Diabetes Flashcards
Are outcomes for diabetes improving?
Yes, they have never been better
What is the official definition of diabetes mellitus?
A metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, insulin action, or both
What is the prevalence of Diabetes?
4 million diagnosed (10% of population), but about 30% have diagnosed, undiagnosed, or prediabetes
How has the prevalence of diabetes among adults in Canada shifted over the last 50 years?
It has almost doubled from 14% in 1970 to 29% in 2021
What are some of the reasons for the shift in the number of Canadian adults with diabetes?
Demographic changes (Canadians are getting older, and more people from risk populations are becoming Canadians)
What are the costs associated with diabetes?
Estimated economic impact: $30 billion/yr
Medical costs are 2-3x higher in those with diabetes
What are some complications associated with diabetes?
CVD (the main cause of death), kidney dysfunction, blindness, neuropathy, amputation)
80% will die from heart disease and stroke
How much can diabetes reduce life expectancy?
an estimated 5-15 years
What is the role of the pancreas in blood sugar maintenance?
Euglycemia (ideal blood sugar) is maintained by the following three hormones
Alpha (produce glucagon, account for 30% of islet cells)
Beta (produce insulin, account for 60% of islet cells)
Delta (produce somatostatin, account for 10% of islet cells)
View slides 13-14 to review the interplay of insulin and glucagon
What is the effect of insulin on skeletal muscle?
Muscle is the major site of glucose uptake, and insulin stimulates glucose uptake
Glucose is stored as glycogen in muscle and it is used in energy metabolism (glycogenesis)
Insulin also stimulates the production of proteins from amino acids.
Between meals, energy stored in proteins is harvested by breaking them down back into amino acids. These amino acids can undergo gluconeogenesis, producing glucose
What happens in diabetes with respect to skeletal muscle?
Glucose is never able to be taken up by skeletal muscle cells, therefore limiting energy sources
What is the effect of insulin on the liver?
The liver produces glycogen (product of insulin-induced uptake of glucose), and insulin release following a meal will stimulate the liver to pull glucose from the blood and form glycogen
Insulin also suppresses gluconeogenesis
If the amount of glucose entering the liver is more than the storage capacity for glycogen, insulin promotes its conversion to fatty acids
Between meals, glucagon is released. This hormone promotes glycogenesis and gluconeogenesis, producing glucose
What is the effect of insulin on adipose tissue?
Insulin is effectively a fat storing hormone
Excess carbs are converted into fatty acids and stored as triglycerides in adipose tissue
In starvation or insulin deficiency, fats break down and form ketones. These ketones can be used as an energy source (lipolysis)
What is the effect of insulin on the brain?
The brain gets all of its energy from glucose, but does not depend on insulin for glucose uptake.
The brain is not directly effected by insulin, but low blood sugar due to insulin activity can cause states of confusion to unconsciousness
What are the different classifications of diabetes covered in this course?
Prediabetes:
Impaired glucose tolerance (IGT)
Impaired fasting glucose (IFG)
Diabetes:
Type 1
Type 2
Gestational Diabetes
Describe Type 1 Diabetes Mellitus (T1DM)
Characterized by an absolute lack of insulin secretion
Primarily due to autoimmune beta-cell destruction
Typically, markers of immune destruction are present: islet cell antibodies and insulin antibodies.
Not uncommon to see patients with T1DM to also have other autoimmune diseases
Is Type 1 Diabetes (T1DM) a disease often seen in children?
Yes, it is most commonly has its incidence in patients under 25 (13-14 yo. peak)
But we can occasionally see cases that emerge in the sixth and seventh decade of life
In children with diabetes, most of them have Type 2 diabetes. True or False?
False, most children (95%) have Type 1 diabetes
Adults with diabetes on the other hand show Type 2 diabetes (90%) of the time
Are Type 1 Diabetes (T1DM) incidence rates falling now?
No, it appears that they have a doubling time of a few decades
What initiates Type 1 diabetes and the subsequent breakdown of beta cells?
This immunologic trigger remains elusive, perhaps due to exposure to a virus or toxin
Review slide 24 to closely see how Type 1 diabetes (T1DM) progresses in terms of beta cell function
When do symptoms in Type 1 Diabetes manifest?
After 80-90% of beta cells have been destroyed
What is the “honeymoon phase” in Type 1 Diabetes (T1DM)?
Following initial correction of hyperglycemia with exogenous insulin, causes endogenous insulin production to recover temporarily
This usually occurs in the days to weeks following starting insulin
This “recovery” is temporary, so insulin therapy and monitoring continues
What is significant about treatment in prediabetes?
Many trials have shown diabetes can be prevented in those with prediabetes via lifestyle modifications or medications. Many patients will revert to normoglycemia
What are the details of prediabetes diagnosis in terms of relevant lab values?
Fasting plasma glucose (mmol/L): 6.1-6.9, IFG (impaired fasting glucose)
Glucose levels 2h after 75g of glucose is consumed (mmol/L): 7.8-11.0, IGT (impaired glucose tolerance)
A1C%: 6.0-6.4, Prediabetes
What is the relevance of A1C% and risk for developing diabetes?
Slight increased in A1C% = Significant changes in risk for diabetes
ex. A1C% (5.0-5.5) = (less than 5-9% risk of diabetes in the next 5 years)
A1C% (6.0-6.5) = (25-50% risk of diabetes in the next 5 years)
Describe Type 2 Diabetes (T2DM)
It accounts for 90% of DM
It is caused by impaired insulin secretion and resistance
Manifests only in those who lose the ability to produce sufficient quantities of insulin to maintain normoglycemia in the face of insulin resistance
What are some causes of Type 2 Diabetes (T2DM)?
Involves the interaction of genetic and environmental factors
Genetics: certain genes have been shown to determine risk for T2DM
Environ.: excessive caloric intake, sedentary lifestyle
Aging
What are some risk factors for T2DM?
Age over 40
First-degree relative with T2DM
Member of high risk population (African, Arab, Asian, Hispanic, Indigenous, or South Asian, low socioeconomic status)
Overweight/obesity
History of prediabetes
Low HDL, high TG, HTN, smoking
Explain how abdominal obesity is a risk for diabetes?
Insulin resistance is found in most obese people (WC (male over 102cm, and female over 88cm)
The degree of obesity correlates with degree of insulin resistance
Visceral adipose tissue is even worse, and it is especially stubborn to insulin action
Why is insulin secretion impaired in response to food in patients with T2DM?
Impaired cell function (remaining cells put into overdrive and this degrades them)
A reduced stimulus from incretin hormones
What are the consequences of defective insulin secretion?
Hyperglycemia
In early stage, elevated PPG (post-prandial glucose)
In late stage, elevated FPG (fasting plasma glucose)
How does insulin resistance work in different organs?
There is reduced sensitivity yo the actions of insulklin by the target tissues (muscle, liver, adipocytes)
Skeletal muscle (primary site of resistance): Decreased glucose uptake
Liver: inability to suppress hepatic glucose production (gluconeogenesis)
Adipose tissues: Elevated fatty acids in circulation can stimulate liver glucose production, impair skeletal muscle sensitivity, and impair insulin release
review the Ominous Octet on page 35, to examine the many causes and effects of hyperglycemia
Are the symptoms of T2DM apparent from the get go?
No, T2DM is a progressive disease. This means that that insulin secretion and resistance gradually decreases over long periods of time (years)
What is the clinical presentation of Type 1 Diabetes (T1DM)?
Usually presents as acute symptoms of short duration:
Polyuria (frequent urination)
Polyphagia (frequent eating)
Polydipsia (excessive thirst)
Weight loss
Fatigue
Blurred vision
Infections
What is the clinical presentation of Type 2 Diabetes (T2DM)?
Is commonly discovered incidentally, as patients may be asymptomatic. If symptoms exist, they are non-specific:
Fatigue
Polyuria
Polydipsia
Nocturia
Due to T2DM slow progression, at time of diagnosis, the patient may have already developed complications (ex. micro/macrovasular damage)
Review slide 40 and 41 to study clinical features in both Type 1 and Type 2 Diabetes
Are people with Type 1 Diabetes usually obese?
They are usually thin, but due to general widespread obesity in the population, they may be obese (Type 1 diabetes is not making them obese)
What is the relationship between Type 2 Diabetes (T2DM) and children?
Traditionally children have not been affected by T2DM
It’s predicted that 1 in 3 kids born 2000 will develop diabetes at some point, and 1/3 of diagnoses in patients under 18 will be of T2DM
What is the trend of obese children in terms of their body weight in adulthood?
They will usually remain obese. Adults are getting more obese every generation as obese children become adults
What is gestational diabetes mellitus (GDM)?
A condition that develops during pregnancy primarily due to insulin resistance
Overall prevalence 4% (indigenous women 8-18%)
Gestational diabetes mellitus increases the risk of fetal hyperinsulinemia, heavier birth weight, higher rates of C-sections, and neonatal hypoglycemia.
Increases the risk of both mother and child eventually developing T2DM
What are some risk factors for gestational diabetes mellitus (GDM)?
