Diabetes Mellitus

• Canadian Diabetes Association (CDA): Blood glucose targets for diabetes
• American Association of Clinical Endocrinologists (AACE): Blood glucose targets for diabetes
• American Diabetes Association (ADA): Blood glucose targets for diabetes

NON-PHARMACOLOGICAL MANAGEMENT:

a) Diabetes self-management education (DSME):

• Ongoing process to facilitate knowledge, skills, and ability necessary for diabetes self-care
• Objectives are to support decision-making, self-care behaviors, problem-solving and coordination with the health care provider to improve adherence to the treatment, and its outcomes, and quality of life

b) Exercise: Improves glycemic control and strength, lipid profile, increases cardiorespiratory fitness and maintain weight.

Aerobic exercises:

• Recommended for a minimum of 2.5 hr/week, with >10min per session of moderate to vigorous-intensity, with no more than 2 consecutive days without exercise

Moderate exercises:

Examples of recommended exercises in patients who have 50-70% of maximum heart rate.

• Biking/brisk walking
• Swimming
• Dancing/raking leaves
• Water aerobics

Vigorous exercises:

Recommended in patients who have >70% of maximum heart rate

• Brisk walking up an incline
• Jogging/aerobics
• Hockey/basketball
• Fast swimming
• Fast dancing

Resistance exercises:

Weight-bearing or other forms of resistance exercises that require muscular strength conducted 3 times per week, in addition to aerobic exercise. Suggest beginning initially with instruction by an exercise specialist. Examples:

• Exercise with weight machines
• Weight lifting: Start with 1 set of 10-15 repetitions at moderate weight. Progress to 2 sets of 10-15 repetitions, then 3 sets of 8 repetitions at a heavier weight

Note: Conditions which may contraindicate certain types of exercise

• Severe autonomic/peripheral neuropathy
• Preproliferative or proliferative retinopathy
• Individuals with or at high risk of CVD
• Perform stress test before initiating exercise. Monitor glucose level before, during and after exercise and ingest carbohydrate if needed to prevent hypoglycemia

c) Nutritional behavioral management:

Is adapted to the individual’s lifestyle, culture, pharmacological management of DM and concomitant medical conditions

Weight Loss:

Gradual weight loss advised to obese individuals (especially T2DM) with reasonable, achievable short term goal such as 5 kg in 3 months

• Recommended caloric restriction for overweight
  • Men = 1200-1800 kcal/day
  • Women = 1000-1500 kcal/day

Carbohydrate (45-60% of energy): Consume low-glycemic-index foods (55 or less) in place of high-glycemic-index foods (70 or more) [Glycemic Index (GI): Rise in blood glucose level per each gram of carbohydrate in consumed food relative to glucose consumption; Glucose has 100 GI ].

Low-glycemic-index foods: Example beans, vegetables, most fruits (apples), whole grain wheat bread, rye, pita bread, high bran cereals, skim or 1% milk, chicken, turkey, fish, sweet potato, pasta, converted rice.

Sucrose: Intake of up to 10% of total daily energy (e.g. 50 to 65 g/day in a 2000 to 2600 kcal/day diet) is acceptable.

Fructose: Up to 60 g of added fructose in place of an equal amount of sucrose is acceptable.

Sugar alcohols: Intake of <10 g/day of sugar alcohols (maltitol, mannitol, sorbitol, lactitol, isomalt, and xylitol) is acceptable.

Protein (15-20% of energy): Recommended intake should be at least 0.86 g/kg/day. Preference is given to vegetable protein rather than the animal protein.

Fat (<35% of energy): Restrict saturated fats to <7% of total daily energy intake and restrict trans fat intake to a minimum. Limit polyunsaturated fat to <10% of energy intake. Monounsaturated fats are preferred instead of saturated fats. Include foods rich in polyunsaturated omega-3 fatty acids and plant oils.

Vitamin and mineral supplements: Balanced diet is sufficient source, except for

• Vitamin D: 10 μg (400 IU) supplementation is recommended in persons aged >50 years
• Folic acid: 0.4 mg to 1.0 mg/day folic acid prior to conception and during the early weeks of pregnancy is recommended

Alcohol: Ingestion may mask the symptoms of hypoglycemia, reduce hepatic production of glucose and impair an individual’s judgment

Alcohol avoidance: Advised in certain medical conditions such as severe hypertriglyceridemia, pancreatitis, advanced neuropathy, liver disease, prior history of alcohol abuse, pregnancy, and lactation.

