Module 5 Section 5 (Drugs for Diabetes)

Question 1

What is diabetes mellitus?

Answer 1

Diabetes mellitus is a chronic disease characterized by elevated blood glucose levels that are a result of the body not being able to produce insulin, or not being able to use the insulin it does produce.

Question 2

Increased blood glucose levels have numerous deleterious effects on organs, nerves, and blood vessels. List some examples.

Answer 2

Diabetes is associated with chronic kidney disease, foot problems, eye disease, heart attack, stroke, and nerve damage.

Some of these complications are very serious and can be life-threatening.

Question 3

True or false: the body needs insulin to use glucose as an energy source, and the pancreas is responsible for producing insulin.

Answer 3

True

Question 4

How do blood glucose levels vary throughout the day?

Answer 4

In the fasting state, normal blood glucose levels should be below 5.6 mM.

Two hours after eating a meal, normal blood glucose levels will range from 6.7 mM to 7.8 mM.

Question 5

What is the difference between hypoglycemia and hyperglycemia?

Answer 5

Hypoglycemia is the term used to described lower than normal blood glucose levels.

Hyperglycemia refers to higher than normal blood glucose levels.

Question 6

What are the diagnostic criteria for diabetes?

Answer 6

• fasting plasma glucose ≥ 7mM or
• two-hour plasma-glucose ≥ 11.1 mM during an oral glucose tolerance test or
• HbA1c≥ 6.5%, where HbA1c represents an indirect measure of the average glucose concentration to which the hemoglobin has been exposed.

Question 7

What are the common clinical features of diabetes?

Answer 7

The common clinical features of diabetes include polydipsia (excessive thirst), polyuria (excessive urination) and nocturia (urination at night).

Question 8

What are the 4 types of diabetes mellitus?

Answer 8

1) Type 1: Insulin-Dependent: this is known as insulin-dependent diabetes, and is characterized by pancreatic beta cell destruction, leading to insulin deficiency.
- About 5% to 10% of people with diabetes have type 1 diabetes.
- The age of onset of type 1 diabetes is generally younger than 30 years old.

2) Type 2: Non-Insulin Dependent: this is known as non-insulin-dependent diabetes, and is characterized by pancreatic beta cell dysfunction, leading to insulin resistance.
- About 90% of people with diabetes have type 2 diabetes.
- The age of onset of type 2 diabetes is generally 40 years of age or older and is associated with obesity.
- Specifically, a 10 kg increase in body weight results in an approximate three-fold increase in the risk of developing diabetes.
- Obesity also leads to an earlier age of onset of diabetes.

3) Other Causes: this type of diabetes refers to multiple other specific causes of an elevated blood glucose, such as pancreatitis and drug therapy.

4) Gestational Diabetes: it’s defined as any abnormality in glucose levels that is noted for the first time during pregnancy.
- It’s diagnosed in about 3% of all pregnancies in Canada.
- The placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester of pregnancy.
- Having gestational diabetes increases the risk of the mother and the child developing diabetes in the future.

Question 9

Discuss the acute and chronic complications of diabetes

Answer 9

Acute:

• Diabetic ketoacidosis: a life-threatening medical emergency caused by inadequate or absent insulin replacement. Treatment involves intravenously administered insulin.
• Hyperosmolar hyperglycemic syndrome: diagnosed in type 2 diabetics and is characterized by severe hyperglycemia and dehydration. Treatment is slow rehydration and restoration of glucose and electrolyte homeostasis.

Chronic:

• Chronic kidney disease
• Foot problems (due to peripheral vascular disease, can progress to the point that amputation is required)
• Retinopathy due to damage to vessels in the eye
• Nerve damage
• Heart attack, stroke, coronary artery disease (all due to vascular damage)

Question 10

What are the benefits of controlling blood glucose levels?

Answer 10

Results from a large clinical study of type 1 diabetics indicated that “near normalization” of blood glucose levels resulted in a delay in onset and a major slowing of progression of complications associated with diabetes.
- More specifically, in the tight control group (i.e. mean blood glucose 8.7 mM and mean HbA1c7.2%), the risk of developing diabetic eye, kidney, or nerve disease was reduced 60% compared to the standard control group (i.e. mean blood glucose 12.6 mM and mean HbA1c8.9%).

