Diabetes Revision Notes

Diabetes Mellitus Notes

Classification of Diabetes

• Type 1 diabetes mellitus (T1DM) - autoimmune beta cell destruction resulting in an absolute deficiency of insulin
• Type 2 diabetes mellitus (T2DM) - insulin resistance along with some degree of insulin deficiency
• Gestational diabetes mellitus (GDM) - onset or recognition of glucose intolerance in pregnancy
• Maturity-onset diabetes of the young (MODY) - genetic condition; occurs in young patients, often < 25 years old. Commonly, MODY 1-4 seen in white non-Hispanic families and MODY 5 in Japanese patients. Most MODY patients are thin. 
• Atypical Diabetes in African Americans (ADAA) - genetic condition; acute onset of diabetes but no need for insulin to prevent diabetic ketoacidosis. These patients do not lose beta-cell function over time. 

Clinical presentation of Diabetes

• asymptomatic - found on screening
• non-specific symptoms -  fatigue, weight changes
• metabolic symptoms - polyuria, polydipsia, weight loss
• vascular complications - neuropathy, kidney disease, erectile dysfunction, vision changes
• metabolic decompensation  
• Diabetic Ketoacidosis in type 1 diabetics and sometimes occurs in type 2 diabetics also. Presents with fruity breath, abdominal pain, nausea/ vomiting, confusion, dehydration, etc. It may be how a type 1 diabetic first presents when they are diagnosed. It can also be associated with severe/ sudden illness.

Diagnosis

• Any of the following will provide a diagnosis of diabetes, however, in the absence of symptoms of hyperglycemia, repeat the test another day. 
• Random blood glucose ≥11.1 mmol/L (200 mg/dL)
• Fasting plasma glucose (FPG) ≥7 mmol/L (126 mg/dL)
• Oral glucose tolerance test (OGTT) - glucose level ≥11.1 mmol/L 2h after 75g oral glucose load
• Glycated hemoglobin (HbA1c) ≥6.5% -- in non-pregnant adults

Screening for Type 2 Diabetes Mellitus

• Every 3 years if ≥ 40 years old or at high risk*. Screen more often/ earlier if risk factors for diabetes, or very high risk*. This table will help convert mmol/L to mg/dL. 
• Tests: Fasting plasma glucose (FPG) and/or HbA1c. 
• Normal: FPG < 5.6 mmol/L, HbA1c < 5.5%
• At Risk: FPG ≥ 5.6-6.0 mmol/L and/or A1C ≥ 5.5-5.9%
• Prediabetic: FPG ≥ 6.1-6.9 mmol/L and/or A1C ≥ 6.0-6.4%
• Diabetic: FPG ≥ 7 mmol/L and/or A1C ≥ 6.5%
• *CANRISK = Canadian Diabetes Risk score, it is used for those 40-74 years old. 
• At risk - patients with slightly elevated blood glucose levels are said to be at risk. If they do not have any risk factors, they can be simply reassessed more often. However, if they have one or more risk factors for diabetes mellitus, they should have an oral glucose tolerance test done.
• Prediabetes - patients who have elevated blood glucose (abnormal FPG, HbA1c, or OGTT) but not enough to be diagnosed with diabetes mellitus are said to be "pre-diabetic" and need to be reassessed more often. Prediabetes encompasses:
• Impaired fasting glucose (IFG) - FPG of 6.1-6.9 mmol/L
• Impaired glucose tolerance (IGT) - OGTT of 7.8-11 mmol/L
• HbA1c of 6.0-6.4%

• Screening for gestational diabetes mellitus (GDM) -- between 24 and 28 weeks gestation, but if at high risk screen at any time during pregnancy. OGTT with 50g glucose and check blood glucose after 1h. 
• Normal: 1h glucose < 7.8 mmol/L
• Elevated: 1h glucose 7.8-11mmol/L, follow-up with
• OGTT with 75g glucose, then check blood glucose fasting, 1h and 2h later. Any of the following will lead to diagnosis of GDM. 
• FPG ≥ 5.3 mmol/L (target is < 5.3)
• 1h glucose ≥ 9 mmol/L (target is 7.8)
• 2h glucose ≥ 10.6 mmol/L (target is 6.7)
• Gestational diabetes mellitus: 1h glucose ≥ 11.1 mmol/L.

