DiabetesMellitusMasterclass MedmasteryHandbook

DIABETES
MELLITUS
MASTERCLASS
HANDBOOK
Tracy Tylee, MD
Table of contents
What is diabetes?
Basics of glucose regulation 5
Type 1 diabetes 6
Type 2 diabetes 7
Other forms of diabetes 8
Reading list 10
Making the diagnosis

Risk factors and screening 12
Diagnosing diabetes 13
Hemoglobin A1c 15
Pre-diabetes 17
Reading list 18
What’s your goal?

Markers of glycemic control 20
Setting individual goals 22
Blood glucose monitoring 23
Lifestyle interventions 26
Reading list 28
Starting treatment?
Metformin 31
Sulfonylureas 32
Thiazolidinediones (TZDs) 34
Incretins 35
SGLT-2 inhibitors 38
Reading list 39
Using oral medications

Avoiding hypoglycemia 41
Avoiding weight gain 42
Minimizing cardiovascular risk 43
Minimizing cost 44
Reading list 45
Adding insulin
Insulin basics 47
Basal insulin 49
Mealtime insulin 50
Alternative forms of insulin 52
Insulin pumps 53
Reading list 55
Adjusting insulin
Correcting fasting hyperglycemia 57
Adjusting mealtime insulin 59
Avoiding hyperglycemia 60
Managing non-compliance 62
Using lower cost insulin 64
Reading list 66
When things go wrong

Cardiovascular disease 68
Hyperlipidemia 69
Microvascular disease 71
Diabetic neuropathy 73
Reading list 75
Special populations
The elderly 77
Chronic kidney disease 78
Diabetes in pregnancy 80
Hospitalized patients 82
Steroid-induced hyperglycemia 84
Reading list 87
Chapter 1
WHAT IS DIABETES?
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BASICS OF
GLUCOSE REGULATION
In the fasting state, the majority of glucose is produced by the liver. This glucose is used by the brain for fuel,
and by other tissues, including the gut and muscle.
Glucose production and uptake are balanced, maintaining fasting blood glucose levels between
70–90 mg / dL (3.9–5.0 mmol / L).
Impairments in insulin production (insulin deficiency) or insulin action (insulin resistance) can cause
diabetes, a disorder characterized by high blood sugars. Increased glucose production from the liver leads to
fasting hyperglycemia. Impaired insulin response with meals leads to post-meal hyperglycemia.
Insulin deficiency Insulin resistance
Hyperglycemia
High blood sugars can cause multiple symptoms
• Polyuria due to osmotic diuresis

• Polydipsia also due to osmotic diuresis and volume depletion
• Blurred vision due to changes in lens shape
• Genital yeast infections due to high glucose levels in urine
Treatment of diabetes is initially aimed at decreasing the immediate symptoms of hyperglycemia, but the
ultimate goal is to limit the long-term complications related to diabetes.
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TYPE11DIABETETS
TYPE DIABETES
Type 1 diabetes is also known as autoimmune diabetes, and results from destruction of the beta cells in the
pancreas, which leads to absolute insulin deficiency.
Features of type 1 diabetes
• Patients tend to be thinner, with normal BMI

• Symptoms present abruptly
• Presence of insulin autoantibodies (GAD65, IA-2, anti-insulin Ab and ZnT8 zinc finger Ab)
• Low insulin, as measured by C-peptide
• Can present at any age, with at least 25% of patients diagnosed as adults
• Requires insulin for therapy from time of diagnosis
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TYPE 2 DIABETES
Type 2 diabetes occurs as a result of insulin resistance. These patients often have high insulin levels, but
suffer from insulin resistance, meaning the target organs are unable to see the insulin—resulting in a relative
insulin deficiency.
Features of type 2 diabetes
• Patients are typically overweight adults

• Strong genetic component
• Insidious onset
• May be initially controlled with diet and exercise
• As disease progresses, additional medications are often needed
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OTHER FORMS OF DIABETES

Latent autoimmune diabetes of adults (LADA)
This is a variation of autoimmune, or type 1 diabetes, that progresses more slowly than typical type 1
diabetes. It is sometimes referred to as type 1.5 diabetes.
Clinical features
• Presents in adulthood
• Can be managed without insulin for more than six months
• Patients lack clinical features of type 2 diabetes (e.g., obesity, metabolic syndrome, family history)
• Positive insulin autoantibodies on labs
• Will ultimately need insulin treatment
Maturity onset diabetes of the young (MODY)
MODY is an inherited form of diabetes that results from a single gene mutation that leads to impaired insulin
release from beta cells.
Clinical features
• Diagnosed in late teens or early 20s

• May be misdiagnosed as either type 1 or type 2 diabetes
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• Patients lack clinical features of type 2 diabetes

• Negative insulin autoantibodies
• Strong multigenerational history of similar diabetes presentations
Most common mutations involve
• Glucokinase gene
- patients present with mild fasting hyperglycemia
- does not require treatment
• HNF-1A and HNF-4A genes
- requires treatment
- responds very well to sulfonylureas
Gestational diabetes (GDM)
GDM is diabetes that develops during pregnancy, and is usually detected

during screening for diabetes between 24–28 weeks gestation. These glucose
abnormalities will often resolve following delivery, but it is important to recognize
and appropriately treat GDM to prevent complications for both mother and baby.
This will be covered in more detail in a later chapter.
Post-transplant diabetes
Patients who have had solid organ transplants are at risk of developing what is known as post-transplant
diabetes. This is often due to medications required to prevent rejection of the transplanted organ.
• Prednisone
- can cause insulin resistance
• Tacrolimus
- inhibits insulin release and is directly toxic to beta cells, causing insulin deficiency
• Sirolimus
- causes insulin resistance
Patients should be screened for the development of post-transplant diabetes 90 days following transplant
and often require insulin therapy to control blood sugars if diagnosed.
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READING LIST
An overview of the different classifications of diabetes:
American Diabetes Association. 2011. Diagnosis and classification of diabetes mellitus. Diabetes Care.
34: S62–S69.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006051/
Review of LADA:
Stenström, G, Gottsäter, A, Bakhtadze, E, et al. 2005. Latent autoimmune diabetes in adults: definition, prevalence,
beta-cell function, and treatment. Diabetes. 54: S68–S72.
https://www.ncbi.nlm.nih.gov/pubmed/16306343
Review of MODY:
Fajans, SS, Bell, GI, and Polonksy, KS. 2001. Molecular mechanisms and clinical pathophysiology of maturity-onset
diabetes of the young. N Eng J Med. 345: 971–980.
A more detailed article discussing the discovery of MODY and the underlying pathophysiology:
Fajans, SS and Bell, GI. 2011. MODY: history, genetics, pathophysiology, and clinical decision making.
Diabetes Care. 34: 1878–1884.
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Chapter 2
MAKING THE DIAGNOSIS
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RISK FACTORS AND SCREENING

Risks for type 1 diabetes
There are (as of yet) no screening tests that allow us to intervene and prevent the development of type 1
diabetes. Research continues to explore the possibility of type 1 diabetes prevention.
Risks for type 2 diabetes
Screening for type 2 diabetes is important for early diagnosis. Currently, 25% of patients with type 2 diabetes
are undiagnosed. This number is significantly higher, as high as 50%, for Asian and Hispanic populations.
Risk factors for developing type 2 diabetes
• First degree relative with type 2 diabetes

• African American, Latino, Native American, Southeast Asian or Pacific Islander heritage
• History of gestational diabetes
• Conditions associated with insulin resistance (e.g., polycystic ovary syndrome or acanthosis nigricans)
• Cardiovascular disease, hypertension or hyperlipidemia
• Obesity (BMI of ≥ 25 kg / m2 or for Asian patients ≥ 23 kg / m2)
Who should be screened for type 2 diabetes?
Recommendations from different societies vary, but in general
• All overweight patients

• Adults aged 40–45 with at least one risk factor for type 2 diabetes
If results are normal, it is reasonable to repeat screening every three years.
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DIAGNOSING DIABETES
There are three tests used to diagnose diabetes
Fasting Oral glucose Hemoglobin

blood glucose tolerance test A1c
Fasting blood sugar

Blood sugar is measured on a blood draw after eight hours of fasting. Normal values are < 100 mg / dL
(5.6 mmol / L). Between 100–125 mg / dL (5.6–6.9 mmol / L) is considered pre-diabetes. Diabetes is
diagnosed with values ≥ 126 mg / dL (7 mmol / L).
Oral glucose tolerance test