Alcohol restriction:

• Two standard drinks per day or 14 drinks per week for men
• One standard drink/day or 9 drinks/week for women and lighter weight men
• One standard drink is equivalent to:
  • 5oz/142 ml of wine (12% alcohol)
  • 1.5oz/43 ml of spirits (40% alcohol)
  • 12oz/341 ml regular strength beer (5% alcohol)

Smoking: Cessation of smoking and smoke-free environment is important in the overall management of diabetics to reduce cardiovascular risk.

Vaccination:

• An annual influenza vaccine is advised to reduce the risk of complications associated with influenza epidemics
• One-time pneumococcal revaccination is recommended for individuals >64 years old if the original vaccine was given >5 years prior

Ref: Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2008; 32:S1-S201.

d) Co-existing medical conditions

Hypertension:

• An intake of <100 mmol/day of sodium or 6g/day of sodium chloride (2.4 g/day sodium) is recommended (equivalent to <1.25 teaspoons of salt or 3 teaspoons of monosodium glutamate)
• Incorporate the ‘DASH Diet’ (Dietary Approaches to Stop Hypertension)
• Target blood pressure = systolic <130 mmHg / diastolic ≤80 mmHg

Dyslipidemia

• Restriction saturated fat to <7% and cholesterol to <200 mg/day of energy
• Omega-3 PUFA rich fish are encouraged at least once a week

Nephropathy

• Mild: Limit protein intake to 0.8-1.0 g/kg/day
• Overt nephropathy: Limit protein intake to 0.86 g/kg/day in adults
• In the presence of anemia, emphasize heme-iron (lean red meat) choices of protein while maintaining a 0.86 g/kg/day restricted intake

Neuropathy (to avoid or minimize gastropathy symptoms)

• Chew food thoroughly
• Small frequent low-fat meals
• Increase intake of foods of higher liquid consistency

PHARMACOLOGICAL THERAPY:

If the patient’s glycemic target is not achieved after 4 weeks of medical nutrition therapy, pharmacologic therapy is indicated.

Antihyperglycemic agents often used are; insulin therapy and oral glucose-lowering agents and more recently injectable incretin agents.

Type 1 diabetes mellitus (T1DM)

Basal-bolus insulin regimens (e.g. multiple daily injections or continuous subcutaneous insulin infusion) are the regimens of choice for all adults with T1DM.

Insulin regimens should be customized to the individual’s

• Treatment goals
• Lifestyle/general health
• Diet/age
• Motivation
• Hypoglycemia awareness status
• Ability for self-management

All individuals with type 1 diabetes should be counseled about the risk, prevention, and treatment of insulin-induced hypoglycemia. In some cases, you may see a honeymoon period.

Insulin regimens:

Total daily dosing (TDD) for 70 kg person

TDD = 0.5 x 70 = 35 units approximately

Basal-bolus regimens/multiple daily injections (MDI)

• Bolus (60% of TDD): Short or rapid-acting insulin before each meal
• Basal (40% of TDD): Intermediate or long-acting insulin at bedtime or intermediate insulin split twice per day

CSII (continuous subcutaneous insulin infusion)

Fast-acting insulin is used and multiple basal infusion rates can be programmed according to requirement.

• Initially calculate dose as total pre-pump dose “x” and multiply it by 80% = 0.8x
• Start the basal rate at 50% of that (0.4x) and divide it by 24 hours = (x/60) units/hr
• Divide the total carbohydrates/day into 3 equal meals and give 50% of the pre-pump dose as three equal boluses of (0.4x/3) = (x/7.5) units/meal
• If no prior insulin history is known, estimate total dose by 0.44 times the weight in kilograms

Available Insulin Preparations

Type 2 Diabetes Mellitus

Once T2DM established, initiate and maintain lifestyle modification. It is recommended to begin oral antihyperglycemic agents for patients with T2DM; who do not achieve glucose control with diet and exercise alone as per recommendations.

Hyperglycemia management in type 2 diabetes

• Available Insulin Preparations
• Commonly used oral antihyperglycemic agents

GLP-1 receptor agonist

Exenatide:

Currently approved as adjunctive therapy for use in combination with sulfonylurea, metformin, or both.