All women should be screened for GDM between 24-28 weeks of pregancy
Previous GDM
Member of high-risk population
Previous delivery of macrosomic infant (heavy baby)
Age over 35
Obesity
Can Type 1 Diabetes (T1DM) be prevented?
No successful preventative interventions thus far
Can Type 2 Diabetes (T2DM) be prevented?
Yes, primarily targeting high risk individuals (IGT or obesity to prevent progression)
Methods:
Lifestyle modification
Metformin
Other Antihyperglycemic agents (Acarbose, Pioglitazone, Rosiglitazone, Orlistat, Liraglutide)
Is lifestyle modification effective in preventing prediabetes from advancing into T2DM?
Yes, intensive lifestyle modification can reduce the incidence of diabetes more than antihyperglycemics like Metformin.
The effects of lifestyle modification, even if return to previous habit for years, the incidence of diabetes is still lower vs. patients that were on antihyperglycemics alone
Is screening done in T1DM?
No, screening is not recommended due to low prevalence of T1DM and there is nothing we can do to prevent T1DM
Is screening important in T2DM?
Yes, it is important because a large number of people are undiagnosed. We use FPG and A1C as our initial screening tests
Review Slide 56 for details on screening guidelines for T2DM
What is a common tool used to determine risk level in diabetes?
CANRISK (Canadian Risk Assessment Questionnaire)
This risk assessment tool takes into consideration the following:
Patient age, sex, height, BMI, WC, physical activity, HTN, hyperglycaemia during illness or pregnancy, family history, ethnic group, and education
This test helps identify which patients should be referred to physicians for further work-up
What are some test results that result in a diabetes diagnosis?
FPG more than 7.0mmol/L
A1C more than 6.5%
2hPG(75mg) more than 11.1mmol/L
Random PG more than 11.1mmol/L
Is FPG more convenient vs A1C?
No, FPG requires fasting (fasting plasma glucose), while a blood sample for A1C can be administered at anytime without respect to meals
What are some advantages and disadvantages of FPG (fasting plasma glucose)?
Advantages:
Established standard of reliability
Fast and easy
Disadvantages:
Inconvenient
Less sensitive than 2hrPG(75mg)
What are some advantages and disadvantages of A1C?
Advantages:
Convenient
Better predictor of CVD
No day-to-day variability
Disadvantages:
Cost
Results invalid in some medical conditions (anemia, hemoglobinopathies)
Altered by ethnicity and aging
Do not use in children, gestational diabetes mellitus, and suspected T1DM
What are some of the advantages and disadvantages of 2hrPG(75mg)?
Advantages:
Like FPG, 2hrPG(75mg) is an established standard
Disadvantages:
Inconvenient (need to wait 2h before patient can test themselves
Taste
Cost
What are some complications of diabetes that first come to patients when they are first told they have diabetes?
Patients often think about end stage outcomes of poorly managed diabetes.
Amputation, and kidney failure/dialysis are some common worries
What are some general treatment goals for diabetes?
- Be symptom free (avoid hyper or hypoglycaemia)
- Achieve personalized target glucose levels
- Address modifiable CV risk factors
- Prevent or slow the progression of micro vascular complications
- Empowerment to self-manage condition
How can glucose control be adequately monitored?
This is an essential component of diabetes management
Blood glucose lab evaluations
Hemoglobin A1C
Capillary blood glucose (cBG)
Continuous glucose monitoring (CGM):
Intermittently scanned CGGM (isCGM), ex. Libre
Real-time CGM (rtCGM), ex. Dexcom G6
Ketone testing (urine or blood)
What is the significance of glycosylated hemoglobin?
The percentage of glycosylated hemoglobin A is represented by A1C. This glycosylation reaction is irreversible, so glycosylated hemoglobin remains in the blood supply until they breakdown in 3 month
How often should a A1C testing be preformed on a patient?
Should be checked at least every 3 months. You may feel like you are okay, but could be silently at high risk of developing diabetes
Normal A1C levels are 4-6%
What are some general conditions that could affect A1C levels?
Any condition that can effect RBC, will change their A1C values.
ASA and Vitamin C and E can decrease A1C
Review slide 68 for more details on how different conditions can effect A1C
What are some A1C targets?
Selected adults with T2DM who have the potential to return to normoglycemia (under 6.0%)
Adults with T2DM to reduce CKD and retinopathy if at low risk for hypoglycaemia( 6.0-6.5%)
Most adults with T1DM or T2DM (6.5-7.0%)
Functionally dependent people (7.1-8.0%)
Recurrent severe hypoglycaemia, limited life expectancy, and frail elderly and/or with dementia (7.1-8.5%)
Avoid any A1C target above 8.5%
What is the A1C target for most diabetes patients?
7.0%
What are the FPG and 2hrPG(75mg) targets to achieve an A1C score below 7.0?
FPG: 4.0-7.0mmol/L (4.0-6.0 is more aggressive)
2hrPG(75mg): 5.0-10.0mmol/L (5.0-8.0 is aggressive)
Why do HCPs like to bring A1C below 7.0?
Great decreases in retinopathy (-63%), neuropathy (-60%), and microalbuminuria (-39%).
Is intensive treatment that results in A1C being depressed below an A1C of 7.0% worth it?
Yes, although this increases risk of hypoglycaemia, overall reductions in other diseases associated with diabetes are well worth it
Do the effects of intensive A1C depression persist?
Although A1C may return to a level above 7.0 in a shorter period of time (1 year), risk reductions persist for over a decade
If reducing A1C to below 7.0% presents great benefits, why is the A1C target not set lower?
In a trial where the A1C target was set to 6.0%, there were more deaths than usual. This trial was stopped early due to the number of deaths
Increase in mortality is likely due to increased severe hypoglycaemia or other less understood reasons
What are some limitations with A1C?
A1C is an average value, we cannot detect lows and highs in blood glucose levels
A1C cannot tell us changes in the day-to-day, because it is an average value of 3 months of glycosylation
What are capillary blood glucose monitors?
These are the standard glucose monitors
They determine the glucose level in a capillary blood via a finger stick
This monitor can tell a patient their blood glucose level at a particular point in time (immediate feedback)
What do patients need to know about CBGs (capillary blood glucose monitors)?
How to perform a CBG
How often and when to perform a CBG (before or after meals)
The meaning of various blood glucose levels:
FPG - reflects glucose derived from hepatic production (gluconeogenesis)
PPG - how meals effect glucose
How behaviour and actions affect CBG results (interpretation of trends in blood glucose)
How many times should diabetes patients check their blood sugar?
At least as many. Times as insulin is injected.
Test before injecting insulin to determine required insulin quanity.
Optional: Test 2 hours after meal to see the efficacy of insulin (lower blood sugar)
DO diabetes patients need to test themselves regularly if they are not on insulin or have stable blood sugar levels?
No, there is no point plus it is expensive to test everyday for no reason
This is why the Sask Drug Plan only covers for 200 strips in diabetic patients in this category
How do intermittently scanned CGM monitors work?
They measure glucose levels in the subcutaneous interstitial fluid via a sensor that is inserted into the skin. These monitors can help identify when a patient goes into either hyper or hypoglycaemia
Ex. Libre
What is glucose lag?
Intermittently scanning CGMs measure blood sugar in subcutaneous tissue. Changes in actual blood sugar can take up to 5-15 minutes to be reflected in subcutaneous tissue.
This is a minor issue, focus on the overall trend
What is the difference between intermittently scanning CGMs (isCGM) and real-time continuous glucose CGMs (rtCGM)?
rtCGMs like isCGMs detect glucose levels in the subcutaneous tissues, instead of blood glucose directly
The main difference is the continuous data visibility 24/7 offered by rtCGMs. rtCGMs punch out data every 5 minutes vs. every 15 min in isCGMs
rtCGMs can be applied on back of arms, abdomen, buttocks while isCGMs can only be applied on the back of arm.
Ex. Dexcom G6
What is Time in Range (TIR)?
Newer CGMs continuously check glucose levels, diabetes patients can monitor the time they spend within their target blood glucose range
Most diabetes patients should aim to be within TIR for 70% of the time (17h/24h)
There is a shift away from FPG and PPG and towards using TIR
What is the exact relationship between TIR and A1C?
Every 10% (2.4h/24h) increase in TIR = 0.5% decrease in A1C
What is the relevance of ketones in diabetes?
Ketones are formed as a byproduct of fat breakdown. Fats are broken down because the body is unable to pull glucose from the blood. Increased ketones can indicate cell starvation and poorly managed diabetes
What are the two main approaches to achieving glucose targets?
Non-pharmacological
Pharmacological
What is the non-pharmacological treatment for Diabetes?
Diet modification is the cornerstone of diabetes care. It can be 1st line + exercise for T2DM
How does nutritional education play out in T1DM and T2DM treatment?
T1DM: Nutritional education is vital to understand the relationship between carbohydrates, insulin, and blood glucose
T1DM and T2DM: Nutritional education should focus on understanding the relationship between food and its effects on body weight, blood glucose, BP, and lipids (CV risk)
Is there a standardized diabetic diet?
No, there is nor such thing as a diabetic diet
Each patient should meet with a dietitian if possible to individualize diet based on patient goals and preferences(be mindful of the cultural importance of food)
What are some diets that are popular in diabetes control?