For this test, the patient consumes a standardized dose of 75 g glucose (usually in the form of an orange-
flavored soda). Blood sugar is measured two hours later. Normal values are < 140 mg / dL (7.8 mmol / L).
Between 140–200 mg / dL (7.8–11.1 mmol / L) is considered pre-diabetes and any value ≥ 200 mg / dL
(11.1 mmol / L) is diagnostic of diabetes.
Hemoglobin A1c
This is a measure of the average blood sugar over the last three months. While there are some limitations
to this test, it is considered a tool for use in diagnosing diabetes. Normal values are < 5.7%, values between
5.7–6.4% indicate pre-diabetes, with values ≥ 6.5% diagnostic of diabetes.
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For all of these tests, the abnormal result must be confirmed on repeat testing using either the same test or
one of the other testing options.
In addition to these tests, if the patient has classic symptoms of hyperglycemia, such as frequent urination,
increased thirst, or unexplained weight loss, a random glucose of ≥ 200 mg / dL (11.1 mmol / L) is
diagnostic of diabetes.
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HEMOGLOBIN A1C
Hemoglobin A1c is a hemoglobin molecule that has
been glycated, or modified, by exposure to glucose.
Once modified, the hemoglobin remains this way
until the red cell turns over (usually 120 days).
The higher the glucose levels, the more hemoglobin

molecules are modified, thus hyperglycemia results
in a higher % of A1c
There are some issues with the hemoglobin A1c, however, which have caused some people to question
whether this lab marker is an appropriate tool for diagnosing diabetes:
• A1c is an estimate of average blood sugar, but ranges of blood glucose levels overlap for the different
A1c values. So a patient with an average blood sugar of 180 mg / dL can have an A1c of 7%, while a
patient with better blood sugar control, and an average of 150 mg / dL, can have a higher A1c (8%).
• The A1c measurement assumes a normal red blood cell life span of approximately 3–4 months (120
days), so anything that alters the red blood cell life span will cause the A1c to be inaccurate.
Hemolytic anemia Blood loss Pregnancy
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• A1c values tend to be higher for African American patients at the same glucose level compared to other
ethnicities. If we use the A1c for diagnosis of diabetes, we may be overdiagnosing in these populations.
This may not accurately reflect their true risk of diabetes complications.
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PRE-DIABETES
When screening shows values that are abnormal but do not meet the criteria for a diagnosis of diabetes,
patients are diagnosed with pre-diabetes.
• Impaired fasting glucose

- fasting glucose = 100–125 mg / dL (5.6–6.9 mmol / L)
• Impaired glucose tolerance
- glucose level two hours after oral glucose tolerance test = 140–200 mg / dL (7.8–11.1 mmol / L)
• Pre-diabetes
- hemoglobin A1c = 5.6–6.5%
Patients with pre-diabetes are at high risk of developing overt type 2 diabetes. If pre-diabetes is identified
when screening patients for diabetes, there are some interventions that have been shown to prevent
progression to type 2 diabetes.
• Intensive lifestyle intervention

- 7% weight loss and 150 minutes physical activity weekly leads to a 58% decline in progression to
diabetes after five years
• Metformin
- 850 mg twice daily, reduced progression by 31%; 58% decrease for patients with a BMI > 35
• Acarbose
- reduced progression by 25%, but is poorly tolerated
• Pioglitazone
- reduced progression by 72%, but with significant weight gain
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READING LIST
American Diabetes Association Guidelines for Diabetes Screening
American Diabetes Association. 2017. 2. Classification and Diagnosis of Diabetes. Diabetes Care. 40: S11–S24.
Diagnostic tests for diabetes

American Diabetes Association. 2017. 2. Classification and Diagnosis of Diabetes. Diabetes Care. 40: S11–S24.
Review of the limitations of A1c

Radin, MS. 2014. Pitfalls in Hemoglobin A1c Measurement: When Results may be Misleading.
J Gen Intern Med. 29: 388–394.
Prevention of type 2 diabetes

Chiasson, JL, Josse, RG, Gomis, R, et al. 2002. Acarbose for prevention of type 2 diabetes mellitus: the STOP-
NIDDM randomised trial. Lancet. 359: 2072–2077.
DeFronzo, RA, Tripathy, D, Schwenke, DC, et al. 2011. Pioglitazone for diabetes prevention in impaired glucose
tolerance. N Engl J Med. 364: 1104–1115.
Knowler, WC, Barrett-Connor, E, Fowler, SE, et al. 2002. Reduction in the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med. 346: 393–403.
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Chapter 3
WHAT’S YOUR GOAL?
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MARKERS OF GLYCEMIC CONTROL

Prior to 1990–2000, it was unclear whether intensive glucose control actually prevented complications of
diabetes. Several in-depth studies have since confirmed that intensive treatment to lower blood sugars
minimizes the risk of long-term complications.
Hemoglobin A1c
The hemoglobin A1c is the most commonly used tool for assessing glucose
control.
Benefits
• Direct reflection of high glucose

• Reflects long-term glucose control (90–120 days, based on normal lifespan
of a red blood cell)
• Does not require fasting and can be drawn at any time of day
Limitations
• Requires normal RBC lifespan (anything that causes a shorter or longer lifespan will lead to inaccurate
values)
• Only reflects average blood sugars (doesn’t provide details about glucose swings)
• May be inaccurate in patients with abnormal hemoglobin structure or in renal failure
If hemoglobin A1c is inaccurate, consider using an alternative marker.
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Alternative markers
Fructosamine or glycated albumin
• Proteins modified by glucose (similar to hemoglobin)
• Do not rely on normal RBC lifespan
• Require normal protein levels
• Reflect glucose control over the last 2–4 weeks
1,5 anhydroglucitrol (1,5-AG)

• Useful for measuring frequency of hyperglycemia and glucose variability
• Competes with glucose for reabsorption from the kidneys
• If glucose is low, 1,5-AG is reabsorbed, leading to high levels in the blood
• If glucose is high, glucose is reabsorbed and 1,5-AG is lost in the urine, leading to low levels in the blood
• Inaccurate with average blood sugars > 200 mg / dL or A1c of 8.5%, due to persistent glucosuria
• Best used in patients with A1c at goal, when you suspect wide variability in glucose levels
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SETTING INDIVIDUAL GOALS

Current guidelines recommend patients with diabetes target a hemoglobin A1c of 6.5–7.0%, but
advise individualizing these goals to best suit each patient. The ultimate goal is to minimize the risk of
complications from hyperglycemia, while avoiding hypoglycemia. There are a number of factors to consider.
Psychosocial factors
Encourage tight control Less aggressive control
• Motivated • Poor social support

• Good disease insight • Struggling with self-care
• Excellent support systems • Difficult living situations
• Mental illness
Risk of hypoglycemia
• Young patients • Hypoglycemia unawareness

• Clear symptoms with hypoglycemia • Elderly patients
• No complications • Multiple complications of diabetes
• Multiple comorbidities
Age, disease duration, and diabetes complications
• Young patients • Elderly patients

• Newly diagnosed • Long-standing diabetes (less likely to prevent
• Long-term diabetes without complications cardiovascular disease)
• Established diabetic complications
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BLOOD GLUCOSE MONITORING

Self-monitoring of blood glucose (SMBG)
One of the primary tools we have for managing diabetes is self-monitoring of blood glucose levels, or SMBG.
This involves the patient using a small lancet to prick the tip of their finger to obtain a small drop of blood. This
is applied to a strip, which has been inserted into their blood glucose meter. After a few seconds, the blood
glucose value appears.
Benefits of SMBG
• Allows patients to evaluate their response to new therapies

