscule difference is clinically meaningless; it takes an increase of at least 1 percent in A1C level to barely increase the relative risk of a cardiovascular event to 1.18 (95% CI, 1.1 to 1.26).1

And what did the study show about the clinical end points that we are really interested in, such as cardiovascular events? Patients on rosiglitazone had more CHF and a greater number of cardiovascular events than those on metformin or glyburide. These are the end points that matter.

Bob: Also, there was an average weight gain of 10.6 lb (4.8 kg) with rosiglitazone and 3.5 lb (1.6 kg) with glyburide, which is not something we need in patients with type 2 diabetes. Metformin resulted in a net weight loss of 6.4 lb (2.9 kg) over five years.

Mark: What disturbs me most is that the conclusion in the abstract is different from the conclusion in the body of the paper. What the authors conclude in the paper is that the “findings confirm the value of metformin as an initial treatment for type 2 diabetes.” This is entirely different than what they concluded in the abstract.

Andrea: This disconnect between what is reported in the body of a paper and what is promoted in the abstract is not a new problem. In a review of first-tier journals, the data in the abstract differed from the data in the paper up to 68 percent of the time.2 This tells you that if you just read the abstract, you may be misled.

Additionally, the common use of surrogate outcomes is problematic. For example, we don't care about a blood pressure measurement—we care about cardiovascular events. You can reduce the blood pressure and still not reduce all cardiovascular events.3,4 So anytime you see a published article, make sure the outcome is something we care about: the patient.

What should the family physician do?

Mark: I would begin medical therapy with metformin and use sulfonylureas and insulin as second-line treatment options. If you use glitazones, watch for adverse events, including increased fluid retention, CHF, and cardiovascular events.

Bob: CHF has been seen with glitazone use in the past. In 2002, the FDA recognized the increased rates of CHF associated with glitazones and required the makers of pioglitazone (Actos) and Avandia to strengthen the warnings concerning adverse cardiovascular events.

Also, there have been numerous headlines and news reports on a meta-analysis published in the New England Journal of Medicine that documented a small but increased risk of death from cardiovascular causes in patients taking rosiglitazone.5 It has been said that the risk of death is small; however, even if the risk is small, why would you prescribe this drug at all? When prescribing drugs, you want a benefit, but with rosiglitazone, you are basically saying, “I have this drug that will cost you a lot of money, won't help your heart, oh, and by the way, there is a small chance it may make you worse.” Any takers?

Andrea: I agree. Start with metformin. This study should also serve as a warning that abstracts may not reflect the true results of a study, even in journals like the New England Journal of Medicine. You should evaluate the study yourself before you change your clinical practice (or find a group of medical nerds like us to do it for you).

Glitazones are associated with fluid retention, increased CHF rates, and, possibly, increased rates of cardiovascular events compared with sulfonylureas and metformin.
The FDA and the Canadian government have issued warnings about CHF and cardiovascular events with rosiglitazone.
Metformin should be the first-line drug for managing type 2 diabetes. Insulin and sulfonylureas should be second line, and glitazones should be reserved for third line.
Metformin is the only drug for type 2 diabetes that does not cause weight gain, which is an important advantage.

The data and conclusion in the abstract of an article may not be the same as the data in the paper. If you read only the abstract, you may be misled.
A lot of studies use surrogate markers as outcomes (e.g., fasting or postprandial blood glucose, FEV1). These are DOEs. What we care about are POEMs (e.g., stroke rates, MI rates, quality of life).
Something can be statistically significant but clinically meaningless (for example, A1C difference of 0.08 percent).