• Indicated in combination with metformin, and/or sulfonylurea to improve glycemic control in patients with T2DM, when maximally tolerated doses of these oral therapies in addition to diet and exercise do not provide adequate glycemic control

Liraglutide:

• Once-daily dosing in patients with T2DM in combination with metformin therapy or combined metformin and sulfonylurea therapy, when maximally tolerated doses of these oral therapies in addition to diet and exercise do not provide adequate glycemic control

Combined formulations are also available:

• Rosiglitazone + Metformin
• Rosiglitazone + Glimepiride
• Sitagliptin + Metformin

Newer therapeutic agents:

Amylin analogue

Pramlintide: (available in Canada now)

• Adjunctive treatment with mealtime insulin in T2DM; in patients who have failed to achieve desired glucose control despite optimal insulin therapy

Bromocriptine mesylate-(available in the USA):

• FDA-approved novel treatment for type 2 diabetes as an adjunct to diet and exercise to improve glycemic control in adults with T2DM

Gestational diabetes mellitus (GDM):

Once diagnosed monitor four times daily.

Goals:

• Fasting: 3.8-5.2 mmol/L (68-94 mg/dL)
• 1 hour postprandial: 5.5-7.7 mmol/L (99-139 mg/dL)
• 2 hour postprandial: 5.0-6.6 mmol/L (90-119 mg/dL)

Patients with GDM are high risk patients for type 2 diabetes, should be re-evaluated 6 wks and 6 months after delivery.

Diabetes sick-day

During illness or infection blood glucose level often rises even though the person is not eating.

Goals for sick-day management

• Prevention of hyperglycemia and hypoglycemia
• Maintenance of hydration

Sick-day guidelines

• Always take insulin or diabetes medication
  • Take at least the usual dosage of insulin
  • Sometimes an increase in the dosage of insulin is required
• Monitor blood glucose and urine ketones every 4 hrs
  • Drink plenty of fluids, 6-8 oz of fluid every hour is recommended
• If unable to eat, drink fluids that contain carbohydrates (e.g. fruit juices, regular soda)
  • Try to eat usual amount of carbohydrate (CHO), may be divided into smaller meals and snack, if having difficulty eating, eat or drink 15 g of carbohydrate every hour or 45-50 g of carbohydrate every 3-4 hrs

Metabolic syndrome

• Treat underlying causes (overweight/obesity and physical inactivity)
  • Intensify weight management
  • Increase physical activity
• Treat lipid and non-lipid risk factors
• Treat hypertension
  • ACE inhibitor or ARB (angiotensin receptor blocker) is usually prescribed for patients with diabetes
• Treat elevated triglycerides
  • Statin if predominantly high LDL
  • Fibrate if predominantly high triglycerides
• Use antiplatelet therapy (e.g. aspirin) for patients with CAD, stroke, PAD unless otherwise contraindicated

Acute complications of diabetes mellitus:

• Hypoglycemia
• Diabetic ketoacidosis (DKA)
• Hyperosmolar hyperglycemic state (HHS)

Hypoglycemia

Indications for hospitalization hypoglycemia:

• If induced by sulfonylurea
• Deliberate drug overdose
• Coma, seizure
• Persistent neurological changes

Management:

Mild to moderate hypoglycemia:
15 gm of fast-acting carbohydrate can be given in any one of the following ways as follows:

• Three or four commercially prepared glucose tablets
• Regular soft drink or fruit juice (120-180 ml)
• Hard candies or 6 lifesavers (1 = 2.5 g of carbohydrate)
• 3 teaspoons) or 3 packets of table sugar dissolved in water
• 15 mL (1 tablespoon) of honey

Retest blood glucose levels after ~15 minutes, and administer another 15 g glucose if BG remains <4.0 mmol/L (72 mg/dL).

Note: 15 gm of carbohydrate will produce a blood glucose increment of approximately 2.1 mmol/L (38 mg/dL) in 20 minutes.

Severe hypoglycemia in a conscious person:

• Oral ingestion of 20 g of carbohydrate, preferably as glucose tablets or equivalent.is administered
• Retest blood glucose levels after ~15 minutes, and retreat with another 15 g of glucose if the blood glucose level remains <4.0 mmol/L (72 mg/dL)

Note: 20 g oral glucose dose will produce a BG increment of approximately 3.6 mmol/L (65 mg/dL) at 45 minutes.

Severe hypoglycemia in an unconscious person or unable to have oral intake at home:

• Administer glucagon 1mg, either SC or IM in the deltoid or anterior thigh
• This should produce blood glucose rise from 3.0-12 mmol/L (54-216 mg/dL) within 60 minutes
• Once patient regains consciousness regains, high carbohydrate source snack is provided provided

Severe hypoglycemia in an unconscious person with IV access (usually hospital setting):

• Administer glucose 10-25 g (20-50 ml of D₅₀W) IV over 1 to 3 minutes
• Assure patency of IV line because hypertonic solution of 50% DW is very irritable to the veins

Diabetic ketoacidosis (DKA):

Potentially fatal complication occurs in up to 5% of Type1 DM patients.