• Provides information regarding effects of dietary changes
• Helps patients recognize symptoms of hypoglycemia and hyperglycemia
• Helps patients on basal insulin determine appropriate dose titration
• Helps patients on mealtime insulin with appropriate dosing at meals
SMBG can be difficult for patients to perform on a regular basis, especially if they are unsure how to use the
data. Some tips for using SMBG to provide useful information for you and your patient.
• Check several times per day, only for the week prior to patient’s clinic visit, using a glucose log.
• Use a three day glucose diary with blood sugar checks seven times daily, but just for three days.
• Consider continuous glucose monitoring for certain patients.
Continuous glucose monitoring (CGM)
Continuous glucose monitors involve inserting a small sensor under the skin.
This sensor measures glucose levels in the interstitial fluid between cells and
transmits the value to a receiver. The patient can then monitor their blood sugars
in real time, as well as monitor trends over hours, days or weeks.
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Benefits
• Alarms to alert patients to high blood sugars, low blood sugars or rapid changes in blood sugars
• Newer CGM devices allow for glucose monitoring without any fingersticks
• Can help patients with A1c < 7.0 % to maintain control with lower risk of hypoglycemia
• Can help patients with A1c above goal with insulin adjustments and improve control
• Can help prevent severe lows for patients with hypoglycemia unawareness
The example of a CGM tracing below shows where the patient would get an alarm, notifying them of a rapid
drop in blood sugar. This would allow them to act before experiencing symptoms of hypoglycemia and avoid
a severe low, or decrease the duration of the low.
In the tracing below, the patient would get a high alert, allowing them to treat their high blood glucose
between meals and before developing symptoms of hyperglycemia.
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Here, if the patient were checking their blood sugar in anticipation of a meal, they would see that blood
sugar is above goal, but dropping. They may need to take less insulin than they normally would for that meal,
to prevent overshooting their target blood sugar.
Another type of CGM is the intermittent, retrospective or professional CGM, typically performed through
the physician’s office. The patient wears a blinded CGM for 3–7 days to help diagnose problems with
blood sugars that may not be obvious with SMBG.
Consider this option in several situations
• Concern for nocturnal hypoglycemia, since the continuous monitor will allow you to review your patient’s
blood sugars overnight.
• Detecting what is known as the dawn phenomena—early morning hyperglycemia, which occurs due to an
increase in stress hormones. This can help you understand the cause of morning hyperglycemia for your
patients.
• Evaluating post-prandial hyperglycemia—which can be missed if it resolves quickly, but can still cause
significant elevations in hemoglobin A1c.
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LIFESTYLE INTERVENTIONS
An important element of diabetes control, particularly for patients with type 2 diabetes, is lifestyle
modification including dietary changes, increased physical activity, and weight loss. This should be started
at time of diagnosis, whether or not other medications are needed at that time.
Nutrition recommendations
• There is no one-size-fits-all diabetes diet

• Emphasis should be on portion control
• Avoid sweetened beverages
• Address patient’s personal and cultural preferences to maximize success with any diet
• Consider having patients meet with a registered dietician at time of diagnosis
Patients on mealtime insulin do need to be aware of the concept of carbohydrate counting—being able to
calculate the amount of carbohydrates in a meal. Larger carbohydrate intake will require more insulin, while
low carbohydrate meals will require less.
Other basic advice for your patients with type 2 diabetes includes choosing high fiber, low glycemic index
foods. The glycemic index ranks foods on how quickly they raise blood sugars after eating. Foods with
a high glycemic index, such as white rice, bagels, and pretzels, are rapidly digested and can cause larger
fluctuations in blood sugars. Low glycemic index foods, such as oatmeal, lentils, and fruits, result in more
stable blood sugars.
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Exercise and weight loss recommendations
• 150 minutes of moderate intensity exercise (e.g., brisk walk) per week, or 75 minutes / week of vigorous
activity
• For type 2 diabetes, strive for 5% weight loss from their weight at initial diagnosis
• If a patient is obese, a 7% weight loss is optimal
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READING LIST
Review of alternative markers for monitoring glycemic control
Radin, MS. 2014. Pitfalls in Hemoglobin A1c Measurement: When Results may be Misleading.
J Gen Intern Med. 29: 388–394.
Benefit of intensive diabetes management

Action to Control Cardiovascular Risk in Diabetes Study, Gernstein, HC, Miller ME, et al. 2008. Effects of intensive
glucose lowering in type 2 diabetes. N Engl J Med. 358: 2545–2559.
ADVANCE Collaborative Group, Patel, A, MacMahon, S, et al. 2008. Intensive blood glucose control and vascular
outcomes in patients with type 2 diabetes. N Engl J Med. 358: 2560–2572.
Diabetes Control and Complications Trial Research Group, Nathan, DM, Genuth, S, et al. 1993. The effect of
intensive treatment of diabetes on the development and progression of long-term complications in insulin-
dependent diabetes mellitus. N Engl J Med. 329: 977–986.
Duckworth, W, Abraira, C, Mortiz, T, et al. 2009. Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med. 360: 129–139.
The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications
(EDIC) Research Group. 2015. Effect of Intensive Diabetes Therapy on the Progression of Diabetic Retinopathy in
Patients With Type 1 Diabetes: 18 Years of Follow-up in the DCCT/EDIC. Diabetes. 64: 631–642.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303965/
UK Prospective Diabetes Study (UKPDS) Group. 1998. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS)
Group. Lancet. 352: 854–865.
Glycemic targets
American Diabetes Association. 2017. 6. Glycemic Targets. Diabetes Care. 40: S48–S56.
Individualizing A1c goals

Inzucchi, SE, Bergenstal, RM, Buse, JB, et al. 2015. Management of hyperglycemia in type 2 diabetes, 2015:
a patient-centered approach: update to a position statement of the American Diabetes Association and the
European Association for the Study of Diabetes. Diabetes Care. 38: 140–149.
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SMBG in type 2 diabetes

Polonsky, WH, Fisher, L, Schikman, CH, et al. 2011. Structured self-monitoring of blood glucose significantly
reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the Structured Testing
Program study. Diabetes Care. 34: 262–267.
Use of CGM (guidelines from the Endocrine Society)

Peters, AL, Ahmann, AJ, Battelino, T, et al. 2016. Diabetes Technology-Continuous Subcutaneous Insulin Infusion
Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab. 101: 3922–3937.
Lifestyle management
American Diabetes Association. 2017. 4. Lifestyle Management. Diabetes Care. 40: S33–S43.
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Chapter 4
STARTING TREATMENT
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METFORMIN
Several oral medications are available for use in treating diabetes.
First line therapy for patients with type 2 diabetes is metformin.
Mechanism of action
Its mechanism of action is unclear, but it acts to lower hepatic glucose production, and also helps increase
peripheral glucose uptake, likely through improved insulin sensitivity.
Benefits
• 1–2% A1c lowering
• Generally well tolerated
• Can help to prevent cardiovascular disease
Dosing
• Start at 500 mg once daily
• Increase by 500 mg every week to maximum tolerated dose of 1000 mg twice daily
Side effects
• Diarrhea, bloating, and gas (25%)
• Vitamin B12 deficiency (10%)
Contraindications
• Significant renal dysfunction
- Glomerular filtration rates (GFR) is over 60: no contraindications to using metformin
- GFR is 45–60: no dose adjustment needed, monitor creatinine every three months
- GFR is 30–45: do not start metformin, decrease maximum dose to 1000 mg daily for those already
on it
- GFR is < 30: discontinue metformin
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SULFONYLUREAS
Sulfonylureas are a commonly used second-line agent for treatment of type 2 diabetes. They are often used
in combination with metformin.
Mechanism of action
Sulfonylureas help regulate blood sugar levels by stimulating insulin release from the pancreas. This requires
functioning beta cells so sulfonylureas are only used for type 2 diabetes.
Type 2
Type 1
Benefits
• 1% A1c lowering when added to metformin
• Well tolerated with minimal side effects
• Low cost
Dosing
• Glimepiride: 1 mg–8 mg daily
• Glyburide: 2.5 mg–10 mg daily
• Gliclazide: 40–240 mg daily (not available in the US)
• Glipizide: 2.5 mg–10 mg twice daily
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Maximal glycemic effect is usually achieved at half maximal dose
Side effects
• Increased risk of hypoglycemia (due to increased insulin production)
• Weight gain
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THIAZOLIDINEDIONES (TZDs)
TZDs are most often combined with other drugs, such as metformin, and are rarely used as monotherapy.
Mechanism of action
TZDs act to improve insulin sensitivity through activation of the PPAR gamma receptors. This leads to
alterations in gene transcriptions and changes in protein expression in adipose tissue, liver, and skeletal
muscle. This ultimately results in increased glucose utilization and decreased insulin resistance.
Benefits
• 1–1.5% A1c lowering when added to metformin
• No risk of hypoglycemia
• Durable effect (only 15% failure at 5 years)
Dosing
• Pioglitazone: start at 15 mg daily (can be increased to 45 mg daily)
• Dose changes can take several weeks to have full effect
• Side effects are dose dependent (use lowest effective dose)
Side effects
• Fluid retention
• Weight gain
• Osteoporosis
• Possible risk of bladder cancer
Contraindications
• History of congestive heart failure (CHF)—due to increased fluid retention and risk of CHF exacerbation
• History of bladder cancer
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INCRETINS
One of the newer classes of diabetes medications is the incretins, which are related to hormones secreted
from the gastrointestinal system that stimulate insulin release in response to food intake. These hormones
are responsible for what is known as the incretin effect, where oral glucose causes a greater increase in
insulin levels compared to the same amount of glucose given intravenously (IV). This effect is blunted in type
2 diabetes.
This group includes two classes of medications.