Mediterranean
Vegan/ vegetarian
Low CHO (50-130g/d)
DASH (Dietary Approaches to Stop Hypertension)
Intermittent Fasting
Is all weight loss beneficial in terms of health?
5-10% weight loss has shown to provide health benefits, but weight should only be reduced if it poses a health benefit (do not be underweight)
What is the place of carbohydrates in the diet of a diabetes patient?
Generally people should consume 45-60% of their diet from carbohydrates
In patients that use insulin, know the relationship between carbohydrates, insulin, and blood glucose is paramount. Ensure diabetes patients who are on insulin, are counting carbohydrates to accurately adjust insulin doses
What is glycemic index, and is a smaller number better?
Glycemic Index is a measure of how quickly a given piece food will elevate blood glucose levels. More simple sugars=higher glycemic index
A smaller Glycemic Index value suggests that the piece of food in question delivers glucose over a longer period of time (shorter peak). This is reduces the risk of being hyperglycemic while on insulin (if not adjusting dose)
Do whole fruits have a higher glycemic index vs. Fruit juice?
No, fruit juice has a higher glycemic index vs. whole fruits
Fruit juice will increase blood glucose much more faster and will have a higher peak glucose blood glucose concentration
What groups of food have little or no carbohydrate?
Meat & Alternative (except for some beans)
Vegetables (except squash, parsnips, and peas)
Fats
What is the utility of fibre in diabetic patients?
Soluble fibre slows gastric emptying and delays sugar absorption in small intestine (it is a type of carbohydrate that cannot be digested, so subtract from total carbohydrates)
For patients 19-50, 25g/d(women), and 38g/d (men)
For patients over 50, 21g/d(women), and 30g/d(men)
Review Slides 118-120 to look at some diets followed by diabetes patients
What are some definitions for servings for different groups of food?
Grains & Starches, Fruits: 1 serving = size of patient’s fist
Meat & Alternatives: Size of the patient’s palm
Vegetable: As much as the patient can hold in their two hands
Fats: Limit fat to a amount the size of your thumb
Can practicing Muslim diabetes patients follow Ramadan safely?
Depends on their individual risk factors
Guidelines encourage consultation with dieticians/diabetes educators two months before Ramadan
Advise T1DM patients across the board to not fast (it is their choice ultimately)
T2DM patients with the following are advised to fast during Ramadan with medical advise:
Well controlled diabetes
Treated with lifestyle modifications alone, or with antihyperglycemics, or basal insulin (not bolus insulin) in otherwise healthy individuals
What are some nutritional tips that can help control blood sugar?
Consistent spacing of meals
Snacking between meals could help with hyperglycemia
Sugar is acceptable up to 10% of daily energy intake
Coffee is fine in moderation
What is the effect of alcohol on diabetes patients?
With people with T1DM, or with T2DM on insulin or sulfonylureas; alcohol can delay hypoglycaemia
Hypoglycaemia can persist for up to 24h after the last drink
It is important that diabetes patients test regularly when they are drinking alcohol
What is the effect of physical activity on diabetes patients?
Physical activity increases cardio/respiratory fitness and can decrease insulin resistance
Physical activity has been proven to improve A1C in T2DM and T1DM in kids, but evidence is less clear for T1DM in adults
Exercise still reduces risk of CVD and stroke even if it does not directly reduce diabetes markers
What are the recommendations for exercise in diabetes patients?
More than 150 min of moderate to vigorous intensity aerobic exercise/week
Spread over more than 3 days/week
No more than 2 consecutive days of no activity
Resistance training more than 2 times/week
Should diabetes start the recommended level of exercise immediately after diagnosis?
No, MD has to assess for conditions that can predispose to injury (neuropathy, retinopathy, CAD)
Ensure patient can tolerate exercise from a cardiovascular aspect (perform ECG)
What is the effect of exercise on blood glucose?
Low-moderate intensity:
Decreases blood glucose during and after due to increased insulin sensitivity (decreased insulin resistance lasts for up to 48h)
Very intense exercise:
Increases blood glucose during and after due to increased glucose demand
What are some tips for exercising in patients with T1DM?
The goal is to maintain safety (minimize risk of hypoglycemia)
Strategies:
INject insulin at a non-exercise site
Consume extra carbohydrates before/during/after exercise
Decrease bolus insulin that is closest to time of actvity
OR
Decrease basal insulin overnight by 20%
Perform resistance training before aerobic exercise
What should T2DM patients do when they have high blood glucose and are about to start exercising?
It is okay for T2DM patients to exercise on high blood glucose as long as there are no signs of dehydration and patient feels fine
What should a T1DM patient do if they wanted to exercise, but their blood glucose is high?
If blood sugar is above 16.7mmol/L + feel unwell:
Check ketones and postpone vigorous exercise until insulin is given and ketones are resolves
If sugar is high, but feel fine and no ketones, go ahead and exercise
What is insulin?
It is a hormone secreted from pancreatic beta-cells to help regulate blood glucose
In the body, proinsulin is cleaved into insulin and C-peptide
Commercially available products only contain insulin
What is the difference between basal and bolus release of insulin?
Basal release:
Beta cells secrete small amounts of insulin throughout the day (maintain baseload)
Bolus release:
At mealtime, insulin is rapidly released in response to food (increases secretion at times of increased glucose)
What do the onset, peak, and duration of rapid acting insulin analogues (RAIA) look like?
RAIA onset:
10-15 min
RAIA peak:
1-2 hours
RAIA duration:
3-4 hours
What do the onset, peak, and duration of short-acting insulin analogues look like?
Short acting onset:
30min
Short acting peak:
2-3 hours
Short acting duration:
6.5 hours
What does the onset, peak, and duration of Insulin regular U-500 look like?
U-500 onset:
15 min
U-500 peak:
4-8 hours
U-500 duration:
17-24 hours
What makes rapid acting insulin analogues (RAIA) have a short onset, high peak, and short duration of effect?
They have modifications to the basic Humulin Insulin. These modifications allow them to have more rapid absorption vs. Short acting insulins. RAIAs also more closely mimic endogenous insulin release
What are some advantages of RAIA over short acting insulin?
More rapid absorption
Quicker peak
Shorter duration of action
More convienent:
Can be taken 0-15 min before a mean or within 15 minutes of eating, short acting is 30-45 min (more flexibility on what patient want’s to eat, can adjust insulin dose appropriately)
How is Insulin regular U-500 administered?
It is a very concentrated form of insulin (extreme caution is required to avoid inadvertent overdose)
Given 2-3 times per week
What does the onset, peak, and duration of intermediate-acting insulin look like?
Intermediate Onset: 1-3h
Intermediate Peak 5-8h
Intermediate duration: up to 18h
What does the onset, peak, and duration of long-acting insulins look like?
long-acting onset: 90 min
Long-acting peak: no real peak, very flat curve
Long-acting duration: (24-42h)
Describe intermediate-acting insulins
Administered once or twice daily to provide a basal amount of insulin
Appear cloudy (need to resuspend by hand-rolling or inverting 10x)
Describe long-acting insulin?
3 main versions (glargine, detemir, and degludec). All have amino acid modifications to help them achieve long durations of effect
Glargine: forms micropreciptates which slowly dissolve, 24-30h duration of effect
Detemir: Prolonged duration of effect due to hexamer stability
Degludec: longest duration of effect (42h)
What are the advantages of long acting insulin analogues (LAIAs) vs. intermediate acting insulin?
They are “peak less” (long duration of effect)
More consistent blood glucose
Less hypoglycaemia due to consistent reduction in blood glucose (less variable)
When switching between long acting insulin analogues (LAIAs), what are some dosing considerations?
Maintain the same dose unless patient is moving from the following:
Reduce new insulin dose by 20% when moving from the following:
Insulin glargine 300u/mL (Toujeo)
Insulin detemir (Levemir) BID
Insulin NPH BID
*Insulin glargine 100u/mL (Lantas), but only when switching to Degludec (Tresiba)
What are the main types of insulin delivery devices commonly used by patients?
Syringes and vials (least popular, but rational choice)
Insulin pens
Insulin pumps
What are some advantages of syringes as an insulin delivery device?
Traditional method of insulin delivery, but some prefer it due to the following reasons:
Least expensive
Used to it (familiarity)
Prefer less injections and want to combine some insulin sin same syringes
What does the gauge number mean for needles?
Higher gauge=thinner needle
What are some advantages of insulin pens?
Insulin pens have largely supplanted vials/syringes for the following reasons:
Portable/convenient/easier to use
Advantageous if dexterity/visually impaired
Allows for precision dosing (easier to administer an accurate dose)
What are insulin pumps?
Also known as a continuous subcutaneous insulin infusion (CSII)
It is a small computerized devices that delivers insulin continuously 24h a day, but can also increase release rate when a bolus release is needed
The pump is worn on the outside of the body and only delivers RAIAs via a tube which is attached to a cannula placed under the skin (changed every 3 days)
What are the advantages of insulin pumps?
Patient/guardians should be motivated and able to understand what is entailed before deciding on using a insulin pump
Consider insulin pumps for the following patients:
Poorly controlled with optimized injections
Significant glucose variability
Frequent severe hypoglycaemia
Pregnancy
What is the SK Insulin Pump Program?