Risk Factors:

• Interruption in insulin therapy
• Sepsis, trauma, and MI, etc.
• Pregnancy

Indications for hospitalization with DKA include:

• Plasma Glucose Levels: 14.0 mmol/L (>250 mg/dL)
• Arterial PH: < 7.30
• Serum Bicarbonate: <15 mEq/L
• Moderate ketonemia or ketonuria

Management:

• Oxygen and airway management as needed
• Immediate IV access
• Hydration: as follows

0.9% NaCl IV usually 1-2 liters should be given rapidly (if cardiac functions are normal) followed by 0.5 to 1 liter/hr until vital signs are stabilized, and urine output has been maintained.

Hypotonic saline (0.45%) in patients with severe hypernatremia (>150mEq/L).

Replenish total body water deficit by giving:

• High or normal sodium levels: 0.45% saline at 150-500 ml/hr
• Low sodium levels: 0.9% NaCl saline 150-500 ml/hr

Note: Avoid the risk of cerebral edema, do not exceed the change in osmolality >3 mmol/kg/hr.

The goal is to replace approximately 50% of the total body water (TBW) deficit in the first 8 hours and the remainder in the subsequent 16 hours.

Formula: Total body water deficit (L) = 0.6 x wt (kg) x [1-140/serum sodium]

Potassium replacement

• Potassium deficit should always be assumed. Insulin therapy should be held if K⁺ is <3.3 mmol/L, and potassium should be replaced immediately at the rate of 40 mmol/hr in a solution of one liter of 0.9% normal saline
• 10-20 mEq/hr of potassium should be added to the 2^nd or 3^rd liter of fluid unless the patient has hyperkalemia (>5.5 mmol/L or ECG evidence) or renal failure or oliguria

Monitoring

• Blood glucose levels hourly and serum electrolytes every 1-2 hours
• Continuous ECG monitoring is required

Insulin therapy:

Is necessary for resolution of the ketoacidosis, can be withheld initially in patients with marked hypokalemia.

• Immediately give IV bolus of 10-15 unit of Insulin, followed by continuous infusion of regular insulin at an initial rate of 5-10 units/hr. Dilute 100 units in 100 ml of 0.9% saline, infuse at the rate of 10 ml/hr will deliver 10 units/hr
• Target: Decrease of 2.8-4.1 mmol/hr (50-75 mg/dL/hr) of blood glucose levels

Do’s And Don’ts:

• If insulin resistance is suspected then hourly dose of regular insulin should be increased by 50-100%
• Avoid reduction at rate >5.5 mmol/L/hr (100 mg/dL/hr) due to osmotic encephalopathy
• Maintain insulin infusion over 1-2 units/hr, and continue till patient clinically improved. Once oral intake resumes insulin can be given SC

Dextrose:

• Administer Dextrose 5% in IV fluid once plasma glucose level decrease to 14.0 mmol/L (250 mg/dL). Decrease insulin rate to 0.05 units/kg/hr to avoid hypoglycemia

Bicarbonate

• Serum bicarbonate levels and closure to anion gap is a reliable parameter to evaluate metabolic recovery
• Bicarbonate therapy is considered in shock or coma, severe acidosis (pH <7.0), plasma Bicarbonate (<5 mEq/L), acidosis induced cardiac or respiratory dysfunction, and severe Hyperkalemia
• Sodium bicarbonate, 50 mEq/L of 200 ml D5W can be given over 1 hr, can be repeated every 1-2 hrs until pH≥7.0

Phosphate and magnesium

• Stores are depleted but are not replaced if the patients resume oral intake. However, magnesium is replaced if the patient is at risk of ventricular arrhythmias

Antibiotics

Should be started promptly if there are documented infections.

• Empiric broad-spectrum antibiotics can be considered if the patient is in sepsis

Complications of DKA requiring immediate recognition and prompt treatment:

Lactic acidosis:

Despite of optimal DKA management, some patients may exhibit persistent anion gap with refractory metabolic acidosis, due to prolonged dehydration, shock, and sepsis or tissue hypoxia.

Management requires the following:

• Adequate volume replacement
• Control of sepsis
• Liberal and judicious use of bicarbonates

Arterial thrombosis results in stroke, MI or ischemic limb.