GLP-1 agonists are administered as an injection,
while DPP-4 inhibitors are taken orally.
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GLP-1 is a hormone released by the L-cells of the small intestine in response to a meal. GLP-1 then travels
to the pancreas, where it enhances insulin release. Normally, GLP-1 is rapidly degraded by a dipeptidyl
peptidase-4 (DPP-4). This limits its activity.
GLP-1 receptor agonists

Mechanism of action
These synthetic GLP-1 agonists bind and trigger signaling via the GLP-1 receptor, but are resistant to DPP-4
degradation, so they increase GLP-1 signaling to supraphysiologic levels. They also delay gastric emptying,
which slows the post-meal rise in glucose and increases satiety.
Benefits
• Low risk of hypoglycemia
• May cause weight loss
• 1.0–1.5% A1c lowering
Dosing
• Exenatide: 5–10 mcg twice daily or 2 mg once weekly
• Lixisenatide: 10–20 mcg once daily
• Liraglutide: 1.2–1.8 mg once daily
• Dulaglutide: 0.75–1.5 mg once weekly
• Semaglutide: 0.5–1.0 mg weekly
Side effects
• Nausea (less common with once weekly formulations)
Contraindications
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• History of pancreatitis or pancreatic cancer

• History of medullary thyroid cancer (increase in MTC seen in preclinical rodent studies)
• Some require dose adjustment with renal dysfunction
• Gastroparesis
DPP-4 inhibitors
Mechanism of action
Inhibition of DPP-4 prevents the breakdown of GLP-1, and prolongs the activity of endogenous GLP-1. Unlike
GLP-1 receptor agonists, DPP-4 inhibitors have limited effects on gastric emptying and satiety.
Benefits
• Weight neutral
• 0.5–1.0% A1c lowering
Dosing
• Sitagliptin: 100 mg daily
• Saxagliptin: 5 mg daily
• Vildagliptin: 50 mg twice daily (not available in the US)
• Linagliptin: 5 mg once daily
• Alogliptin: 25 mg once daily
Side effects
• No significant side effects
Contraindications
• Dose adjustment needed in renal dysfunction (except with linagliptin)
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SGLT-2 INHIBITORS
SGLT-2 are effective as monotherapy and in combination with other medications.
Mechanism of action
The SGLT-2 inhibitors block the reuptake of glucose in the renal tubules, and cause glycosuria at much lower
levels of glucose. This results in lower blood sugars, via increased renal glucose losses.
Benefits
• ~1% A1c lowering in nearly all cases

• May result in weight loss
The SGLT-2 inhibitors do appear to provide cardiovascular protection, particularly for high-risk patients, with
lower rates of death related to cardiovascular disease, hospitalization for congestive heart failure, and all
causes of mortality in patients taking these medications.
Dosing
• Canagliflozin: 100–300 mg daily
• Dapagliflozin: 10 mg daily
• Empagliflozin: 10–25 mg daily
• Ertugliflozin: 5–15 mg daily
Side effects
• Polyuria
• Vaginal yeast infections
• Balanitis
• Urinary tract infections
• Orthostatic hypotension (due to volume depletion)
Contraindications
• Renal dysfunction
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READING LIST
A review of medications for treatment of type 2 diabetes
Wright, JJ and Tylee, TS. 2016. Pharmacologic Therapy of Type 2 Diabetes. Med Clin North Am. 100: 647–663.
The controversy surrounding TZDs

Home, PD, Pocock, SJ, Beck-Nielsen, H, et al. 2009. Rosiglitazone evaluated for cardiovascular outcomes in oral
agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet.
373: 2125–2135.
Mannucci, E, Monami, M, Lamanna, C, et al. 2008. Pioglitazone and cardiovascular risk. A comprehensive meta-
analysis of randomized clinical trials. Diabetes Obes Metab. 10: 1221–1238.
Nissen, SE and Wolski, KN. 2007. Effect of rosiglitazone on the risk of myocardial infarction and death from
cardiovascular causes. N Engl J Med. 357: 100.
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Chapter 5
USING ORAL MEDICATIONS
www.medmastery.com
AVOIDING HYPOGLYCEMIA
For patients at high risk of hypoglycemia, we want to use medications that are
low risk for causing low blood sugars. These typically include the medications
that do not increase insulin and primarily target insulin resistance.
Stepwise approach to adjusting medications when goal is to avoid hypoglycemia
1. Metformin is the first-line therapy for nearly all patients, including those at high risk of hypoglycemia.
2. If A1c is still above goal after three months on the maximum dose of metformin, add a second agent.
• DPP-4 inhibitors have the fewest side effects

• GLP-1 receptor agonists to minimize weight gain
• SGLT-2 inhibitors minimize weight gain
• TZDs for patients with significant insulin resistance
3. If A1c is still above goal after three months on two medications, consider adding a third agent.
• If currently on Metformin + DPP-4 inhibitor—consider switching to GLP-1 agonist (more effective than a
DPP-4 inhibitor)
• If currently on Metformin + GLP-1 RA or DPP-4 inhibitor—add SGLT-2 inhibitor
• If currently on Metformin + SGLT-2 inhibitor—add GLP-1 agonist or DPP-4 inhibitor
• If currently on Metformin + GLP-1 agonist, DPP-4 inhibitor or SGLT-2 inhibitor—add TZD
4. If not at goal after three months on three medications, you need to consider starting insulin.
DPP-4 inhibitor DPP-4 inhibitor

OR OR
Add GLP-1 agonist Add GLP-1 agonist Add
Metformin OR OR Insulin
SGLT-2 inhibitor SGLT-2 inhibitor
OR OR
TZD TZD
When trying to minimize hypoglycemia,

sulfonylureas should be avoided.
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AVOIDING WEIGHT GAIN

For patients who are concerned with weight gain (which unfortunately is a side
effect of many diabetes medications), we want to use medications that minimize
weight gain, or may even aid in weight loss.
Stepwise approach to adjusting medications when goal is to minimize weight gain
1. Metformin is the first-line therapy, as it is weight neutral, and may even result in weight loss for some
patients. It is important to emphasize lifestyle interventions as well.
2. If A1c is still above goal after three months on the maximum dose of metformin, add a second agent
• DPP-4 inhibitors have the fewest side effects—no weight loss (these are considered weight neutral)
• GLP-1 receptor agonists for some weight loss (associated with nausea)
• SGLT-2 inhibitors for weight loss (associated with urinary symptoms)
• Metformin + GLP-1 agonist (or DPP-4 inhibitor) + SGLT-2 inhibitor—best option for weight loss
4. If not at goal after three months on three medications, you need to consider starting insulin. Unfortunately,
nearly all patients will gain weight on insulin, but with continued efforts at diet and lifestyle, you can minimize
this while improving glucose control.
DPP-4 inhibitor DPP-4 inhibitor

OR OR
Add Add Add
Metformin GLP-1 agonist GLP-1 agonist Insulin
OR OR
SGLT-2 inhibitor SGLT-2 inhibitor
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MINIMIZING
CARDIOVASCULAR RISK
The leading cause of death for patients with diabetes is cardiovascular disease.
For patients at high risk of cardiovascular disease, choosing diabetes medications that have the additional
benefit of protecting against heart disease, should be a high priority.
Stepwise approach to adjusting medications when goal is to minimize cardiovascular risk
1. As with all patients with type 2 diabetes, metformin is first-line therapy. Compared to lifestyle changes
alone, metformin can reduce cardiovascular events by as much as 30%.
• SGLT-2 inhibitors (empagliflozin) have been shown to decrease cardiovascular events in patients with
established cardiovascular disease. Similar effects were seen with canagliflozin, but unexplained
increase in lower extremity amputations for the treatment group (not seen with empagliflozin).
• GLP-1 receptor agonists (liraglutide) are associated with a decrease in cardiovascular events. Similar
results were seen with semaglutide, but with an increased risk of retinopathy. No benefit seen with
lixisenatide (but no increased risk).
• Metformin + SGLT-2 inhibitor + GLP-1 agonist has not been studied for cardiovascular protection, but is
an effective combination for glucose lowering and reasonable to consider.
• Insulin has not shown cardiovascular benefit, but is effective at lowering blood glucose, which may help
lower cardiovascular risk.
• DPP-4 inhibitors and sulfonylureas are likely safe, although no benefit for cardiovascular disease.
GLP-1 agonist
GLP-1 agonist OR
Add Add
Metformin OR SGLT-2 inhibitor
SGLT-2 inhibitor OR
Insulin
Avoid TZDs in patients with high cardiovascular risk

and congestive heart failure.
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MINIMIZING COST
Many patients with type 2 diabetes will require multiple medications to
manage their diabetes. For many patients, the cost of these medications can be a
significant concern, and minimizing the cost may be a priority when selecting which
medications to use.
Stepwise approach to adjusting medications when goal is to minimize cost
1. As with all patients with type 2 diabetes, metformin is first-line therapy. It is an effective low-cost
medication, accessible to nearly all patients.
• Sulfonylureas are generally well tolerated, but have an increased risk of hypoglycemia (risk is minimized
by avoiding glyburide).
• TZDs have low risk of hypoglycemia, but significant side effects including weight gain and osteoporosis.
3. If A1c is still above goal after three months on two medications, consider adding a third agent:
• Insulin is the most cost-effective third agent.