For T1DM patients, 1 pump is covered every 5 years (up to $6300)
Pump supplies are covered for initial trial period (3 months)
Pump supplies are only further covered if patient is under Sask Income Support or SAIL program
What is a closed loop system in terms of glucose management?
This is an integrated insulin pump and CGM system that automatically adjusts insulin in response to elevation in blood sugar.
A closed loop system can mimic the pancreas (artificial pancreas)
What are some adverse effects of insulin?
Hypoglycaemia (Most common AE)
Weight gain:
Promoted glucose uptake by target cells = increased nutrition
Insulin is also a anabolic hormones that promotes energy storage via glycogen, protein, and lipid synthesis (localized fat hypertrophy)
What are some factors that affect insulin absorption?
Exercise of injected area = increased
Massage = increased
HIgher temperature = increased
Depth of insulin IV>IM>SC
Lipohypertrophy = decreased
Reduced renal function = decreased
What is the recommended injection technique for insulin?
Wash your hands
Alcohol swab cartridge/vial (don’t need to wipe injection area)
Rotate injections systematically within the same anatomical region (impact on absorption rate and lipohypertrophy)
Avoid moles, scars, and other blemishes
Use a quick, smooth movement
What are the preferred injection sites?
Around the belly button
Side of upper thigh
Love handle region (above buttocks)
Under arm region
Review slides 171-173 for rotating sites
What is proper technique for injecting insulin with a syringe?
- Pull in hair
- Push air into the bottle
- Pull in and push out a little insulin to remove air bubbles
- Pull your exact dose of insulin into the syringe
Inject with or without skin lift, but inject at 90* regardless
After pushing the plunger, leave the syringe in place for 10 seconds
After removing syringe, the skin should look normal
What is the proper technique for delivering insulin via an insulin pen?
- Wash hands (remove the pen cap)
- Wipe pen tip with alcohol swab
- Safety test (priming with 2 units)
- Dial up amount of insulin required
- Inject ideally at 90*
- Count until 10 and then remove needle
How should insulin be stored?
Unopened: fridge
In-use: room temperature (discard after 28 days, degludec can last up to 56 days)
Avoid freezing, extreme heat, or direct sunlight
What insulin mixtures are stable?
R+NPH (can be pre-mixed and stored together)
RAIA+NPH: (may mix together, but cannot be stored for future use)
LAIA (cannot mix in the same syringe as any other insulins)
What are some typical insulin doses in T1DM?
Initial dose: 0.5-0.6u/kg
Honeymoon phase: 0.1-0.4u/kg
Ketosis or acute illness: 0.5-1.0u/kg
What are some typical insulin doses in T2DM?
Initial dose: 0.1u/kg
With insulin resistance: 2.5u/kg
What is the importance of insulin T1DM?
Insulin is necessary, and it is ideally delivered in a manner that mimics normal physiologic insulin secretion
MDI (multiple daily injections = (3 bolus + 1 basal dose)/day)
What is the distribution of insulin delivered in basal and bolus doses?
Basal: 40-50%
Bolus: 50-60%
Does the exact regimen of insulin change over time?
Yes, it can change depending on patient age, goals, general health, glucose levels, physical activity
Insulin adjustment is an art and science, and is always changing
What is the carbohydrate to insulin ration (C:I)?
This ration is used to estimate how many grams of carbohydrates each unit of meal-time insulin will cover
Typical C:I is 15:1, therefore 15g of carbs is taken care of by 1g of insulin
What is correction factor (CF) in terms of insulin dose adjustment?
Correction factor (CF) can help bring down high blood glucose detected before meals (allows patient to take care of high blood sugar and future increase in blood sugar after eating a meal)
CF=100/total daily dose
What is the Somogyi Effect?
Unrecognized nocturnal hypoglycemia (under 4mmol/L) that patient sleeps through
Likely due to excess or ill-timed insulin
What is the Dawn Phenomenon?
This is fasting hyperglycaemia that is the result of growth hormones, cortisol, glucagon being released in the early morning
Avoid carbohydrates after dinner/eat earlier
Be active after dinner
What are some general rules for adjusting doses?
Fix the low readings first (hypoglycemia)
Generally adjust by 1-2 units at a time (1u of insulin can reduce blood glucose can reduce blood glucose 2-3 mmol/L
ONly adjust 1 dose at a time, begin with correcting the first problem blood glucose of the day
Make dose adjustments every few days based on glucose trends, not just single readings
What is the mechanism of action for Metformin?
Not fully understood, but it reduces hepatic glucose production and enhances insulin sensitivity
What are some doses for Metformin?
Start at 250-500mg OD
Titration up by 500mg weekly if no GI side effects
Desired usual dose: 850-1000mg BID, max dose = 850mg TID
What is the efficacy of Metformin?
Reduces A1C% by 1-1.5% in most patients (up to 2% in patients with especially high A1C (9%))
Metformin also decreases triglycerides, LDL (-8 to -15%) and slightly increases HDL (+2%)
What are some drug interactions with Metformin?
Cimetidine (competes for renal tubular secretion, increases circulating Metformin)
Dolutegravir (can increase Metformin concentration)
Alcohol (potentiates Metformin’s effect on lactate metabolism, enhanced hypoglycemic effect)
Contrast media (continues for 48h after imaging)
What are the adverse effects of Metformin?
GI symptoms: Diarrhea, nausea, abdominal discomfort (30% will experience, and about 5% will d/c)
Less common:
Metallic taste
Vitamin B12 deficiency with long-term use
Hypoglycemia (rare in mono therapy)
What is a rare medical emergency associated with Metformin use?
Lactic acidosis: Decrease in arterial pH and an accumulation of serum lactate (medical emergency)
Accumulation occurs due to metformin-mediated inhibition of the conversion of lactate into glucose. This condition is worsened in patients with CKD as they are unable to clear lactate effectively
How are metformin doses adjusted to patients with CKD?
eGFR (45-59mL/min): 1500mg/d
eGFR (30-44mL/min): 1000mg/d
eGFR (under 30mL/min): do not start, but continue 500mg OD
What are some risk factors for lactic acidosis?
History of lactic acidosis
Severe liver disease
Alcohol abuse
Radiologic procedures (contrast dye)
Acute illness (severe infection and trauma)
Severe dehydration
What is the mechanism of action for sulfonylureas?
They enhance the secretin of insulin by binding to sulfonylurea receptors in the beta cells of the pancreas.
Once binded to the beta cells, it promotes the closure of K+ channels and the opening of Ca2+ channels. This in turn stimulates insulin secretion
What are some examples of sulfonylureas?
Glyburide, gliclazide, glimepiride
What is the dosing of different sulfonylureas?
Glyburide and Gliclazide MR are the most prescribed sulfonylureas in Sask (bc they are coved by the drug plan)
Glyburide (5-20mg/d), d/c after eGFR falls below 60mL/min
Gliclazide MR (30-120mg OD), d/c after eGFR falls below 30mL/min
What is the efficacy of sulfonyureas ?
A1C reduction from 1-1.5%
Can titration up to regular dose after 2 weeks
Effective at 1/2 of max dose, but max effective dose is about 60-70% of max dose
Need to adjust dose in CKD patients
What is the impact of sulfonylureas on reducing CV risk?
Do not appear to cause harm, but also no benefit (neutral)
What are some adverse effects associated with sulfonylureas?
Hypoglycemia (2-30%)
Glyburide is on the BEERS list of agents to avoid in elderly patients due to its risk of causing hypoglycemia
Weight gain (2kg)
Less frequent:
Nausea, skin reaction, rash, photosensitivity
Are sulfonylureas safe for use in pregnancy?
Glyburide is the only sulfonylureas that does not cross the placenta (desirable for fetal health)
What is the mechanism of action for repaglinide (Meglitinides)?
Repaglinide was bound to site adjacent to the sulfonylureas receptor, resulting in stimulation of the secretion of insulin from the pancreas
What is the efficacy of Repaglinide?
Reduced A1C by 1-1.5%
Works primarily to decrease PPG, is intended to be taken before meals to improve their meal-induced and secretion
What are some dosing guidelines for repaglinide?
A1C under 8%: initiate at 0.5mg before each meal and titrate up
A1C over 8%: Initiate at 1-2mg before each meal and titrate up
Max dose: 4mg before each meal (max dose 16mg/d)
It needs to be administered shortly after a meal due to sort duration of action
What are some adverse effects associated with repaglinide?
Hypoglycemia (especially when combined with other agents)
Weight gain: 0.3-1kg
What are some precautions drug interactions that are associated with repaglinide?
CYP450 (precaution in patients with moderate hepatic impairment)
Increased repaglinide with:
CYP 3A4 inhibitors (clarithromycin, grapefruit, azoles)
What is the mechanism of action for acarbose (alpha-glucosidase inhibitors)?
a-Glucosidase enzymes are responsible for breaking down polysaccharides into glucose. By inhibiting a-Glucosidase enzymes, we reduce the about of glucose being absorbed
Net effect is on post-prandial glucose, rather than fasting glucose unlike most antihyperglycemics
What is the efficacy of acarbose?