Lifestyle Changes for All patients with Diabetes Mellitus: ABCDES

• A -- A1C – optimal glycemic control (usually ≤7%)
• B -- BP – optimal blood pressure control (<130/80 mmHg)
• C -- Cholesterol – LDL-C ≤2.0 mmol/L if decision made to treat
• D -- Drugs to protect the heart: 
• A – ACEi/ARB 
• S – Statin 
• A – ASA if indicated 
• E -- Exercise/Eating – regular physical activity, healthy diet, achievement and maintenance of healthy body weight 
• S -- Smoking cessation

Who needs drugs to protect the heart? 

• Give a statin if age 40-54 years old, high lipids, or Age > 30 with >15 years of diabetes. 
• Give a statin + ACEI/ARB if age ≥ 55 or microvascular damage (retinopathy, neuropathy, nephropathy). 
• Give statin + ACEI/ARB + ASA/Clopidogrel if macrovascular damage (coronary artery disease, cerebrovascular disease, peripheral artery disease)

Medications for Type 2 Diabetes Mellitus

Benefits and Side-effects of Oral-Antihyperglycemic Drugs and Weight loss drugs

• Biguanides: Metformin is the only drug in this class available in Canada. It is the first drug given for type 2 diabetes mellitus, because it does not cause weight gain or hypoglycemia and works well with other anti-hyperglycemics. It works by decreasing hepatic glucose production.  Side effects: Lactic acidosis is a rare complication in those with heart/ kidney/ liver disease. Minor effects: GI upset, to avoid take with food. 
• Insulin Sensitizers aka thiazolidinediones (TZDs): rosiglitazone and pioglitazone are the two available in Canada. They work as agonists at PPARγ receptors on the cell nucleus and cause increased cellular sensitivity to insulin i.e. increased peripheral glucose uptake. They have the benefit of not causing hypoglycemia and work well with metformin. It can take up to 3 months for them to take full effect. Contraindicated in congestive heart failure and severe liver disease. Can cause fluid retention and weight gain.
• Insulin Secretagogues: These are a third line choice after biguanides and insulin sensitizers. 
• Sulfonylureas (glyburide, gliclazide, glimepiride) -- increase insulin release from the pancreas --> insulin drives glucose into cells --> weight gain. In obese and overweight patients the weight gain can be a problem. 
• Non-sulfonylureas aka Meglitinides (repaglinide, nateglinide). -- increase insulin release by the pancreas, but are sulfa free. These are not approved in Canada (as of 2017). 
• Alpha-glucosidase inhibitors: acarbose is available in Canada.  Taken with the first bite of a meal and prevents breakdown of complex carbohydrates --> can cause bloating, gas, abdominal pain and diarrhea. They are safe to use in patients with renal dysfunction.  
• Dipeptidyl Peptidase-4 Inhibitors: alogliptin, linagliptin, sitagliptin, saxagliptin. Work by preventing degradation of glucagon-like peptide-1, which results in lowering of HbA1c by ≤1%. Used as a second or third drug in combination with other oral anti-hyperglycemic agents.
• Glucagon-Like Peptide-1 agonists: dulaglutide, liraglutide, exenatide. Work by mimicking the action of glucagon-like peptide-1. 
• Sodium-Glucose Cotransporter 2 Inhibitors: canagliflozin, dapagliflozin, empagliflozin. These are the newest anti-hyperglycemic agents, and they work by preventing glucose reabsorption in the kidneys. Side effects: mycotic genital infections, urinary tract infections, decreased bone mineral density. 
• Anti-obesity drugs: Orlistat is the only weight loss drug approved for the treatment of diabetes in obese patients in Canada. It decreases the absorption of fat in food -> fat in feces 