• Metformin + sulfonylureas + TZDs are an option, but side effects are usually limiting.
Sulfonylureas
Add Add
Metformin OR Insulin
TZDs
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READING LIST
Review of pharmacologic therapies for type 2 diabetes
Review of cardiovascular effects of diabetes medications

Younk, LM, Lamos, EM, and Davis, SN. 2016. Cardiovascular effects of anti-diabetes drugs. Expert Opin Drug Saf.
15: 1239–1257.
Recent online article reviewing most recently published trials

https://www.acc.org/latest-in-cardiology/articles/2018/05/22/16/59/the-role-of-newer-anti-diabetic-drugs-in-
cv-disease
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Chapter 6
ADDING INSULIN
www.medmastery.com
INSULIN BASICS
All patients with type 1 diabetes require insulin for survival.
Many patients with type 2 diabetes can be treated with oral medications. By ten years after diagnosis, up to
75% of patients, with type 2 diabetes, will require insulin therapy.
Insulin has two roles in controlling blood sugars
1. In the fasting state, insulin controls glucose release from the liver, maintaining normal fasting blood
sugars.
2. After eating, increases in insulin levels help control post-meal increases in glucose levels.
Physiologic insulin levels are stable during fasting and between meals, with short term surges in insulin
levels associated with meals.
Patients with type 1 diabetes have no insulin production, so exogenous insulin is used to recreate this profile
as best as possible. This typically requires two different types of insulin, one to provide the long-acting basal
coverage (red line below), and a second short-acting insulin to provide mealtime coverage (blue line below).
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Patients with type 2 diabetes often need insulin to overcome their insulin resistance. These patients benefit
from just long-acting basal insulin to provide coverage in the fasting state.
Types of insulin
There are several types of insulin available for clinical use.
Name Time of onset Time to peak Duration of action Dosing frequency
Basal insulin
Glargine 60–90 min No peak 20–24 hrs Once daily
Detemir 60 min No peak 16–24 hrs Once or twice daily
Degludec 30 min No peak > 40 hrs Once daily
NPH (neutral 30–60 min 4–6 hrs 10–16 hrs Twice daily
protamine
Hagedorn)
Mealtime insulin
Aspart, lispro, 15 min 1 hr 4–6 hrs Before meals

glulisine
Regular 30 min 4 hr 5–8 hrs Before meals
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BASAL INSULIN
Who needs basal insulin?
• All patients with type 1 diabetes

• Patients with type 2 diabetes who are not well controlled on three non-insulin agents
• Patients with type 2 diabetes who are symptomatic from their hyperglycemia
• Patients with type 2 diabetes who have an A1c over 10%
How do you choose which basal insulin to use?
All basal insulins work to lower the fasting blood sugars, so you can choose whichever insulin you are most
familiar with, or whichever is most convenient for the patient.
NPH
• Requires twice daily dosing for 24 hour basal coverage
• Peak levels 4–6 hours after injection (may increase risk of hypoglycemia)
Glargine
• Once daily dosing without discernable peak
• May cause burning with injection due to lower pH
Detemir
• No peak (may require twice daily dosing for some patients)
• Less weight gain compared to glargine
Degludec
• No peak (lower risk of hypoglycemia)
• Dosing flexibility (good for patients with irregular schedules)
How to start basal insulin
• If A1c is < 9.0%—start 10 units at bedtime

• If A1c is > 9.0% or patient is symptomatic—start 0.2 units / kg / day
• Titrate dose based on fasting blood sugars
- if fasting blood sugar is over 120 mg / dL for three days in a row—increase basal insulin by 1 unit
- continue to increase basal insulin until fasting blood sugars are consistently < 120 mg / dL or insulin
dose is 0.5 units / kg
• Continue oral medications
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MEALTIME INSULIN
Mealtime insulin is necessary for all patients with type 1 diabetes, and for certain
patients with type 2 diabetes.
When to consider mealtime insulin for patients with type 2 diabetes

• Normal fasting blood sugars but A1c still elevated
• Basal insulin dose is > 0.5–1.0 units / kg / day
• Blood sugars are dropping more than 50 mg / dL overnight
Analog versus regular insulin for type 2 diabetes

• No difference in efficacy
• No significant difference in hypoglycemia risk
• Analog insulins can be taken just before eating / regular insulin requires 30 minute lag time
• Analog insulins are significantly more expensive
Starting mealtime insulin

• Calculate patient’s total daily insulin needs (type 2 diabetes: 0.3–0.5 units / kg / day)
• Divide total daily dose into 50% basal and 50% mealtime
• Divide mealtime dose by three (three meals daily)
• Most patients can start with one mealtime dose before their largest meal of the day
Example
Mr. M has type 2 diabetes, is overweight, and has some signs of insulin resistance on exam.
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50
He weighs 80 kg. You calculate his total daily insulin dose to be 40 units (0.5 units / kg / day x 80 kg). This
would be (40 units / 2) 20 units basal and 20 units mealtime, divided between three meals, which would be
6–7 units of insulin per meal (20 units / 3 meals).
Since his largest meal of the day is dinner, you ask him to start by taking 6 units of mealtime insulin before
dinner.
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ALTERNATIVE FORMS OF INSULIN

Concentrated insulin
There are multiple insulin concentrations available. Most are U-100, which means they contain 100 units
per 1 mL. Others include
• U-100 (100 units / 1 mL)—glargine, detemir, degludec, NPH, regular, aspart, lispro, glulisine
• U-200 (200 units / 1 mL)—concentrated lispro, concentrated degludec
• U-300 (300 units / 1 mL)—concentrated glargine
• U-500 (500 units / 1 mL)—concentrated regular insulin
Benefits of concentrated insulin

• Smaller injection volume
- improves patient comfort and insulin absorption
• Fewer injections per day
- can improve patient compliance
U-200 and U-300 insulins can be used interchangeably with their U-100 counterparts without dose
adjustment. U-500, however, has unique pharmacokinetics. It has a longer duration of action than U-100
regular insulin, so is able to provide both basal and mealtime coverage in a single injection.
Using U-500 insulin

• Calculate total daily insulin dose
• Start with 2/3 of dose before breakfast and 1/3 of dose before dinner
• If predinner blood sugar is elevated—increase breakfast dose by 10%
• If morning blood sugar is elevated—increase dinner dose by 10%
Inhaled insulin
Another alternative for mealtime insulin is inhaled insulin. This is a

convenient option for patients who have difficulty giving themselves multiple
daily injections, or have problems with taking insulin in public.
• This is only available as mealtime insulin

• Cartridges are only available in multiples of 4 units (4, 8, 12 units)—dose must be a multiple of four
• May require multiple inhalations for patients on high dose of mealtime insulin
• Contraindicated in lung disease
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INSULIN PUMPS
Patients using the insulin pump insert a small catheter under their skin,
connected to a pump with a reservoir containing three days worth of fast-acting
insulin.
Fast-acting (aspart, lispro, glulisine) insulin is infused continuously to provide 24-hour basal coverage. When
patients eat, they determine how much mealtime insulin they will need based on their blood sugar and what
they are eating. They then enter this value into the pump, which delivers a bolus of fast-acting insulin to
cover the meal.
The insulin pump does NOT automate

insulin administration.
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Who would benefit from an insulin pump?