Can reduce A1C by 0.5-0.8% (less than others)
What are some doses for acarbose?
Initial 25-50mg OD, titrate up every couple weeks to 50mg TID
Assess for efficacy every 4-8 weeks to a max dose of 100mg TID
Take with the first bite of each main meal
What are some adverse effects associated with acarbose?
Flatulence (40-80%) and Diarrhea (30%)
This is the main reason why acarbose is an unpopular antihyperglycemic agent
Negligible hypoglycemia risk
Weight neutral
In what patient populations should caution be used when using acarbose?
Those with IBD or GI conditions
eGFR under 25mL/min and severe liver disease
What is the mechanism of action for Thiazolidinediones (Rosiglitazone and Pioglitazone)?
They bind to PPAR-y receptors which are primarily found in adipose tissue. Their activation alters genes that influence glucose and lipid metabolism.
Due to activation by either “Rosi” or “Pio”, insulin sensitivity is enhanced at muscle, liver, and fat tissues
What is the efficacy of Thiazolidinediones (Rosiglitazone and Posiglitazone)?
They reduce A1C by 1-1.5%
Effects on TG: “Pio” decreases by 10-20%, “Rosi” is neutral
Effects on LDL: “Rosi” increase LDL by 5-15%, “Pio” is neutral
Effects on HDL: Both may increase HDL to some degree
What is the dosing for Thiazolidinediones (Rosiglitazone and Pioglitazone)?
“Rosi”: initiate at 2-4mg ODD, may increase to 4mg BID
“Pio”: initiate at 15mg OD, titrate up to 30-45mg OD
Give 4-8 weeks before making dose adjustments
Larger people need a larger dose
Caution in patients with eGFR under 60mL/min (no dose adjustment required)
What are some drug interactions associated with Thiazolidinediones (Rosiglitazone and Pioglitazone)?
Metabolized by CYP 2C8
What are some common adverse effects associated with Thiazolidinediones (Rosiglitazone and Pioglitazone)?
Peripheral edema (5%), and jumps to 15% when on insulin (do not use with insulin)
Weight gain (2.5-4.8kg), increased distal fractures in post-menopausal women
Increased distal fractures in post menopausal women
What is the current opinion on the use of Thiazolidinediones (Rosiglitazone and Pioglitazone) in terms of CV risk?
Due to mixed results, Rosiglitazone has restricted access
What are the two incretin-based therapies?
GLP-1 receptor agonists
DPP-4 Inhibitors
Describe incretin hormones
GLP-1 and GIP are secreted from the gut in response to ingestion of nutrients
Main role is to augment insulin secretion
People with T2DM have a reduced incretin effect
What happens when the GLP-1 receptor is activated?
Potent inhibition of gastric emptying
Potent inhibition of glucagon secretion
Reduction of food intake and body weight
What is the mechanism of action for DPP4-inhibition?
Block the enzyme DPP4 which rapidly hydrolyzes incretins, thus enhancing the action of endogenous incretins (promoting increased insulin release)
What is the efficacy of DPP4-inhibitors?
Reduces A1C by 0.7% (less than a lot of other agents, it is more gentle so preferred by the elderly)
Works quickly, see effects within a couple of weeks
What are some adverse effects associated with DPP4 inhibitors?
Overall, well tolerated medications (headache, nasopharyngitis, URTI)
No hypoglycemia on their own
Weight neutral
What are some drug interactions with DPP4 inhibitors?
When combined with sulfonylureas or insulin, it may increase the risk of hypoglycemia
Avoid with GLP1RA (similar MOA and increased risk of pancreatitis)
What is the mechanism of action for GLP1RAs?
They stimulate insulin secretion in a glucose-dependent manner, reduces glucagon, slow district emptying, and increase satiety
How are GLP1RAs safely stored?
At the pharmacy or at home and not in use: in the fridge
When at home and in use: room temperature or fridge
What are the short-acting GLP1RAs?
Exenatide
Lixisenatide
What is the dosing for short-acting GLP1RAs?
Exenatide: 5mcg BID sc x1 month, then 10mcg BID
Lixisenatide: 10mcg OD sc x 14 days, then 20mcg OD
What are the long-acting GLP1RAs?
Liraglutide
Exenatide QW
Dulaglutide
Semaglutide
What is the dosing for long-acting GLP1RAs?
Liraglutide: 0.6mg OD x 1 week, then 1.2-1.8mg OD
Exenatide QW: 2mg sc every week
Dulaglutide: o.75mg sc every week (can increase to. 1.5mg every week)
Semaglutide: 0.25mg sc weekly, increase to 0.5mg after 4 weeks then 1mg
How is the bioavailability of oral Semaglutide increased (only GLP1RA that comes in an oral formulation)?
It is co-formulated with SNAC (forms a bubble around Semaglutide, preventing degradation from stomach acid) only 1% makes the journey
What are some renal dosing considerations for GLP1RAs?
Dulaglutide: Caution eGFR under 15mL/min
Liraglutide: Caution eGFR under 15mL/min
Semaglutide SC: Caution eGFR under 15mL/min
Semaglutide po: Caution eGFR under 30mL/min
Exenatide QW and Exenatide: Caution under 30mL/min
Lixisenatide: Caution under eGFR 30mL/min
What is the efficacy of GLP1RAs?
Reduce A1C by 1-1.5% (Semaglutide sc seems to be more potent than Dulaglutide)
Long-acting GLPs are more potent (more effect on FPG) vs. Short-acting (more effect on PPG)
What are some adverse effects associated with GLP1RAs?
N/V/D (up to 40%), especially nausea (20-50%)
Nausea and vomiting are generally mild and transient. They will typically resolve after 4-8 weeks
What are some tips to minimize nausea?
Tell patients what to expect
Eat smaller portions and slowly
Titrate slowly (stay on low dose until nausea improves)
Avoid fatty, spicy, and high fiber foods
Is there a concern for cancer in GLP1RA use?
Rodents showed increased risk for people with a family history of medullary thyroid cancer (MEN2)
This is a minor concern, but it is contraindicated in humans if they have family history for MEN2
What is the effect of GLP1RAs on weight?
GLP1RAs cause significantly more weight loss vs. other antihyperglycemics (average loss 3kg)
Semaglutide (ozempic) reduced weight by 6.5kg
GLP1RAs slow gastric emptying and cause a sense of satiety. This results in reduced food intake and weight loss
What are some drug interactions with GLP1RAs?
GLP1RAs decrease gastric emptying, so any drugs that require rapidGI absorption, space these oral agent out (1 hour before taking GLP1RA)
Ex. Oral contraceptives, antibiotics, and narrow TI drugs
How do GLP1RAs have cardio protective and renal benefits?
Most likely due a combination of metabolic, CV, and anti-inflammatory effects
What is the mechanism of action for SGLT2 inhibitors?
SGLT2 is a high capacity transporter that is responsible for glucose reabsoprtion from the glomerular filtrate
By inhibiting this transporter, we effectively limit how much glucose is reabsorbed
They are insulin-independent, therefore no chance for hypoglycemia
What is the efficacy of SGLT2 inhibitors?
Reduce A1C by 0.5-0.8%
Works on both FPG and PPG
Require functioning nephrons to reduce glucose (eGFR above 45). SGLT2 inhibitors also have cardio renal protection until eGFR above 25mL/min)
What are some kidney related effects associated with starting SGLT inhibitors?
When initiating, SGLT2 inhibitors can cause a very early decrease in kidney function (about 5mL/min decrease in eGFR)
This is not kidney damage, but if eGFR decreases by 30% (lower dose or stop and investigate CKD)
What are some adverse effects associated with SGLT2 inhibitors?
Increased urination and thirst
Mycotic genital infections (rinse and wipe after urination)
What are some contraindications for SGLT2 inhibitors?
Dehydration potential for patients that are also have the following apply to them:
Elderly
Loop diuretics
Low SBP
CKD
ACEi/ARB use
Are patients on SGLT2 inhibitors cause an increased risk for diabetic ketoacidosis (DKA)?
Rare, but it can be serious. Withhold SGLT2 inhibitors if patient has developed diabetic ketoacidosis.
Diabetic ketoacidosis is characterized by the following:
Difficulty breathing
Extreme thirst
N/V
Abdominal discomfort
Confusion
Review slide 260 for a great treatment algorithm for concurrent diuretic and SGLT2 inhibitors use
What are some examples of SGLT2 inhibitors?
End with the suffix (-glifozin)
Dapaglifozin
Canaglifozin
Empaglifozin
What is the relationship between Canaglifozin and amputations?
Occur primarily in those with prior amputations, high A1C, severe neuropathy
What is the relationship between Canaglifozin and bone fracture?
Only increased risk in patients who were already at risk for fractures
Older adults with high fracture risk, fall risk, and hydration status
What is Fournier’s gangrene?
Very rare reaction to SGLT inhibitors
Characterized by pain, swelling, tenderness in the genital region
What is the effect of SGLT2 inhibitors on CV risk?
They all lowered risk and showed beneficial effects to CV and renal outcomes
What is the effect of SGLT2 inhibitors on renal risk factors?
In multiple studies, SGLT2 inhibitors all show reduced risk
What is the the value of SGLT2 inhibitors on heart failure?