Insulin for Diabetes

• Types of insulin
• Long acting insulins
• Glargine, Detemir -- provides a steady insulin level throughout the day (24h duration), however it takes 1-2 hours to begin to work. These are used once a day, best taken at night or after dinner. May also be used twice a day.
• NPH -- provides a steady insulin level for about half a day (10-20h duration), and it takes a few hours (2-4h) to begin to work. It is used twice a day (breakfast, supper).
• Short acting insulins
• Rapid acting (lispro, aspart, glulisine) -- used to control glucose levels after meals, these work quickly (5-15 minutes), however they only last for a few hours (3-4h).
• Regular human insulin - used to control glucose levels after meals, works quickly (30min-1h) and lasts for a few hours (6-8h).

• Insulin regimens
• Intensive regimens  -- better control of blood glucose levels than conventional regimens and reduced long term complications. Used for type 1 diabetics and in some type 2 diabetics.
• Basal-bolus regimen
• Bolus (prandial) -- short acting insulin before each meal; monitor glucose and calculate dose with each meal. 
• Basal -- long acting insulin
• Insulin pump (continuous subcutaneous infusion)
• rapid acting insulin (lispro or aspart) delivered according to programmable settings by electronic infusion. 
• Conventional -- fixed doses given with each meal (2-3 times a day). 
• Basal insulin regimens -- used for type 2 diabetes only
• Basal only -- detemir or glargine once daily preferred; NPH can be used as an alternative
• Basal plus -- short acting insulin before the single largest daily meal, plus a long-acting insulin. detemir or glargine once daily or NPH at breakfast and supper. 

• Insulin complications / adverse effects
• Hypoglycemia -- often due to missing meals or too much exercise or high dose of insulin.
• Mild to moderate -- sweating, tremors, tachycardia, hunger, nausea, weakness. 15g or oral glucose can raise blood glucose by 2 mmol/L in 20 minutes. E.g. about 3 tbsp of sugar dissolved in water, 3/4 cup of juice, 4 glucose tablets, or 6 hard candies. 
• Severe -- confusion, altered behaviour, difficulty speaking and disorientation. 20g of oral glucose to be swallowed.
• Very severe -- seizures, coma. Unconscious patients need subcutaneous (SC), intramuscular (IM) glucagon or intravascular (IV) glucose, preferably IV dextrose if there is an IV line in place. 
• 1 mg of glucagon IM or SC. Note that glucagon is not effective in malnourished patients or in alcohol-induced hypoglycemia. 
• 20–50 mL of 50% dextrose IV over 1–3 minutes
• Hypoglycemia unawareness -- occurs after many episodes of hypoglycemia. Patients can have their blood glucose targets relaxed for 3 months while increasing self-monitoring of blood glucose.
• Immune-mediated insulin resistance -- in rare cases, antibodies against animal-insulin can be made by patients. They can be switched to human-insulin and initially with a reduced dose. 