• Routine anticoagulation is not recommended
• Treatment guided by clinical scenario

Cerebral edema may occur from over rehydration, especially in children, and should be quickly recognized (headache, papilledema, altered sensorium); brain CT scan may assist diagnosis.

• Treat immediately by IV mannitol

Rebound ketoacidosis may result from premature discontinuation of IV insulin or inadequate SC doses of insulin.

Hyperosmolar hyperglycemic state (HHS):

Usually occurs in patients with type 2 diabetes mellitus and has no or little ketosis.

Indications for hospitalization HHS includes:

• Plasma Glucose Levels: 22.1 mmol/L (≥400 mg/dL)
• Serum osmolality: >320 mmol/kg
• Impaired mental status

Management:

• Oxygen and airway management as needed
• Immediate IV access
• Hydration
  • Do not exceed the change in osmolality >3mmol/kg/hr
  • The goal in fluid administration is to replace approximately 50% of the total body water (TBW) deficit in the first 8 hours and the remainder in the subsequent 16 hours

Potassium replacement

• Potassium deficit should always be assumed. Insulin therapy should be held if K⁺ is <3.3 mmol/L, and potassium should be replaced immediately at the rate of 40 mmol/hr in a solution of one liter of 0.9% normal saline
• 10-20 mEq/hr of potassium should be added to the 2^nd or 3^rd liter of fluid unless the patient has hyperkalemia (>5.5 mmol/L or ECG evidence) or renal failure or oliguria

Monitoring

• Blood glucose levels hourly and serum electrolytes every 1-2 hours
• Continuous ECG monitoring is required

Insulin therapy
Not critical for the treatment of HHS as compared to hydration which should always precede insulin administration.

• Generally, insulin use is recommended to reduce plasma glucose levels

Dextrose

• Administer Dextrose 5% in IV fluid once plasma glucose level decrease to 14.0 mmol/L (250 mg/dL), to avoid hypoglycemia

Seizure control

• Requires normalization of osmolality and glucose; standard antiepileptics may be ineffective.
• Avoid phenytoin, which inhibits the release of endogenous insulin and has been associated with HHS

Bicarbonate

• One ampoule (50 mmol) of sodium bicarb in 200 ml of D5W over 1 hr, repeated every 1-2 hrs, until pH ≥7.0 is considered in adults with shock or who are having pH ≤7.0
• Watch for delayed metabolic acidosis and hypokalemia

Phosphate and magnesium

• Stores are depleted but are not replaced if the patients resume oral intake. However, magnesium is replaced if the patient is at risk of ventricular arrhythmias

Antibiotics
Should be started promptly if there is documented infections.

• Empiric broad-spectrum antibiotics can be considered if the patient is in sepsis

Complications of HHS include:
Thromboembolic events, cerebral edema, adult respiratory distress syndrome, and rhabdomyolysis.

Management of chronic complications of Diabetes Mellitus

(i) Microvascular complications include:

• Diabetic retinopathy
• Diabetic neuropathy: Includes peripheral and autonomic neuropathy, as briefly summarized in the tables
• Diabetic nephropathy

(ii) Macrovascular

Coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD) account for 80% of deaths in patients with diabetes.

• Cardiovascular risk should be assessed and treated aggressively
• Cigarette smoking should be discouraged
• Good hyperglycemic control after acute MI is beneficial
• In peripheral vascular disease (PVD) similar goals are to be achieved as described above for (CHD)
• Antiplatelet agents are recommended for secondary prevention in patients with stroke or heart disease and may have modest benefit in primary prevention in high-risk vascular patients (Framingham >20%-excluding diabetes)
• Exercise and agents such as pentoxifylline 400 mg TID and cilostazol 100 mg BID (the latter not currently available in Canada) may be helpful in intermittent claudication

(iii) The Diabetic Foot:

Proper foot care is advised to avoid problems, which includes; bathing, drying and lubricating without leaving the moisture to accumulate between the toes. Wear closed toe shoes which fit well, and trimming toenails straight across and file sharp corners.