SGLTis showed reduction in hospitalization for heart failure
Dapa is the only SGLT2i that is covered by the SK formulary for the treatment of heart failure
How do SGLT2 inhibitors provide cardio protective and renal benefits?
We aren’t completely sure, but we have a few ideas:
They induce natriuesis and glucosuria, which lowers pre-load
Decrease BP
Stimulates erthyropoietin release = more RBC = more oxygen = heart beats works less hard to deliver same amount of O2
Decreases oxidative stress and local inflammation
What are the cardio renal benefits of SGLT2i use in associated diseases?
For secondary CV prevention: Empaglifozin and Canaglifozin reduce MACE (Major adverse CV events)
In patients with HF: SGLTi decrease hospitalizations in heart failure and death
In patients with CKD: SGLTi decrease cardio renal outcomes
What are some barriers to insulin for patients?
More complex dosing and monitoring
Sense of failure
Fear of hypoglycemia
Needle phobia (better now with weekly injections)
Fear/denial of disease progresssion
MIsconceptions
What are some barriers to insulin for HCPs?
More complex
Fear of patient getting hypoglycemic
Patient’s cognitive ability to manage insulin effectively
How is insulin initiated into a patient’s therapy profile?
- Basal insulin + antihyperglycemic agent:
Usually added to existing antihyperglycemic agent
(Started at 10U of insulin, titrate up 1U every night until FPG is within 4-7mmol/L)
- Basal and bolus insulin
- Biphasic (premixed) insulin (RAIA + intermediate acting insulin)
Why would insulin be initiated as basal only?
It is preferred for the following reasons:
Simplicity
Minimization of weight gain and hypoglycemia
Keeping oral agents on board helps with sensitization
What is overbasalization in glucose control with insulin?
This occurs when a basal insulin dose of over 0.5U/kg/d, they get no additional benefits
If this patient seems like they need more insulin-like activity, consider other options rather than continuing to increase the basal insulin dose
What are some options for when basal insulin are not doing the trick?
Evaluate/ add other antihyperglycemics (DDP4i, GLP1RA, SGLT2i)
Basal insulin/GLP1RA combos
Basal/bolus insulin
How to initiate basal-bolus insulin?
If patient is okay with injecting insulin four times a day, then introduce one prandial insulin at a time
- Start with largest meal (2-4U)
- Titrate by 1-2U/week until FPG and PPG at target
- As insulin gets added, consider removing secretagogues
- Monitor for effectiveness (blood glucose targets) as well as hypoglycemia
Review slides 283-285 for a great treatment algorithm for T2DM
What are some factors pharmacists should consider when choosing a second line drug for T2DM?
After metformin, considerations to be made:
Clinical CV disease
Hypoglycemia
Affect on weight
Renal function
Degree of hyperglycaemia
Other comorbidities (HF)
Cost
Patient preference
What is the mechanism of action for Tirzepatide?
It is a GIP and GLP1 dual agonist
Tirzepatide enhances the secretion of insulin in response to food and reduces glucagon
What is the dosing for Tirzepatide?
Initiate at 2.5mg sc once weekly
Increase by 2.5mg increments every 4 weeks to max dose of 15mg
What are some adverse effects associated with Tirzepatide?
Mostly GI
Nausea
Diarrhea
Vomiting
Dyspepsia, constipation, abdominal pain
What is the potential for Tirzepatide in weight loss?
The SURPASS-4 study showed Tirzepatide to reduce body weight by 25.8lbs vs. 4.3lbs with glargine (LAIA)
What are some concerns with Tirzepatide use?
Mean increase in HR of 2-4 BPM
Delays gastric emptying and could inhibit absorption of drugs that depend on GI motility
Ex. Oral contraception
Can SGLT2 inhibitors and GLP1RAs be used in T1DM?
Not enough evidence for safety and efficacy
Risks outweigh benefits
What is the traditional T2DM treatment strategy?
Can be described as treat to fail
T2DM diagnosis—> lifestyle —> metformin —> other oral agents —> insulin
What is an alternate T2DM treatment strategy?
Induce glycemic remission (in early T2DM, it is thought it can be reversed back to normal glucose control)
Short-term insulin therapy (2-5 weeks) to modify disease and preserve beta-cell function
What actions do women who want to get pregnant need to take to manage their diabetes and reduce risk?
Use reliable birth control until blood glucose is optimized
Aim for A1C of under 7% (under 6.5% if safe)
Poorly controlled diabetes increases the risk of miscarriage, stillborn, and malformations
Get ophthalmological assessment to assess retinopathy before, during, and after conception
Screen for CKD
What medications can be used before pregnancy?
Preconception:
Folic acid for normal neural tube development
d/c potential embryopathic drugs (ACEi/ARB, Statins)
T1DM: Insulin
T2DM: Can continue metformin, Glyburide, or insulin
What antihyperglycemics are safe for use during pregnancy?
Once pregnancy occurs, insulin is the drug of choice for both T1DM and T2DM
*Metformin and then Glyburide may be considered as alternatives for women unwilling to use insulin
What are some treatment options for new-onset gestational diabetes?
First line: diet and exercise (if glycemic targets are not achieved in 2 weeks, start pharmacotherapy)
Second line: insulin (metformin and Glyburide are alternatives)
Screen for diabetes after pregnancy as well
What are the advantages of breastfeeding in terms of glucose control?
It can reduce offspring obesity and for at least 4 months it can reduce the risk of developing diabetes (both mother and child)
What is the risk of insulin to infants when they drink breast milk?
Insulin can be found in the breast milk, but it breaks down in the infants stomach before it can reach the infant’s systemic circulation
What are some concerns with diabetes in children ?
Psychological risks (they are different, can be picked on)
Eating disorders
Insulin omission
Need access to a dietician
Smoking cessation
Contraception
What are glucose targets for children with T1DM?
They are given intensive insulin whenever possible
A1C target of under 7-7.5% for all children under 18
FPG: 4-8mmol/L
2hr PPG: 5-10mmol/L
What are some treatment options for T2DM in children?
Often need to address lifestyle for whole family
Individualize targets based on patient (A1C could be different)
Pharmacologic options:
Metformin (first line)
Metformin + basal insulin (for severe hyperglycaemia)
Metformin + Liraglutide (Liraglutide can be used instead of basal insulin)
What are some treatment considerations for T2DM in elderly?
No two elderly patients are the same, so individualize targets
Need to consider fragility and risk of hypoglycemia (both increase fracture risk). Use DPP4is over SUs
Use a clock drawing test to gauge cognitive and dexterity ability to administer insulin accurately
Review slide 302 for a more detailed chart of glycemic targets in older adults
What are some acute diabetes-related complications?
Hypoglycemia (under 4mmol/L)
Hyperglycaemia (Diabetic ketoacidosis, Hyperglycemuic Hyperosmolar State)
Infections (Influenza, pneumonia, COVID-19)
What are some chronic diabetes complications?
Macrovascular (CVD, Dyslipidemia, HTN)
MIcrovascular (Nephropathy, Retinopathy, Neuropathy)
Other Considerations (Diabetes and Mental Health, Obstructive Sleep Apnea, Diabetes and driving)
What is the definition of hypoglycemia?
- Low blood glucose levels (under 4mmol/L)
- Development of autonomic (adrenergic) or neuroglyopenic (CNS) symptoms
- Symptoms respond to the intake of carbohydrates
What are some common causes of hypoglycemia?
Not eating on time (missed meals or not eating enough)
Unusual amount (excessive) of physical activity
taking too much of an antihyperglycemic medication
Alcohol (mimics the symptoms of hypoglycemia)
Prior episode of severe hypoglycemia, hypoglycemia unawareness
What are some autonomic symptoms associated with hypoglycemia?
When blood glucose falls below 4mmol/L, the following autonomic symptoms can develop:
TRembling
Palpitations
Sweating
Anxiety
Hunger
Nausea
TIngling
What are some neuroglycopenic symptoms associated with hypoglycemia?
The following symptoms can develop after blood glucose levels fall below 2.8mmol/L:
Difficulty concentrating
Confusion
Weakness
Drowsiness
Vision changes
Difficulty speaking
Headache
Dizziness
What are the different severity levels in hypoglycemia?
Mild (BG between 3.9-3.0mmol/L):
Autonomic symptoms present
Moderate (BG is between 3.0-2.8mmol/L):
Autonomic and neuroglycopenic symptoms present
Severe (BG is below 2.8mmol/L): In addition to autonomic and neuroglycopenic symptoms, they patient is likely to be unresponsive and unconscious.
What are some major risk factors for severe hypoglycemia in T1DM?
Prior episode of severe hypoglycemia
Current low A1C (under 6.0%)
Hypoglycemia Unawareness (symptoms appear at more severe levels of hypoglycemia)
Long duration of diabetes
Autonomic neuropathy
Adolescence
Pre-schooled aged children that are unable to detect and/or treat hypoglycemia on their own
What are some major risk factors for severe hypoglycemia in T2DM?
Advancing age
Severe cognitive impairment
Poor health literacy
Food insecurity
Increased A1C
Hypoglycemia unawareness
Duration of insulin therapy
Renal impairment
Neuropathy
What exactly is hypoglycemia unawareness?