• Motivated patients who check blood sugars more than four times daily and are compliant with treatment
regimens / follow up visits
• Patients with type 1 or type 2 diabetes who are not at goal despite multiple daily injections
• Patients with type 1 diabetes who need greater dosing flexibility
- e.g., higher basal needs in the early morning
- e.g., lower basal needs with physical activity
• Patients with gastroparesis who need slower administration of mealtime insulin
Who is not a good insulin pump candidate?

• Patients with A1c >10%
• Patients with anxiety / depression or other mental illness that interferes with ability to manage diabetes
• Patients with a history of missed appointments and non-compliance
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READING LIST
Pharmacologic therapy for type 1 and type 2 diabetes
American Diabetes Association. 2018. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical
Care in Diabetes-2018. Diabetes Care. 41: S73–S85.
Review of U-500 insulin (including dosing guidelines)

Reutrakul, S, Wroblewski, K, and Brown, RL. 2012. Clinical use of U-500 regular insulin: review and meta-analysis.
J Diabetes Sci Technol. 6: 412–420.
Insulin pump guidelines from the Endocrine Society

Peters, AL, Ahmann, AJ, Battelino, T, et al. 2016. Diabetes Technology-Continuous Subcutaneous Insulin Infusion
Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab. 101: 3922–3937.
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Chapter 7
ADJUSTING INSULIN
www.medmastery.com
CORRECTING
FASTING HYPERGLYCEMIA
There are two main causes of fasting hyperglycemia
1. Persistently elevated blood sugars due to inadequate basal insulin (green curve below)
• Entire glucose curve shifts down with increase of basal insulin

• This brings most blood sugars into range
2. Post-meal hyperglycemia due to inadequate mealtime insulin (black curve below)
• Blood sugars are increasing throughout the day (going up with meals)
• Blood sugar drops significantly overnight due to high doses of basal insulin
• If you increase basal coverage you would get normalization of fasting blood sugars but also increase the
risk of hypoglycemia in the fasting state
• Increase mealtime insulin to bring all blood sugars closer to goal
If your patient is only checking fasting blood sugars, you won’t be able to distinguish between these two
patterns, since fasting blood sugars are similar in both cases. If patients have fasting hyperglycemia, they
need to check twice daily—before breakfast and at bedtime—to help determine the cause.
• If blood sugars are stable or increadsing overnight (green curve above)—patient needs more basal insulin
• If blood sugars are dropping > 50 mg / dL overnight (black curve above)—patient needs more mealtime
insulin
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Example
Meet Mr. H
Mr. H checks his blood sugars every morning and has elevated fasting blood
sugars.
You ask him to complete a three day glucose log, checking fasting and bedtime
blood sugars.
His bedtime blood sugars are markedly elevated, and decrease overnight.
The best choice for him would be to increase his mealtime insulin coverage.
If the log instead showed blood sugars that were stable or increasing overnight,
you would increase his basal insulin to provide better overnight glucose control.
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ADJUSTING MEALTIME INSULIN

To safely adjust mealtime insulin, patients need to be checking blood sugars multiple times daily—before
and 1–2 hours after meals. There are several ways to accomplish this.
• Three day glucose log with seven checks per day (before and after each meal and at bedtime)
• One month glucose log with two checks per day
- week 1—before and after breakfast
- week 2—before and after lunch
- week 3—before and after dinner
- week 4—bedtime and before breakfast
If postmeal blood sugars are > 180 mg / dL, you should adjust mealtime insulin.
If the patient is on one dose of mealtime insulin daily
• Increase dose of mealtime insulin with that meal by 2 units

• Continue to increase dose every 2–3 days until post-meal blood sugar is < 180 mg / dL
• If A1c remains elevated add additional mealtime insulin doses
If patient is on multiple doses of mealtime insulin daily
• Adjust dose for one meal at a time (start with largest meal of the day)
• Consider decreasing basal insulin dose as mealtime insulin is increased (to prevent fasting
hypoglycemia)
There are three roles for insulin—basal coverage, mealtime coverage, and correction for elevated blood
sugars. Correction insulin should rarely be used without scheduled mealtime insulin.
Problems with correction (or sliding scale insulin)
• Patients only take insulin if blood sugars are elevated

• Does not prevent post-meal hyperglycemia
• Insulin has to work backwards—correcting post-meal hyperglycemia rather than preventing it
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AVOIDING HYPOGLYCEMIA
Hypoglycemia is one of the most serious side effects of insulin therapy.
Symptoms of hypoglycemia include
• Palpitations
• Sweating
• Nausea
• Confusion
• Loss of consciousness
• Seizures
For patients with hypoglycemia, it is important to characterize these events in order to help prevent them.
Questions to ask
• Do they occur overnight or when fasting?

• Do the patient's blood sugars drop low if they go too long without eating?
• Are episodes happening shortly after eating?
• Does hypoglycemia occur with exercise?
Each of these situations requires a different approach.
Overnight or fasting hypoglycemia
• Often results from too much basal insulin

• Solution
- decrease basal insulin by 10–20%
Daytime hypoglycemia (occurring with missed meals)
• Too much basal insulin

• Solution
- decrease basal insulin by 10–20%
Daytime hypoglycemia, 1–2 hours following a meal
• Likely due to too much meal time insulin

• Evaluate cause
- inaccurate carbohydrate counting
- poor appetite and inconsistent food intake
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• Solutions
- inaccurate carbohydrate counting—education, adjust insulin dose based on meal size
- poor appetite—take insulin after meal and adjust dose based on amount eaten
Exercise associated hypoglycemia
• Due to improved insulin sensitivity with exercise

• Solution
- decrease insulin with meal prior to exercise or eat prior to exercise to increase pre-exercise blood
sugars
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MANAGING NON-COMPLIANCE
Patients who are non-compliant with their insulin treatment often benefit from simpler regimens. One way to
accomplish that is with premixed insulin formulations.
Premixed insulins are combinations of NPH insulin and fast-acting insulin (regular, or one of the analog
mealtime insulins) in a single vial that allow patients to get both types of insulin in a single injection.
How to use premixed insulin
• Calculate total daily insulin dose

• If dinner is largest meal of the day—divide into 2 equal doses taken before breakfast and before dinner
• If breakfast or lunch are larger meals—take 2/3 total dose before breakfast and 1/3 dose before dinner
Adjusting premixed insulin
If blood sugars before dinner are running high, increase the breakfast dose of insulin.
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If morning blood glucose values are elevated, increase the evening insulin dose.
If the patient is having low blood sugars overnight, decrease their predinner insulin dose.
If lows are happening during the day, decrease the morning insulin dose.
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USING LOWER COST INSULINS

Insulin cost is a significant barrier for many patients. Understanding how to use the lower cost NPH and
regular insulins can be helpful in these situations.
Low-cost basal insulin—NPH
NPH acts as a basal insulin when given twice daily.
• To transition from analog insulin calculate total basal insulin dose

• Give 2/3 dose before breakfast and 1/3 dose at dinner
• If fasting blood sugars are elevated increase evening NPH dose

• If predinner blood sugars are elevated increase morning NPH dose
• If patient is having overnight hypoglycemia move evening NPH dose to bedtime
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Low-cost mealtime insulin—regular insulin
Regular insulin has a short duration of action, but longer time to onset compared to analog insulins.
• To transition from analog insulin similar doses can be used before meals
• Must be given 30 minutes prior to meal
• Can be mixed in same syringe as NPH to minimize number of injections
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READING LIST
Practical guide to insulin adjustments
LaSalle, JR and Berria, R. 2013. Insulin therapy in type 2 diabetes mellitus: a practical approach for primary care
physicians and other health care professionals. J Am Osteopath Assoc. 113: 152–162.
Using lower cost insulins

Lipska, KJ, Hirsch, IB, and Riddle, MC. 2017. Human Insulin for Type 2 Diabetes: An Effective, Less-Expensive
Option. JAMA. 318: 23–24.
Tylee, T and Hirsch, IB. 2015. Costs Associated With Using Different Insulin Preparations. JAMA. 314: 665–666.
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Chapter 8
WHEN THINGS
GO WRONG
www.medmastery.com
CARDIOVASCULAR DISEASE
The primary cause of death for patients with diabetes is cardiovascular disease, so in addition to glucose
control it is important to manage other cardiovascular risk factors.
Hypertension
Blood pressure goal for patients with diabetes should be < 140/90 mmHg.
• If > 130/80 mmHg, recommend lifestyle changes