In another study, tight control of type 2 diabetes was shown to reduce the risk of microvascular complications overall compared to conventional therapy.
- Tight control of hypertension also had a significant effect on microvascular disease in these diabetic patients.

Question 11

It’s recommended that intensive glycemic control that targets normal or near-normal blood glucose levels should become standard therapy in diabetic patients. What are the exceptions to this?

Answer 11

Exceptions to this recommendation include patients with advanced renal disease and the elderly, as the risks of hypoglycemia may outweigh the benefits of normal or near-normal glycemic control in these groups.

Question 12

What are the goals of therapy in diabetic patients?

Answer 12

The goals of therapy in diabetic patients are to alleviate diabetes-associated symptoms and to prevent or reduce diabetes-associated complications.

Question 13

What is a key component to diabetes management?

Answer 13

A key component to diabetes management is patient education on nutrition, exercise, the importance of lowering blood glucose levels, how to self-monitor blood glucose levels, and medications used to lower blood glucose levels.

Question 14

Compare and contrast the treatment for type 1 and type 2 diabetes.

Answer 14

Type 1 diabetes is always managed with insulin.

Depending on the severity of type 2 diabetes, it may be managed through physical activity and meal planning, or may also require medications to control blood glucose levels, such as oral hypoglycemic agents.
- A number of medications are available to manage diabetes.

Question 15

Insulin therapy is necessary for all type 1 diabetics and for treatment of diabetic ketoacidos. What else may it be used for?

Answer 15

Insulin may also be used for type 2 diabetes (when other medications are not providing adequate control of blood glucose levels), during stressful conditions (e.g. infection), or for gestational diabetes.

Question 16

What are the various sources of insulin?

Answer 16

• Injection (subcutaneous, intravenous, or intramuscular).
• By alternative methods, such as an insulin pump, transdermal patch, or oral formulation (designed to resist insulin digestion in the GI tract).

Question 17

What is the standard mode of insulin therapy?

Answer 17

he standard mode of insulin therapy is subcutaneous injection using disposable needles and syringes, or portable pen injectors.

• Absorption of subcutaneously-administered insulin is highly variable, both among different patients, and between doses in the same patient.
• Factors that affect absorption are blood flow to the site of injection, the site of injection (abdomen > arm > buttock > thigh), and the depth of injection.
• Additionally, exercise and massage of the area both increase absorpion.

Question 18

What is the goal for subcutaneous insulin therapy?

Answer 18

The goal of subcutaneous insulin therapy is to replicate normal physiologic insulin secretion and to replace the background or basal (overnight, fasting, between-meal) as well as bolus or prandial (mealtime) insulin.

Question 19

Four main types of injected insulins are available. What are they?

Answer 19

1) Rapid-acting: very fast onset of action and short duration of action
2) Short-acting: rapid onset of action
3) Intermediate-acting: intermediate onset of action
4) Long-acting: slow onset of action and long duration of action

Question 20

What are the complications of insulin therapy?

Answer 20

Hypoglycemia is the most dangerous complication of insulin therapy, and is usually a result of unusual physical exertion, too large a dose of insulin, insulin allergy (rare with human insulin), and insulin resistance.

Symptoms of hypoglycemia include tachycardia, palpitations, sweating, tremulousness, nausea, and hunger.

If untreated, hypoglycemia can progress to convulsions and coma.

The treatment for hypoglycemia is glucose administration, generally a simple sugar should be given, preferably in liquid form.

Question 21

Why is insulin the first line therapy for type 1 diabetes, but not type 2 diabetes?

Answer 21

Patients with type 1 diabetes have destroyed beta cells, which means their pancreas is incapable of making insulin. Therefore, injection of insulin via subcutaneous injection (or other methods) replace the body’s natural store of insulin.

On the other hand, patients with type 2 diabetes are insulin-resistant, meaning their cells are unable to respond normally to insulin. Thus, insulin is not the first-line therapy for these individuals.