The inability to recognize the early warning signs of low blood glucose
The first symptoms experienced in hypoglycemia is confusion or loss of confusion
This develops due to frequent hypoglycemia
What causes frequent hypoglycemia?
A decrease in the hormonal response mechanisms that prevent hypoglycemia (epinephrine and glucagon)
A lowering of the threshold at which hypoglycemia symptoms are experiences
Beta-blockers can contribute to hypoglycemia unawareness
How to address hypoglycemia in general ?
- Recognize autonomic or neuroglycopenic symptoms
- Confirm if possible (with glucose monitoring devices)
3.Treat with “fast sugar” to relive symptoms
- Retest in 15 minutes to ensure blood sugar is above 4.0mmol/L, and retreat with “fast sugar” if needed
- Eat usual snack or meal due at that time of the day
How is mild to moderate hypoglycemia treated specifically?
- Eat or drink 15g of “fast sugar” (will increase blood sugar by 2.0mmol/L in 20 min)
- Wait 15 min then check blood sugar again. If lower than 4.0mmol/L, then treat with 15g of “fast sugar” (15-15 rule)
- Once blood glucose is above 4.0mmol/L, eat within an hour
- Once blood sugar is above 5.0mmol/L, the patinet is safe to drive. This can take 40 min after the meal to achieve this blood sugar reading
What are some “fast sugars” that can be used to reverse hypoglycemia?
These sources of sugar are rapidly absorbed as glucose:
4 glucose tabes (Dex4 tabs)
15mL of sugar dissolved in water
2/3 cup of juice or soft drink
6 Life Savers
15mL (1tbsp of honey)
How is severe hypoglycemia treated in a conscious patient?
If the patient is conscious:
1. Treat with oral ingestion of 20g of “fast sugar” preferably as glucose tabs (will raise blood glucose by 3.5mmol/L over 45 min)
- Wait 15 min and retest blood glucose
- Retreat with another 15g of glucose if the blood glucose level remains under 4.0mmol/L
- Eat usual snack or meal due at that time of day
How is severe hypoglycemia treated in an unconcious patient?
- Treat with glucagon (1mg IM or IV, or 3mg nasal spray): Triggers the release of stored sugar
- Call 911
- Turn the patient into recovery position
- Eat as soon as safely possibel
- Discuss with healthcare team
How do injectable and nasal glucagon compare to each other?
The two products have different storage requirements, but they have similar efficacy and response time
What is pseudo-hypoglycemia?
A state in which an individual experiences symptoms of hypoglycemia without blood sugar being below 4.0mmol/L
Why does pseudo-hypoglycemia occur?
Usually occurs in patients who are accustomed to having chronic high blood glucose levels and have a rapid drop in blood glucose levels following diabetes’ treatment. HCPs still treat to take care of associated symptoms
Once blood glucose is properly managed, pseudo-hypoglycemia resolves
What are some causes of HYPERglycaemia?
Too little or omission of insulin (if needed)
Illness (increased metabolic demands = more glucagon = more blood sugar needed to power everything)
Surgery
Injury
Stress (emotional or physical)
Increased dietary intake
Exercise (in T1DM)
What is Diabetic ketoacidosis (DKA)?
DKA occurs as a result of insulin deficiency and is characterized by the following:
Hyperglycaemia (usually above 14mmol/L)
Metabolic acidosis (pH under 7.3 and/or serum bicarbonate under 15mmol/L)
When does hyperglycaemia cause water loss?
When the patient also has insulin insufficiency, the kidneys will use SGLT transporters to pull glucose from the blood and into the urine. This movement of glucose into the urine causes more water to flow into the urine due to osmotic pressure
Why does keto acidosis develop in hyperglycaemia?
In insulin deficiency and increases in catecholamines stimulate lipolysis (TG and FFA breakdown into ketone bodies). This breakdown produces cellular energy, but also results in an increased ketone concentration
Increased ketone concentration = causes acidosis
What are some signs and symptoms seen in Diabetic ketoacidosis (DKA)?
The following symptoms are due to hyperglycaemic component of DKA:
Excessive thirst
Excessive urination
Fatigue/weakness
Blurred vision
Change in appetite
The following are symptoms of acidosis component of DKA:
Abdominal pain, nausea, vomiting
Air hunger
Fruity acetone breath
Hyperventilation (Kussmaul Respiration, body tries to exhale excess CO2 in blood in attempt to reduce blood glucose concentrations)
Confusion
How is diabetic ketoacidosis treated?
Each hospital has their own protocol, but they have a general pattern.
- Replacement of fluid loss
- Replacement of K+
- Correction of metabolic acidosis
- If patient is in shock or blood pH is under 7, Sodium bicarbonate may be added
- Once blood sugar reaches 14mmol/L, IV glucose should be added to target of 12-14mmol/L to prevent pseudo-hypoglycemia
What is Hyperosmolar hyperglycaemic syndrome (HHS)?
HHS is another type of complication due to hyperglycemia.
It is less common than DKA, predominately affects T2DM patients
Exacerbated by extremely high blood glucose, increased osmolality, significant dehydration, and minimal ketoacidosis
Review slide 326 to review the differences in pathophysiology of DKA and HHS
How is Hyperosmolar hyperglycaemic syndrome (HHS) managed?
Similar to DKA
- Fluid resuscitation
- Avoid hypokalemia
- Insulin administration
- Avoid rapidly falling osmolarity
- Find precipitating cause
How can DKA and HHS be prevented in diabetes patients?
Education around sick day management (more likely to be hyperglycaemic when patient is sick)
Adjust insulin dose as needed, continue using insulin even when not eating
Frequent monitoring of blood glucose when ill
Check for ketones and make changes earlier
Review slide 329 for the differences between Diabetic ketoacidosis and Hyperosmolar Hyperglycaemic Syndrome
How do diabetic patients experience infections differently vs. non-diabetes patients?
People with diabetes are at a greater risk of morbidity and mortality from influenza, pneumonia, and COVID-19 infections
Therefore it is important that diabetes patients are up to date for their vaccination status
Why are infections especially concerning for a diabetic patient ?
People with diabetes need to be mindful of their blood glucose levels and medications in periods of acute illness
- Illness is a stressor causing an exaggerated counter-regulatory hormone response (overproduction of glucose, FFAs, and ketones bc energy demands are greater when sick. Increased risk for hyperglycaemia)
- Illness may be accompanied by dehydration and decreased appetite (increased urination, vomiting, and diarrhea)
How do d iabetes patients perform effective sick day management?
Monitor blood glucose more frequently (q2-4h)
T1DM: Continue insulin, but adjust bolus based on blood glucose (increase total daily dose by 10-20%)
T2DM: If patient uses insulin, they should Increase or decrease dose depending on self-monitoring blood glucose
Drink plenty of glucose-free fluids (water) to limit hyperglycemia and dehydration
If unable to eat solid food, substitute with glucose containing fluids
Review slide 334 for a guideline on sick day management in diabetes
What is SADMANS in terms of sick day management in Diabetes?
Diabetes patients are instructed to d/c the following medications when they are sick due to issues with kidney function decline and increased risk for adverse effects:
S(ulfonylureas)
A(CEi)
D(iuretics, direct renin inhibitors)
M(etformin)
A(RBs)
N(SAIDs)
S(GLT2 inhibitors)
What is the relationship between CV disease and Diabetes?
Diabetes increases the risk of many CV diseases:
Heart Failure (2-4x higher risk and occurs at earlier ages)
Acute Coronary Syndrome (3x higher risk + 15 years sooner + 2x mortality risk)
Stroke (2-5x higher risk + 2x reoccurrence rate)
Can increased CV risk due to Diabetes be reduced?
Yes, if the patient is able to successfully address risk factors
What risk factors should be minimized to reduce risk of CV conditions in the context of Diabetes?
ABCDESSS is a useful acronym
A1C targets should be under 7.0%)
BP should be under 130/80
Cholesterol, LDL should be under 2.0mmol/L
Drugs for CVD risk reduction: ACEi/ARB, ASA, and SGLT2i/GLP1RA in T2DM
Eexercise and healthy Eating
Screening for complications (ECG every 3-5 years, Monofilament annually, eGFR and ACR annually, Retinal exam annually)
Smoking cessation
Self-management (Stress, mental health, financial, or other concerns that could be barriers to achieving goals)
What is the prevalence of HTN in diabetes patients?
70% of Diabetes patients have hypertension
HTN is a major cause of microvascular and CV complications
Goal: 130/80 and should be checked at every appointment
Treatment: Lifestyle intervention and pharmacotherapy
What are some first line drugs for patients with CVD, CKD, or with CV risk factors in addition to Diabetes and HTN?
ACEi or ARB
What are some first line drugs for patients who have no CV risk factors, but have Diabetes and HTN?
ACEi, ARBs, DHP CCBs, TZDs
Should every diabetes patient be on an ACEi or ARB even if blood pressure is normal?
No, only use ACEi or ARBs if patient has diagnosed HTN or CV risk factors (CVD, Age over 55 + a risk factor or target organ damage, Microvascular complication)
What is the relationship between Diabetes and Dyslipidemia?