• If > 140/90 mmHg, need to start medications
Medications that decrease cardiovascular events in diabetes
• Angiotensin converting enzyme (ACE) inhibitors

• Angiotensin receptor blockers (ARB)
• Hydrochlorothiazide (HCTZ)
• Calcium channel blockers
Screening for coronary artery disease (CAD)
• Not recommended for asymptomatic patients

• Exercise or pharmacologic stress test is indicated for any patients with symptoms of CAD
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HYPERLIPIDEMIA
Dyslipidemia treatment—statins
Statins are the treatment of choice. Who should be treated and which statin to
use is based on cardiovascular risk.
Risk factors for cardiovascular disease
• LDL cholesterol > 100 mg / dL (2.6 mmol / L)

• Hypertension
• Current tobacco use
• Family history of premature cardiovascular disease
Primary prevention
• Preventing first cardiac event in patient with no prior history of cardiovascular disease
• Type 2 diabetes, age 40–70 with risk factors for cardiovascular disease—recommend high intensity
statin (see below)
• Type 2 diabetes, age 40–70 without risk factors for cardiovascular disease—recommend moderate
intensity statin (see below)
• Type 2 diabetes, under age 40—no indication for statin
• Type 2 diabetes, over age 70—limited data but consider treatment based on risk
• Type 1 diabetes—limited data but consider treatment based on same guidelines provided for type 2
patients
Secondary prevention
• Preventing second cardiac event in patient with established cardiovascular disease

• All patients with diabetes should be treated for secondary prevention
Name Dose
High-intensity statins
Atorvastatin 40–80 mg daily
Rosuvastatin 20 mg daily
Moderate-intensity statins
Atorvastatin 10–20 mg daily
Rosuvastatin 10 mg daily
Simvastatin 20–40 mg daily
Pravastatin 40 mg daily
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Name Dose
Lovastatin 40 mg daily
Fluvastatin 40 mg daily
Antiplatelet therapy—low-dose aspirin
Primary prevention
• Indicated for high-risk patients over age 50

• Not indicated for low-risk patients
• Not indicated for any patient under 50 years of age
Secondary prevention
• Indicated for all patients with established cardiovascular disease
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MICROVASCULAR DISEASE
Retinopathy
Diabetic retinopathy is the leading cause of preventable blindness.
Nonproliferative diabetic retinopathy (NPDR)

• Results from small hemorrhages in the retinas and other microvascular abnormalities
• Vision loss due to macular edema
Aneurysm
Hemorrhage
Proliferative diabetic retinopathy (PDR)

• New vessel growth (can result in vitreous hemorrhage and retinal detachment)
• Permanent vision loss occurs through retinal detachment or macular ischemia
• Severe proliferative diabetic retinopathy has a 60% risk of vision loss at five years if untreated
Abnormal blood vessels
Screening
• Critical—most patients with diabetic retinopathy are asymptomatic until vision loss occurs
• Type 1—initial screening within five years of diagnosis
• Type 2—initial screening at time of diagnosis
• Normal exam with well controlled blood sugars—screening every two years
• Any abnormalities or blood sugars not well controlled—annual screening
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Diabetic kidney disease
Diabetic kidney disease is the leading cause of end-stage renal disease in the United States.
Clinical progression
1. Hyperfiltration occurs in early disease

2. Followed by microalbuminuria (30–300 mg / day)
3. Then macroalbinuria (> 300 mg / day)
4. Ultimately a decline in glomerular filtration rate (GFR)
Screening
• Allows for early interventions and can prevent progression

• Done with a urine test to measure albumin excretion
• If microalbuminuria is detected treatment should be initiated (see below)
• Type 1 diabetics should be screened starting five years after diagnosis (then annually)
• Type 2 diabetics should be screened at time of diagnosis (then annually)
Treatment
• Glucose and blood pressure control

• Medications
- ACE inhibitors and ARBs can both decrease albumin excretion and slow progression
- ACE and ARBs should not be used in combination due to increased rate of adverse events
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DIABETIC NEUROPATHY
Diabetic neuropathy is the most common complication of diabetes, affecting nearly 50% of patients.
Peripheral neuropathies
• Symmetric distal sensory neuropathy presents in a stocking-glove distribution.

• Small nerve fiber damage causes loss of pain and thermal sensation
• Large nerve fiber damage results in loss of touch and vibration perception
• Sensory fiber damage causes paresthesias and pain
Screening
• Visual inspection of patient’s feet at each visit

• Ensure patient has no ulcers or callouses and shoes fit appropriately
• Assess for loss of protective sensation using the 10g monofilament test
• Assessment of vibratory sense, using a 128-Hz tuning fork
• Assessment for intact peripheral pulses
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If there is a concern for loss of protective function or vascular disease, referral to a podiatrist should be
considered for evaluation for proper footwear, or other interventions to decrease risk of ulceration.
Autonomic neuropathies
• Hypoglycemia unawareness
• Resting tachycardia or postural dizziness
• Gastroparesis, diabetic diarrhea or chronic constipation
• Erectile dysfunction
• Hyperhidrosis—particularly with increased sweating of the upper body and decreased sweating in the
lower body
Treatment
• For hypoglycemia unawareness

- less aggressive glycemic targets
- consider a continuous glucose monitor
• For orthostatic hypotension
- increase salt intake
- use of compression stockings
- fludrocortisone 0.1–0.4 mg daily
• For gastroparesis
- dietary changes—consuming several small meals throughout the day
- metoclopramide 5–10 mg three times daily (acts to stimulate gastric motility)
- domperidone 10–20 mg three times daily (not available in the US)
• For erectile dysfunction
- PDE5 inhibitors
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READING LIST
Cardiovascular disease risk management
American Diabetes Association. 2018. 9. Cardiovascular Disease and Risk Management: Standards of Medical
Care in Diabetes-2018. Diabetes Care. 41: S86–S104.
Microvascular disease risk management and foot care

American Diabetes Association. 2018. 10. Microvascular Complications and Foot Care: Standards of Medical Care
in Diabetes-2018. Diabetes Care. 41: S105–S118.
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Chapter 9
SPECIAL
POPULATIONS
www.medmastery.com
THE ELDERLY
Adjust treatment goals
• An appropriate A1c goal for many older patients is 7.0–8.0%
• This minimizes risks of hypoglycemia and avoids symptomatic
hyperglycemia
Avoid hypoglycemia
• Medications may mask symptoms of hypoglycemia
• Decreased glomerular filtration rate (GFR) with age slows clearance of diabetes medications
• Increased morbidity from hypoglycemia due to fall risk and fractures
• Avoid medications that cause hypoglycemia
Avoid medication side effects

• Elderly patients may be more sensitive to medication side effects
• Avoid medications that increase risk of hypoglycemia
• Avoid medications that increase fall risk
• Avoid medications that cause decreased appetite and weight loss
Choosing medications for elderly patients
Good options
• Metformin
• Sulfonylureas (glipizide or glimepiride—avoid glyburide)
• DPP-4 inhibitors
• Basal insulin at low dose
Bad options
• TZDs (due to increased risk of osteoporosis)

• GLP-1 agonists (due to increased risk of nausea, decreased appetite, and weight loss)
• SGLT-2 inhibitors (due to polyuria and increased risk of genital and urinary tract infections)
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CHRONIC KIDNEY DISEASE

Many diabetes medications need a decrease in dose as kidney function
declines, since they are renally cleared and drug levels may accumulate with
declining renal function.
Metformin
• GFR > 45 mL / min—no dose adjustment needed

• GFR 30–45 mL / min—decrease maximum dose to 1000 mg daily
• GFR < 30 mL / min—discontinue
DPP-4 inhibitors
Sitagliptin
• GFR 30–45 mL / min—decrease to 50 mg daily
• GFR < 30 mL / min—decrease to 25 mg daily
Saxagliptin
• GFR < 45 mL / min—decrease to 2.5 mg daily
Vildagliptin
• Creatinine clearance (CrCl) < 50 mL / min—decrease to 50 mg daily
Linagliptin
• No dose adjustment necessary
Alogliptin
• CrCl 30–60 mL / min—decrease to 12.5 mg daily
• CrCl < 30 mL / min—decrease to 6.25 mg daily
GLP-1 agonists
Exenatide
• Contraindicated for CrCl < 30 mL / min
Lixisenatide
• Contraindicated for GFR < 30 mL / min
Liraglutide
• No dose adjustment necessary (limited data in end-stage renal disease)
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Dulaglutide
Semaglutide
Patients with declining renal function are at higher risk of hypoglycemia due to decreased insulin
clearance. Doses of other medications may need to be adjusted to avoid hypoglycemia.
Sulfonylureas
• Require dose reduction