Mild to moderate ulceration

• Rest, elevation and relief of pressure are essential
• Oral antibiotics should be started immediately e.g. amoxicillin/clavulanic acid 800 mg PO BID; cloxacillin 500 mg QID, first-generation cephalosporin or clindamycin are recommended
• If cellulitis does not respond with oral antibiotics IV should be started

Moderate to severe ulceration

• Infections require hospitalization and IV antibiotics
• Debridement may be required; both aerobic and anaerobic cultures are sent
• Empiric antimicrobials are given intravenously and the coverage is tailored according to response and cultures, agents like clindamycin, vancomycin, and fourth generation cephalosporin’s, ampicillin/sulbactam may be considered

Moderate to severe with ischemia or significant local necrosis

• Determine the presence of bone involvement and peripheral vascular disease
• IV antibiotics, surgical debridement, bed rest, cultures are the mainstay of treatment
• Presence of osteomyelitis requires 6-12 week of IV Antibiotics
• Localized or generalized ulcers with gangrene require amputation

Additional information in patients with or without diabetes who are admitted and managed in the hospitals.[/cq_vc_tab_item][cq_vc_tab_item tabtitle=”Medication Dose”]MEDICATIONS:

Insulin secretagogue

Sulfonylurea, first-generation agents

• Chlorpropamide
• Tolazamide
• Tolbutamide

Sulfonylurea, second-generation agents

• Glimepiride
• Glipizide
• Glyburide

Meglitinide drugs

• Nateglinide
• Repaglinide

Mechanism

• Blocks ATP-dependent potassium channels in the β-cell membrane → Depolarize the β-cell → Facilitating calcium entry through calcium channels → Increased calcium influx induces insulin secretion from the pancreatic beta cells
• Decrease in serum glucagon level
• Enhances peripheral utilization of glucose
• Decrease in hepatic insulin degradation and gluconeogenesis
• First generation sulfonylureas are differed with second-generation in their pharmacokinetics and lower dosage
• Meglitinides do not contain sulfur in their structure and have a rapid onset and short duration of action as compared to sulfonylurea

Dose:

Sulfonylurea, first-generation agents

Chlorpropamide

• 100-250 mg PO once daily; may titrate by 50-125 mg/day at 3-5-day intervals; Max. 500 mg/day

Tolazamide

• 100-250 mg PO once daily; with breakfast or the first main meal of the day; may increase dose by 100-250 mg/day every week if needed; Max. 1 g/day

Note: If >500 mg/day; divide in 2 doses over 24 hrs

Tolbutamide

• 1-2 g/day PO in 2-3 divided doses; usual 500-3000 mg/day; maintenance dose of >2g/day seldom required

Sulfonylurea, second-generation agents

Glimepiride

• 1-2 mg PO once daily; with breakfast or the first main meal; may increase dose by 1-2 mg/day every 1-2 wks; usual 1-4 mg PO once daily; Max. 8 mg/day

Dose in Renal Impairment: Cl_Cr <22 mL/minute à Start 1 mg PO once daily; may increase dose slowly

Glipizide

• 5 mg PO once daily; may titrate dose by 2.5-5 mg/day as needed at least with intervals of several days; Max. 15 mg/dose and 40 mg/day (divide dose if >15 mg/day); for extended-release tablet maximum dose is 20 mg/day

Dose in Hepatic Impairment: Start with 2.5 mg/day

Glyburide

• 2.5-5 mg PO once daily; may titrate by 2.5 mg/day every week; Max. 20 mg/day in divided doses

Meglitinide Drugs

Nateglinide

• Initial and maintenance 120 mg PO TID before meals; 60 mg PO TID in patients who are near HbA_1c goal; can be given alone or in combination with metformin or a thiazolidinedione

Repaglinide

• HbA_1c <8% or Not treated previously → Start 0.5 mg PO with each meal; usual 0.5-4 mg
• HbA_1c is ≥8% or Treated previously → Start 1-2 mg PO with each meal; usual 0.5-4 mg

Note: May titrate dose by double up to 4mg /dose; to a Maximum dose of 16 mg/day. At least lapse of one week is required to reassess the glucose levels

Dose in Renal Impairment: ClCr 20-40 mL/minute → Initial 0.5 mg before each meal, titrate carefully; ClCr <20 mL/minute → Use not established

Dose in Hepatic Impairment: conservative doses should be used

Biguanides

• Metformin

Mechanism

• Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Dose

Metformin

Immediate-release form

• 500 mg PO BID or 850 mg PO daily; may increase by 500 mg/wk or 850 mg/every other week; Max of 2550 mg/day in 3 divided doses

Extended-release form

• 500 mg PO daily; Usual 1-2 gram PO daily; May increase dose 500 mg/day every week to max 2g/day. Always use divided doses if giving >2000 mg/day for better tolerance

Concomitant with insulin therapy

• Start Metformin 500 mg PO daily; may increase by 500 mg/day weekly until adequate control is achieved; Max 2000 mg/day

Alpha-glucosidase inhibitors

• Miglitol
• Acarbose

Mechanism

• Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucoside hydrolase → which results in delayed digestion/absorption of carbohydrates → leading to post-meal lowering of glucose, delaying glucose absorption.