Most adults with diabetes are at greater risk for CV disease (MI and stroke)
Lipid profile should be performed at diagnosis and repeated annually
How can diabetes patients reduce their CV risk in terms of contribution from Dyslipidemia?
Statins are recommended for almost all diabetes patients:
Age over 40
Age over 30 + diabetes duration of over 15 years
Microvascular disease
Goal: Reduce LDL to below 2.0mmol/L
Do any antihyperglycemic agents confer any CV risk reduction?
Yes, GLP1RAs and SGLT2i can reduce CV risk
These agents offer CV risk reduction as a bonus in addition to reducing blood sugar
How can diabetes patients limit the progression of microvascular complications?
Tight control of BP, BG, and lipids is key in preventing and/or delaying progression of microvascular complications
How are diabetes and CKD related?
The primary cause of CKD in diabetes patients is diabetic nephropathy
Risk factors of diabetes nephropathy include:
Longer duration of diabetes
Poor BG, BP, and lipid control
Obesity
Smoking
How often should renal function be screened in diabetes patients?
Random urinary ACR and a serum creatinine levels
T1DM: 5 years after diagnosis in adults
T2DM: At diagnosis
CKD can be diagnosed if eGFR drops by more than 60mL/min or ACR over 2.0mg/mmol on at least 2 of 3 samples over a 3 month period
What patient groups should we avoid screening for CKD?
The following can increase ACR independent of kidney damage:
Exercise within 24h
Infection
Fever
HF
Marked hyperglycemia
Menstruation
Marked hypertension
How is diabetic nephropathy treated?
Treatment is aimed to slow progression of kidney damage.
- Optimize blood glucose control
- Optimize blood pressure control (under 130/80)
- Use SGLT2i
What is the relationship between diabetes and issues with vision?
Diabetic retinopathy is a vascular complication of diabetes. Caused by leaky retinal blood vessels due to damage form high BG and BP
Diabetic retinopathy is the most common cause of legal blindness among adults (20-70yo)
Diabetics also have higher rates of glaucoma and cataracts
What are some risk factors for retinopathy?
Duration of diabetes
Glycemic control
HTN, Dyslipidemia
Anemia
Nephropathy
Tobacco use
African American
Pregnancy
How should diabetic retinopathy be screened?
T1DM: 5 years after diagnosis after older than 15yo
T2DM: At diagnosis (then q 1-2yrs)
How can diabetic retinopathy be prevented?
- Optimize glycemic control
- Optimize BP control
What are some treatment options for diabetic retinopathy?
Varies on the type of ocular problem
Laser therapy, intraocular injections, vitreoretinal surgery
What is diabetic neuropathy?
It is a type of nerve damage that can occur as a result of having diabetes.
Nerve damage most commonly results from reduced blood flow to nerves due to hyperglycemia-induced damage to blood vessels
It is a chronic and often progressive disease, early recognition and management is ideal
What are the different types of diabetic neuropathy?
- Distal Sysmmetric Poly-Neuropathy (DSPN):
Most common
Involves the sensorimotor nervous system - Diabetic Autonomic Neuropathy (DAN):
Involves the autonomic nervous system
Includes the heart, genitourinary system, sexual function, sudomotor abnormalities
What are some risk factors for diabetic neuropathy?
Elevated BG
Elevated triglycerides
High BMI
Smoking
HTN
How should diabetic neuropathy be screened for?
A clinician uses sensitivity to a micro filament to gauge level of neuropathy
T1DM: After 5 years post-pubertal duration (then annually)
T2DM: At diagnosis, then annually
What are some effects of diabetic autonomic neuropathy on the GI tract?
Gastroparesis:
Delayed stomach emptying due to vagus nerve damage. This effectively slows or halts peristalsis, causing inconsistent food absorption and subsequent erratic BG levels
What are some effects of diabetic autonomic neuropathy on the cardiovascular system?
Can cause resting tachycardia, exercise intolerance, orthostatic hypotension, silent MI, risk factor for mortality
What are some effects of diabetic autonomic neuropathy on the genitourinary tract?
Bladder dysfunction
ED (affects 40% of men with diabetes, so ask about ED)
Retrograde ejaculation
What are some effects of diabetic autonomic neuropathy on sexual function?
Women: Decreased vaginal lubrication, arousal, excitement, satisfaction, orgasm. Increased dyspareunia(pain before, during, and after sexual intercourse)
Men: Can experience ED
What are some effects of diabetic autonomic neuropathy on metabolism?
Hypoglycaemia unawareness
Hypoglycaemia unresponsiveness
What are some effects of diabetic autonomic neuropathy on sudumotor function (sweat glands)?
Gustatory sweating (during tasting)
Anhidrosis (reduced sweat production)
Heat intolerance
Dry skin
What is peripheral neuropathy?
It is the most common type of neuropathy
Peripheral neuropathy will develop within 10 years of the onset of T1DM or T2DM in 40-50% of patients
Diabetes is the most common cause of peripheral neuropathy (presents in the feet first)
What are the symptoms of Peripheral Neuropathy?
Early symptoms (small fibres affected):
Pain
Burning
Altered sense of temperature
Involvement of larger fibres:
Loss of protective sensation (LOPS)
Numbness
How is peripheral neuropathy treated?
Optimize blood glucose:
Can be prevented in T1DM
Progression can be slowed in T2DM
How is pain associated with peripheral neuropathy managed?
Oral agents:
Gabapentinoids (pregablin, gabapentin)
SNRIs (duloxetine, desvenlafaxine)
Na+ channel blockers (valproic acid)
TCAs (amitriptyline)
Topical:
Capsaicin (minimal effect)
Cognitive Behavioural Therapy
Can pain management completely eliminate pain?
No, complete pain relief is usually not achieved. 30% of pain reduction is considered a success in clinical trials
Goal is to reduce,not to eliminate pain (improve quality of life)
What is the role of foot care in diabetes?
Good foot care is an important component of diabetes management
Nerve damage as a result of diabetes makes one less likely to notice when feet are injured
What factors that contribute to amputation in diabetes?
Nerve damage or diabetic neuropathy
Skin changes (non-healing ulcers due to nerve damage and reduced circulation)
Calluses
Smoking (increases the risk of non-healing ulcers)
Prolonged hyperglycaemia (causes neuropathy and poor circulation)
HTN (development of non-healing ulcers)
How are the feet screened in diabetes?
Annual foot examinations including visual assessment, pedal pulses, and sensory foot exam with monofilament
What are some good foot care habits to help prevent amputation?
Wash feet in warm water using a mild soap
Dry feet carefully, especially between toes (prevent fungal infections)
Check feet and in between toes to ensure no cuts, cracks, ingrown toenails, blisters
Clean cuts with mild soap and water, then cover with dressing
Trim toenails straight across and file any sharp edges
Apply unscented lotion to heels and soles (prevent cracking)
Don’t put lotion between toes since this can prevent infection
Wear clean socks and well-fitting shoes daily (do not go barefoot)
Test bath water temperature with your hand before you step in to make sure the water is not too hot
Avoid sitting for long periods of time
Do not smoke
Review slide 377 on instructions on how to perform a monofilament exam for peripheral neuropathy
What should pharmacists do for patients at risk for amputation due to peripheral neuropathy?
Educate about proper foot care (daily self exam and HCP at once yearly)
Pharmacists can perform monofilament assessments
Refer patients with foot ulcers and other complications to those specialized in foot care
What is the relationship between diabetes and mental health?
10% of patients with diabetes will have major depression and 30% will experience clinical symptoms
Diabetes patients should be regularly screeds for diabetes-related psychological distress and psychiatric disorders
What is the relationship between Obstructive Sleep Apnea and Diabetes?
18% of diabetes patients have sleep apnea
A lot of diabetes patients are obese, 86% of these individuals have sleep apnea
If a diabetes patient is having difficulties controlling their blood glucose and/or BP despite good adherence to lifestyle mods. and drug therapy. Their sleep apnea could be elevating their blood glucose and pressure
What is T2DM remission?
Achieving specified A1C thresholds without any anti-hyperglycemic medications for a minimum for 3 months:
Remission to prediabetes (A1C between 6.0-6.4%)
Remission to normal glucose concentrations (A1C under 6.0%)
What patients are qualified to undergo T2DM remission?
The patient is interested in attempting remission
Those who do not have significant eating or mental health disorders
Those who do not have a compelling indication for antihyperglycemics (for renal or CV benefit)
What are some options for T2DM remission?
Bariatric surgery:
May induce remission in a non-pregnant adult with BMI over 35 (obese patients)
Health behaviour interventions:
Low-cal diets (800-850kcal/day) with meal replacement products for 3-5 months aimed at achieving more than 15kg weight loss
OR
Calorie-restricted diet (aim for 5-7% weight loss) and exercise (4-7 hours/week of structured physical activity spread over 5 days/week)
Do most patients achieve their A1C targets after therapy?
A significant minority (38%) of patients are not able to achieve their A1C targets
What is the role of a pharmacist in diabetes?
Education
Optimize therapy
Referrals to HCPs (direct patient towards getting help)
Help fill some of the gaps (prevent patients from slipping between the cracks of the healthcare system)