Question 22

What are oral hypoglycemic agents?

Answer 22

Oral hypoglycemic agents are a group of drugs that are used in the management of type 2 diabetes – they are not indicated for management of type 1 diabetes.

Question 23

What are the classes of drugs considered to be oral hypoglycemic agents?

Answer 23

• Biguanides
• Insulin secretagogues
• GLP-1 agonists
• DPP-4 inhibitors
• SGLT2 inhibitors

Question 24

What are the mechanisms of action for biguanides? Provide an example. What is a benefit? List the adverse effects.

Answer 24

Biguanides prevent the production of glucose in the liver.

Metformin is the only biguanide approved for clinical use.

• Metformin decreases gluconeogenesis in the liver and increases glucose uptake by skeletal muscles, thereby decreasing blood glucose levels.
• Metformin is the first-line therapy for type 2 diabetes.
• It can be used in combination with other oral hypoglycemic drugs or insulin in type 2 diabetics in whom monotherapy is inadequate.

An advantage of metformin is that it does not cause hypoglycemia, as it does not alter insulin levels.

Adverse effects:

• Gastrointestinal toxicities (i.e. abdominal discomfort, diarrhea) occur in up to 20% of patients but usually resolve within a couple weeks
• Anorexia and nausea
• Metallic taste
• Lactic acidosis (acidification of blood, contraindicated in renal disease)

Question 25

What are the mechanisms of action for insulin secretagogues? Provide examples. List the adverse effects.

Answer 25

Insulin secretagogues refer to medicines that increase insulin secretion from the pancreas. These drugs function by stimulating the beta cells of the pancreas, which are responsible for producing insulin. This group of drugs include the sulfonylureas and meglitinides.

Sulfonylureas: these drugs act by stimulating insulin secretion from the pancreatic beta cells.

• They inhibit potassium channels on beta cells, causing cell depolarization and an increase in calcium entry.
• The increase in calcium entry leads to an increase in the release of insulin.
• For sulfonylureas to work, the patient must have functional pancreatic beta cells, therefore these drugs are only useful for type 2 diabetes.
• The duration of action of sulfonylureas can be as short as six hours, and as long as 72 hours,depending on the specific drug.
• An example of a second-generation sulfonylurea is glyburide.

Adverse effects include:

• Sulfonylureas are teratogenic and are therefore contraindicated in pregnancy.
• Hypoglycemia
• Gastrointestinal disturbances
• Jaundice
• Allergic skin reactions

Meglitinides: these drugs are short acting insulin secretagogues that function similarly to the sulfonylureas.

• They are not metabolized in the body and are excreted by the kidneys as the active compound.
• As a result, the duration of action of these drugs is short, with a half-life of just one hour.
• Meglitinides are indicated in type 2 diabetes and can be combined with metformin therapy.
• An example of a meglitinide is repaglinide.

Adverse effects are rare but can include hypoglycemia.

Question 26

What are the mechanisms of action for glucagon-like polypeptide (GLP-1) receptor agonists? List the adverse effects.

Answer 26

GLP-1 is an essential gut hormone that contributes to glucose tolerance.

• In type 2 diabetes, GLP-1 secretion is decreased after meals, leading to inadequate glucagon suppression and increased glucose output.
• Synthetic analogs of GLP-1 bind to GLP-1 receptors, helping to restore GLP-1 activity.
• Injection of GLP-1 receptor agonists results in an increase in insulin release, a decrease in glucagon release, and a loss of appetite, all which contribute to lowering blood glucose levels.
• GLP-1 receptor agonists are indicated as adjunct therapy for type 2 diabetes.

Major adverse effects include nausea, vomiting, and diarrhea.
- Weight loss (about 2 to 3 kg) is reported in some users and is thought to be due to the nausea and vomiting associated with these drugs.

Question 27

What are the mechanisms of action for DPP-4 Inhibitors? Provide examples. List the adverse effects.