Dose:

Miglitol

• 25 mg/day PO TID at the start of each meal; may increase to 50 mg PO TID at least after 4-8 weeks and to 100 mg TID after 3 months, if required; Max. 300 mg/day

Acarbose:

• Initial 25 mg PO TID at the start of each meal; usual 150-300 mg/day PO TID; may increase dose every 4-8 weeks prn; Max. in ≤60kg: 150 mg/day in 3 divided doses, >60 kg: 300 mg/day in 3 divided doses

Insulin Sensitizers (Thiazolidinediones)

• Pioglitazone
• Rosiglitazone

Mechanism

Increases insulin sensitivity without increasing pancreatic insulin secretion

• An agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma) → found in key target tissues for insulin action → activate nuclear PPARgamma receptors → this influences the production of a number of gene products involved in glucose and lipid metabolism → lowers blood glucose

Dose:

Pioglitazone

• 15-30 mg/day PO once daily; may increase up to 45 mg/day; Max. 45 mg/day

Rosiglitazone

• Initial 4 mg/day PO once daily or in 2 divided doses; if inadequate response after 8-12 weeks the dose may be increased to 8 mg in 2 divided doses; Max. 8 mg/day

Note: Adjunct with a sulfonylurea, maximum dose is 4 mg/day

Dipeptidyl peptidase IV inhibitors

• Sitagliptin
• Saxagliptin
• Linagliptin (available now in Canada)

Mechanism

Inhibits dipeptidyl peptidase IV (DPP-IV) enzyme resulting in

• Prolonged active incretin levels
• Incretin hormones regulate glucose homeostasis by
  • Increasing insulin synthesis and release from pancreatic beta cells
  • Decreasing glucagon secretion from pancreatic alpha cells

Decreased glucagon secretion results in decreased hepatic glucose production.

Dose:

Sitagliptin

• 100 mg PO once daily; Max 100 mg/day
• 75-85% renally excreted

Dose in Renal Impairment: ClCr 15 to <50 mL/min → 50 mg PO once daily; ClCr <30 mL/min → 25 mg PO once daily

Saxagliptin

• 5 mg PO once daily
• Approximately 50% renal excretion

Dose in Renal Impairment: ClCr 15-50 mL/min → 2.5 mg PO once daily; end-stage renal disease → not recommended

Linagliptin

• 5 mg PO daily with or without food
• Minimal renal excretion

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist

• Exenatide
• Liraglutide

Mechanism

Activates glucagon-like-peptide-1 (GLP-1) receptor, this

• Increases insulin secretion and B-cell growth/replication
• Decreases inappropriate glucagon secretion
• Delay gastric emptying

Doses:

Exenatide:

• Initial 5 mcg SC BID; within 60 minutes prior to meals; may increase to 10 mcg SC BID after 1 month, if needed

Note: Give at least an interval of 6 hours between dosing and do not take after a meal.

Liraglutide:

• Start 0.6 mg SC daily x 1 week at least; then increase to 1.2 mg SC daily; after at least 1 week may increase to 1.8 mg SC daily as needed to achieve maximum effect

TYPES OF INSULIN:

Rapid-acting Insulin

• Insulin lispro
• Insulin aspart
• Insulin glulisine

Short-acting

• Regular insulin

Intermediate-acting

• NPH insulin (NPH = Neutral Protamine Hagedorn, also known as isophane insulin)

Long-acting, subcutaneous

• Insulin detemir
• Insulin glargine

Combinations

• 50/50 (50% NPH, 50% regular)
• 70/30 (70% NPH, 30% regular)
• 70/30 (70% protamine aspart, 30% aspart)
• 75/25 (75% protamine lispro, 25% lispro)
• 50/50-(50% protamine lispro, 50% lispro)

Mechanism

Insulin acts via specific membrane-bound receptors on target tissues.

• Enhanced peripheral glucose uptake and protein synthesis
• Inhibits hepatic glucose production, lipolysis, and proteolysis

Insulin increases the cellular permeability of several electrolytes, such as

• Potassium, magnesium, and phosphate

Insulin activates sodium-potassium ATPase; this promotes the intracellular movement of potassium.