• Avoid glyburide
Insulin
• May also require dose reduction
Certain medications should not be used in patients with renal dysfunction.
TZDs
• Increase fluid retention and osteoporosis (both can be significantly worse with CKD)
SGLT-2 inhibitors
• Require renal filtration for their effect on glucose lowering

• Not recommended for patients with significant renal impairment
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DIABETES IN PREGNANCY
Pregnancy is a state of increased insulin resistance. This can cause trouble
with hyperglycemia for patients without previously diagnosed diabetes, and
necessitates adjustment of treatment regimens for those patients who have
diabetes prior to pregnancy.
Changes in insulin resistance with pregnancy
• Decreased in first trimester

• Increased in second and third trimesters
Monitoring blood glucose in pregnancy
A1c is correlated with complications, but may miss post-meal hyperglycemia. Self-monitoring of blood
glucose, with pre-and post-meal checks, is critical for minimizing pregnancy complications.
Blood glucose goals in pregnancy
• Fasting: < 95 mg / dL (5.3 mmol / L)

• 1 hour post-meal: < 140 mg / dL (7.8 mmol / L)
• 2 hours post-meal: < 120 mg / dL (6.7 mmol / L)
Treatment of diabetes in pregnancy
For patients with gestational diabetes, lifestyle is often enough to control post-meal blood sugars. If
medication is needed, insulin is the best option.
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• Patients on insulin prior to pregnancy may need insulin dose decrease in first trimester
• May need insulin dose increases throughout second and third trimesters (as insulin resistance increases)
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HOSPITALIZED PATIENTS
Blood sugars between 140–180 mg / dL are optimal to prevent adverse
outcomes from hyperglycemia, while avoiding severe hypoglycemia.
Insulin is the best option for hospitalized patients who need glucose treatment.
To determine appropriate treatment
• Check blood sugars before each meal

- if patient is not eating—glucose should be checked every 4–6 hours
• If blood sugars are over 180 mg / dL—insulin should be started with goal to maintain blood sugars
between 140–180 mg / dL (for most patients)
Insulin dosing for critically ill patients
Intravenous (IV) insulin is the best option. Most hospitals have a protocol for adjusting insulin drip rates
based on hourly blood sugars, and this is the safest option for critically ill patients.
As patients improve, they can be transitioned from IV insulin to subcutaneous insulin. To do this, calculate
the total daily insulin dose given IV over the previous 24 hours. You can give 60–80% of this as basal
insulin, and add prandial insulin as the patient’s food intake improves.
It is important to give the basal insulin two hours prior to discontinuing the IV insulin, as the effect of IV
insulin will wear off quickly, but it will take several hours for the long-acting insulin to be effective.
Insulin dosing for non-critically ill patients
If the patient is not eating, start with basal insulin. If on insulin at home, it is appropriate to start with their
home dose. If not previously on insulin, start at 10 units.
If the patient is eating, treat with both basal and mealtime insulin. Total daily dose should be 0.3 units / kg,
with 50% basal, and 50% mealtime insulin.
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Insulin dosing for patients on tube feeds
Continuous tube feeds require basal insulin at 0.1–0.2 units / kg. Mealtime insulin should be given as regular
insulin, 1 unit for every 15 grams of carbohydrate every six hours.
For bolus tube feeds, give the same doses, with mealtime insulin given at the start of each bolus tube feed.
Minimizing risk of hypoglycemia

For patients who are NPO for procedures
• Give half the usual basal insulin dose
• Hold mealtime insulin
• Give correction insulin for hyperglycemia (if needed)
For patients with nausea and unpredictable food intake

• Give the mealtime insulin after they eat
• Adjust dose for amount of food eaten
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83
STEROID-INDUCED
HYPERGLYCEMIA
The effect of steroids on blood sugars usually occurs four hours after the dose.
Thus, if patients are taking steroids with breakfast (as they are often given), they
will experience hyperglycemia post-lunch. The effect will typically wear off several hours after dinner, so
fasting blood sugars are not usually affected.
For patients on long-acting steroids (such as dexamethasone) the hyperglycemia can last for up to 36 hours.
Monitoring blood sugars on steroids
• Check blood sugars 1–2 hours after dinner

- if < 180 mg / dL (10 mmol / L)—discontinue monitoring
- if blood sugars are > 200 mg / dL (12 mmol / L)—increase testing to four times daily (before meals
and at bedtime)
• Consider starting treatment for hyperglycemia if blood sugars are consistently elevated
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84
Treating steroid-induced hyperglycemia
• Once daily basal insulin with breakfast

• If taking once daily prednisone use NPH with breakfast
• If taking longer-acting steroids (like dexamethasone or twice daily prednisone) use glargine or detemir
• Initial insulin dose is 0.1 unit / kg / day for each 10 mg prednisone (or equivalent) up to a maximum of
0.4 units / kg / day
• If already on insulin add this additional insulin to their home dose
Example
An 80 kg patient is taking 30 mg prednisone daily for one week.
0.3 (0.1 per 10 mg prednisone) x 80 kg = 24 units NPH
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If he were already on insulin, we would add this to his home dose.
Managing steroid tapers
• Decrease basal insulin by 0.1 unit / kg / day for every 10 mg decrease in steroid dose
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READING LIST
Reviews of diabetes management in special populations
Elderly patients
American Diabetes Association. 2018. 11. Older Adults: Standards of Medical Care in Diabetes-2018. Diabetes
Care. 41: S119–S125.
Pregnancy
American Diabetes Association. 2018. 13. Management of Diabetes in Pregnancy: Standards of Medical Care in
Diabetes-2018. Diabetes Care. 41: S137–S143.
Hospitalized patients
American Diabetes Association. 2018. 14. Diabetes Care in the Hospital: Standards of Medical Care in
Diabetes-2018. Diabetes Care. 41: S144–S151.
Renal disease
Wallace, MD and Metzger, NL. 2018. Optimizing the Treatment of Steroid-Induced Hyperglycemia. Ann
Pharmacother. 52: 86–90.
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DIABETES

Making the diagnosis

What’s your goal?

Using oral medications

When things go wrong

Insulin deficiency Insulin resistance

High blood sugars can cause multiple symptoms

• Polyuria due to osmotic diuresis

Features of type 1 diabetes

• Patients tend to be thinner, with normal BMI

Features of type 2 diabetes

• Patients are typically overweight adults

OTHER FORMS OF DIABETES

Maturity onset diabetes of the young (MODY)

• Diagnosed in late teens or early 20s

• Patients lack clinical features of type 2 diabetes

Most common mutations involve

Gestational diabetes (GDM)

GDM is diabetes that develops during pregnancy, and is usually detected

MAKING THE DIAGNOSIS

RISK FACTORS AND SCREENING

Risks for type 2 diabetes

Risk factors for developing type 2 diabetes

• First degree relative with type 2 diabetes

Who should be screened for type 2 diabetes?

Recommendations from different societies vary, but in general

• All overweight patients

If results are normal, it is reasonable to repeat screening every three years.

Fasting Oral glucose Hemoglobin

Fasting blood sugar

Oral glucose tolerance test

The higher the glucose levels, the more hemoglobin

Hemolytic anemia Blood loss Pregnancy

• Impaired fasting glucose

• Intensive lifestyle intervention

Diagnostic tests for diabetes

Review of the limitations of A1c

Prevention of type 2 diabetes

WHAT’S YOUR GOAL?

MARKERS OF GLYCEMIC CONTROL

• Direct reflection of high glucose

If hemoglobin A1c is inaccurate, consider using an alternative marker.

1,5 anhydroglucitrol (1,5-AG)

SETTING INDIVIDUAL GOALS

Encourage tight control Less aggressive control

• Motivated • Poor social support

Encourage tight control Less aggressive control

• Young patients • Hypoglycemia unawareness

Age, disease duration, and diabetes complications

Encourage tight control Less aggressive control

• Young patients • Elderly patients

BLOOD GLUCOSE MONITORING

• Allows patients to evaluate their response to new therapies

Continuous glucose monitoring (CGM)

Consider this option in several situations

• There is no one-size-fits-all diabetes diet

Exercise and weight loss recommendations

Benefit of intensive diabetes management

Individualizing A1c goals

SMBG in type 2 diabetes

Use of CGM (guidelines from the Endocrine Society)

First line therapy for patients with type 2 diabetes is metformin.