Answer 27

Dipeptidyl peptidase-4 (DPP-4) is a serine protease (an enzyme that cleaves peptide bonds in proteins) found throughout the body that is critical for the inactivation of GLP-1.

• By inhibiting the inactivation of GLP-1, these drugs increase the proportion of active GLP-1, thus increasing the effects of GLP-1.
• DPP-4 inhibitors are indicated as adjunct therapy for type 2 diabetes and are administered orally.
• An example drug in this class is sitagliptin.

Common adverse effects include upper respiratory tract infections, headaches, and hypoglycemia.
- Some reports of acute pancreatitis and severe allergic and hypersensitivity reactions also exist.

Question 28

What are the mechanisms of action for SGLT2 Inhibitors? List the adverse effects.

Answer 28

The sodium-glucose linked transporters (SGLTs) are a family of glucose transporters found in the intestine and kidneys.

• Specifically, a subclass of these transporters, SGLT-2, is found in the proximal tubule of the nephron and contributes to glucose reabsorption in the kidney.
• SGLT-2 inhibitors can be administered to antagonize the transporter protein and prevent the reabsorption of glucose.
• These drugs can be used by diabetics to decrease their blood sugar levels.

Common adverse effects include increased urination, low blood pressure, and weight loss. These drugs have a low risk of hypoglycemia.

Question 29

Managing type 2 diabetes over time continues to be a challenge as patients often end up having decreased beta-cell mass, reduced physical activity, decreased lean body mass, or increased ectopic fat deposition. Therefore, to achieve glycemic control, multiple medications may be required. Discuss combination therapy in type 2 diabetes.

Answer 29

In general (unless contraindicated), therapy should begin with metformin.

Then if needed, otheroral hypoglycemic agents or insulin can be added to the therapy based on the individual patient characteristics and the advantages and disadvantages of each drug, including cost, adverse effect profile, and frequency/ease of dosing.

Question 30

What are some additional therapies sometimes administered as preventative measures for diabetes-associated complications?

Answer 30

1) Statins: statins are lipid-lowering drugs. In diabetes, it is desirable to have the HDL/LDL ratios as favourable as possible to help protect the vascular system.
2) ACE inhibitors: they act on the RAS to decrease blood pressure. These drugs are sometimes given to diabetic patients to help protect the kidneys.
3) Low dose acetylsalicylic acid: in diabetic patients with multiple risk factors for diabetes-associated complications, they may be prescribed low dose acetylsalicylic acid (ASA) because of its anti-platelet effects.

Question 31

Fill out the following:

Type 1

• Abnormality:
• Incidence:
• Age of onset:
• Etiology:
• Body weight:
• Diabetic ketoacidosis:
• Treatment:

Type 2

• Abnormality:
• Incidence:
• Age of onset:
• Etiology:
• Body weight:
• Diabetic ketoacidosis:
• Treatment:

Answer 31

Type 1

• Abnormality: B-cell destruction leading to insulin deficiency
• Incidence: less common (5-10%)
• Age of onset: most < 30 yrs
• Etiology: most commonly autoimmune
• Body weight: low
• Diabetic ketoacidosis: more common
• Treatment: insulin

Type 2

• Abnormality: B-cell dysfunction leading to insulin resistance
• Incidence: most common (90%)
• Age of onset: most > 40 yrs
• Etiology: multifactorial
• Body weight: overweight/obese
• Diabetic ketoacidosis: less common
• Treatment: oral hypoglycemic + or - insulin

Question 32

Which one of the statements regarding diabetes mellitus is true?

a) Diabetes mellitus is diagnosed as a fasting glucose greater than or equal to 7 mM
b) Insulin is always the first-line therapy for diabetes
c) Type 4 diabetes is known as insulin-dependent diabetes
d) Diabetes mellitus is characterized by decreased blood glucose levels

Answer 32

a) Diabetes mellitus is diagnosed as a fasting glucose greater than or equal to 7 mM

Question 33

Which one of the following drugs is most appropriate for a type 1 diabetic?

a) Biguanides
b) Insulin
c) Sulfonylureas
d) DPP-4 inhibitor

Answer 33

b) Insulin