Management of Diabetes Mellitus Complications

• Diabetic Ketoacidosis (DKA) -- metabolic decompensation -> dehydration (loss of water, K, Cl, Na), hyperglycemia, ketone bodies in the urine, confusion, acidosis. Lack of insulin means that despite total body K+ depletion, serum K+ is elevated. Dehydration may be severe enough to cause pre-renal failure. Note: normal blood glucose does not rule out DKA in pregnancy. 
• Monitoring
• CBC
• glucose, electrolytes -- repeat hourly. Capillary glucose with bedside glucometer for trends, and repeated blood draws for confirmation. 
• urea, creatinine -- pre-renal failure is a possibility with severe dehyrdation
• ABG -- repeat only if severe acidosis persists
• Infection identification -- blood/ urine cultures, radiology looking for infection/trigger, etc
• First line therapy
• Fluids - IV NS (0.9% NaCl)
• Moderate -- 500 mL for 4 h, then 250 mL for 4 h, etc
• Severe -- 1-2 L/h until hypotension/ shock corrected, then give 500 mL for 4 h, then 250 mL for 4 h, etc
• Plasma glucose should be monitored, once it is lowered to 14 mmol/L, maintain at 12-14 mmol/L by adding D5W or D10W to IV fluids
• Postassium - KCl given only when patient is producing urine, to combat K depletion. For serum K <3.5 give 40 mmol/L, and K 3.5-5.5 give 20 mmol/L and if K>5.5 monitor and give fluids, they will drive K into cells lowering serum levels.
• Insulin - only if K+ >3.3 mmol/L, insulin can be given at 0.1 units/kg/h using a second IV line. Always, keep insulin going once started. Remember, correct K first before starting insulin, because insulin will drive K into cells, further worsening any hypokalemia.  
• Second line therapies
• Bicarbonate - not used regularly; if severe acidosis -> ICU care, with 1 ampoule (50 mmol) of sodium bicarbonate in 200 mL D5W over 1 h.
• Supportive Care
• NG tube if vomiting
• Urinary catheter if no urine produced, could have urinary retention
• keep patient warm, rested
• Hyperglycemic Hyperosmolar State (HHS) -- similar to DKA, except that there isn't acidosis, rather the volume and electrolyte depletion and hyperglycemia are the main features. Management is similar -- fluids, potassium, insulin. 
• Peripheral Diabetic Neuropathy -- a chronic peripheral neuropathy pain syndrome. 
• Management of chronic peripheral neuropathic pain conditions (includes postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome II, incisional neuralgias following mastectomy, thoracotomy or bypass surgery, phantom limb pain) -- first choice is TCA or GABA derivatives (pregabalin, gabapentin). Second-line choices include SSNRIs (duloxetine, venlafaxine) and topical lidocaine, this is because these are less effective. 
• Pregabalin -- begin with 50–150 mg daily PO in 2 divided doses, then increase dose weekly by 50–150 mg/day. The usual effective dose is 300–600 mg/day with maximum allowed being 600 mg/day. Side effects include: Sedation, ataxia, edema, diplopia, weight gain, dry mouth. Safety in pregnancy unknown, so avoid if patient is pregnant. Also, this is drug does not have a generic version (as of 2017) and is very expensive. 
• Amitriptyline (Elavil®) -- begin with 10–25 mg PO at bedtime (qhs), then increase by 10–25 mg/d at weekly intervals, until pain relief or side effects. Safe in pregnancy and preferred choice in pregnant patients. Side effects: dry mouth, constipation, drowsiness, blurred vision, urinary retention, weight gain, confusion, tachycardia. Contraindications: prostatic hyperplasia (may cause/exacerbate urinary retention), significant heart disease (cardiotoxic -> arrhythmias). Drug interactions: metabolized by CP450 so many interactions (). Generic version available, less expensive. 