Rate of absorption, onset, and duration of activity may be affected by:

• Site of injection, exercise, lipodystrophy, local blood supply, temperature

Dose:

Rapid-acting Insulin: Duration effect of Rapid-acting Insulin is <5 hours

Insulin Lispro; Insulin Aspart; Insulin Glulisine

• Usual total insulin requirement 0.5-1 units/kg/day SC divided in 3-4 doses
  • Give <15min before meals or within 20 min after starting a meal
• IV infusion: Diluted in NS or D₅W to concentrations of 0.025-2 units/mL. Stable for 48 hours at room temperature

Dose in Renal Impairment:

• Insulin Lispro: ClCr 10-50 → Decrease dose 25%; ClCr <10 → Decrease dose 50%; Dialysis → No supplement
• Insulin Aspart; Insulin Glulisine: Decrease the dose

Short-acting Insulin: Duration effect of Regular Insulin is ~5-8 hours

Regular Insulin:

• Usual insulin requirement 0.5-1 units/kg/day SC divided in 2-3 doses. Give <15min before meals or within 20 min after starting a meal
• IV infusion: Diluted in NS or D₅W to concentrations of 0.025-2 units/mL

Dose in Renal Impairment:

• ClCr 10-50 → decrease dose 25%; ClCr <10 → decrease dose 50%; Dialysis → no supplement

Diabetic ketoacidosis/Hyperosmolar hyperglycemic state

• IV Bolus: 0.1 units/kg bolus (optional)
• IV Infusion: 0.1-0.14 units/kg/hour.

Note: If no IV bolus was administered, patients should receive a continuous infusion of 0.14 units/kg/hour

• SC/IM: 0.4 units/kg bolus (0.2 units/kg as an IV and 0.2 units/kg as SC or IM); then 0.1 units/kg given every hour SC or IM

Hyperkalemia

• IV: 10 units IV regular insulin mixed with 50 mL D₅₀W given over 15-30 minutes OR50 mL D₅₀W over 5 minutes followed by 10 units regular insulin IV push over seconds (in imminent cardiac arrest)

Intermediate-acting Insulin: Duration effect of NPH insulin is ~10-18 hours

NPH insulin:

• Usual total insulin requirement 0.5-1 units/kg/day SC (divided in 2-3 doses). Give <15min before meals or within 20 min after starting a meal

Dose in Renal Impairment:

• ClCr 10-50 → Decrease dose 25%; ClCr <10 → decrease dose 50%; Dialysis → no supplement

Long-acting Insulin: Duration effect of Insulin Detemir is ~16-23.2 hours; and Insulin Glargine is up to 24 hours

Insulin Detemir

• Type 1 DM: Start 0.5-1 units/kg/day SC in divided dose; usual dose 0.5-1.2 units/kg/day SC in divided doses
• Type 2 DM: Start 0.1-0.2 units/kg SC (every evening) or 10 units SC every evening or divided into 2 doses; may increase dose by 2 units/day every third day until glycemic targets achieved

Insulin Glargine

• Type 1 DM: Start 0.5-1 units/kg/day SC in divided dose; usual dose 0.5-1.2 units/kg/day SC in divided doses
• Type 2 DM: Initial 10 units SC daily at bed time; may increase dose by 2 units/day every third day until glycemic targets achieved

Newer therapeutic options

Amylin analogue

• Pramlintide (available in the USA not in Canada)

Mechanism

Decreases the rise of postprandial plasma glucose by

• Prolonging of gastric emptying time
• Suppresses postprandial glucagon secretion
• Promotes satiety leading to reduction of caloric intake and potential weight loss

Doses:

Note: When initiating pramlintide, decrease current insulin dose by 50% to avoid hypoglycemia

• Type 1 DM: Initial 15 mcg SC immediately prior to meals; may increase by 15 mcg SC every third day to target dose of 30-60 mcg, if needed and nausea is tolerable

Note: Consider Pramlintide discontinuation if 30 mcg dose is not tolerated

• Type 2 DM: Initial 60 mcg SC immediately prior to meals; may increase to 120 mcg SC after 3-7 days, if needed and nausea is tolerable

Note: If nausea occurs at 120 mcg dose, decrease dose to 60 mcg

Dopamine receptor agonist

• Bromocriptine

Mechanism

• Exact mechanism is not known
• Activates postsynaptic dopamine receptors in the striatum and substantia nigra
• Bromocriptine also suppresses growth hormone production and decreases prolactin secretion
• Results in the reversal of insulin resistance and decreases in glucose production
• It decreases fasting and postprandial hyperglycemia without increasing insulin levels

Doses:

• Type 2 DM: Start 0.8 mg PO every morning; may increase by 0.8 mg every week as tolerated to the maximum dose of 4.8 mg/day; usual dose 1.6-4.8 mg PO every morning

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