Review Questions

• A 45 year old male has been newly diagnosed with type 2 diabetes mellitus and his HbA1c is 7%. What is the best initial management? 
• He does not have marked hyperglycemia (HbA1c <8.5%) so, two options:
• option 1: lifestyle modifications alone with goal of reaching normal blood glucose control in 2–3 months, if he doesn't start metformin
• option 2: start metformin now 
• The best initial drug is metformin. 
• A 12 year old girl has been newly diagnosed with type 1 diabetes mellitus, what is the best initial management?
• start intensive insulin regimen
• A 47 year old male has been newly diagnosed with type 2 diabetes mellitus and his HbA1c is 8.8%. What is the best initial management? 
• Option 1: start metformin plus another oral anti-hyperglycemic agent
• Option 2: start insulin since he has marked hyperglycemia (HbA1c ≥ 8.5%)
• Which patients should be screened for diabetes mellitus? How often?
• Patients who are 40 years old and over should be screened for type 2 diabetes every 3 years and earlier if high risk for developing diabetes.
• Pregnant women should be screened for gestational diabetes in gestational weeks 24-28. 
• A 17 year old female complains of increased thirst, increased urination and weight loss. Later, she develops abdominal pain, nausea and vomiting, shortness of breath and confusion. Her blood glucose is 30 mmol/L (540 mg/dL) and . What is the most likely diagnosis?
• Diabetic ketoacidosis
• Mrs. Smith is 50 years old and has had type 2 diabetes mellitus for 10 years. She is now concerned about a gradual onset of tingling in her feet that has slowly gotten worse and is now very painful. She takes over the counter pain medications but they don't work that well. Management?
• She has peripheral diabetic neuropathy -- try amitriptyline, initially low dose (10mg at bedtime and increase slowly). Also, ensure tight glucose control to avoid worsening neuropathy. Patient education. 
• Mr. Smith is 50 years old and has had type 2 diabetes mellitus for 10 years. He also has benign prostatic hyperplasia. He has noticed a painful tingling sensation in his feet that has gotten worse over the last few months. Management?
• He has peripheral diabetic neuropathy -- pregabalin because a TCA could cause him to have urinary retention. 
• A 34 year old woman is has a 1h blood glucose of 11.5 mmol/L after 50g of oral glucose during her 24 week gestation visit. Management?
• Gestational diabetes -- lifestyle changes for 2 weeks, if not controlled start a short-acting insulin. After delivery, she should remain in hospital for 24h and blood glucose assessed. Most women return to normal glucose levels after delivery and stop insulin. Arrange for follow-up visit in 6wks-6mo after delivery to do an OGTT with 75g glucose to ensure normal glucose levels. If she has elevated blood glucose after delivery, she should continue insulin and monitor blood glucose more frequently during breastfeeding. Insulin does not pass into breastmilk because it is degraded in the GI tract. 
• A 5 year old boy arrives at the ER with nausea, vomiting, and abdominal pain. His mother reports that he has been drinking more than usual and urinating more. His pulse is rapid, and his breath smells fruity. Management?
• He likely has diabetic ketoacidosis --> Check blood glucose, urine ketones --> admit to hospital and start IV fluids (NS 500ml 4h, 250ml 2h), give KCl if K is <3.5, insulin when K>3.3, and if severe acidosis give NaHCO3
• A 15 year old diabetic boy is brought to the hospital unconscious. Earlier, he was playing basketball with his brother in front of the house. Management?
• Severe hypoglycemia -- check blood glucose level, IM/SC glucagon, place IV line, IV dextrose
• A 65 year old diabetic man is brought to the hospital by his wife. He is confused, dehydrated and has a serum glucose of 80 mmol/L. Management?
• He likely has hyperosmolar hyperglycemic state (HHS)
• Investigations - venous glucose, CBC, electrolytes, BUN/Cr, blood draw for culture, urine culture, EKG, CXR
• Tx - check venous glucose, labs (ABG, CBC, electrolytes, BUN/Cr, etc) --> fluids (NS), KCl if low K, insulin. 

References
Diabetes Canada Clinical Guidelines
http://guidelines.diabetes.ca/
Diabetes Canada 2013 Guideline Quick Reference
http://guidelines.diabetes.ca/cdacpg_resources/CPG_Quick_Reference_Guide_WEB.pdf
http://guidelines.diabetes.ca/bloodglucoselowering/therapiesrefguide
http://guidelines.diabetes.ca/cdacpg_resources/cpg_quick_reference_guide_web.pdf
Canadian Diabetes Risk (CANRISK) Questionnaire
http://health.canada.ca/apps/canrisk-standalone/pdf/canrisk-en.pdf
CANRISK score
https://canadiantaskforce.ca/tools-resources/type-2-diabetes-2/type-2-diabetes-canrisk/
CDA guide for patients on anti-hyperglycemics
https://www.healthstandnutrition.com/wp-content/uploads/2011/09/CDA-guide-to-diabetes-medications.pdf
Types of Insulin - CDA
http://guidelines.diabetes.ca/cdacpg_resources/Ch12_Table1_Types_of_Insulin_updated_Aug_5.pdf
CTC
https://www.e-therapeutics.ca/
Straighthealthcare.com <- Amazing website!
http://www.straighthealthcare.com/
Drug Product Database - government of Canada wesbite
https://health-products.canada.ca/dpd-bdpp/index-eng.jsp
Hyperglycemic Emergencies in Adults - Diabetes Canada
http://guidelines.diabetes.ca/Browse/Chapter15