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Back to Basics: Endocrinology
Diabetes, Obesity and Thyroid
Diagnosis of Diabetes




What are the CDA criteria for the diagnosis of
diabetes?
Who should be screened for type 2 diabetes
Which type of diabetes has a stronger genetic
component type 1 or type 2?
Which type of diabetes only presents in the
elderly population?
Screening for Type 2 Diabetes
Every 3 years in individuals  40 years of age
Earlier and/or more frequently in individuals with
additional risk factors
FPG
5.7-6.9 mmol/L
plus risk factor(s) for diabetes/IGT
2hPG in a 75-g
OGTT
CDA 2003 Clinical Practice Guidelines. Can J Diabetes 2003;27:S11
Fasting Glucose (mmol/L)
Definitions of Impaired Fasting Glucose (IFG)
and Impaired Glucose Tolerance (IGT) and
Diabetes
8.5
Diabetes
7.5
6.9
6.5
6.1
5.6*
5.5
4.5
IFG
IFG + IGT
Normal
Glucose
IGT
3.5
3
4
6
8
7.8
10
12
14
11.1
2-h Post-load Glucose (mmol/L)
* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7,
3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int
The World Wide Epidemic:
Prevalence of Diabetes
5%
8%
3%
14%
4%
The Worldwide Epidemic:
Diabetes Trends
Millions with Diabetes
400
370
350
300
300
250
221
177
200
135
150
100
50
30
0
1985
1995 2000
Sources: www.who.int
www.idf
Zimmet P. et al Nature: 414, 13 Dec 2001
2010
2025 2030
The Diabetes
Epidemic
in Canada
Prevalence, Risk Factors,
and
Current Cost Implications
The Canadian Epidemic:
Prevalence in Canada, 1994/95 to 2000/01, by
Province
Prevalence (%)
1.30 to 2.90
1996 - 1997
1994 - 1995
3.00 to 3.40
3.50 to 3.90
4.00 to 4.40
3.2
2.8
3.1
3.1
3.0
3.50
2.8
3.6
3.
1
2.5
3.40
3.2
3.2
3.20
3.2
3.2
1.3
3.10 3.1
3.9
4.0
3.1
3.6
3.1
3.3
Source: Statistics Canada: CANSIM II
4.6
5.8
5.2
3.1
3.20
2000 - 2001
1998 - 1999
3.4
5.00 to 5.40
4.60
3.90
2.7
4.4
4.0
3.4
4.0
4.1
4.2
5.0
5.1
5.2
5.50 to 5.90
No data
Diabetes Risk Factors
Modifiable Risk Factors
Physical
Activity
 Obesity
Diet
&
Non-Modifiable Risk Factors
Ethnicity
Family
History
Diabetes Risk Factors:
Modifiable
Physical Activity:
Relative Risk For Developing Diabetes
Relative Risk
2
1
0
>7
4 to 7
2 to 4 .5 to 2
Hours per week
Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.
<0.5
Diabetes Risk Factors:
Modifiable
Healthy Diet:
Relative Risk for Developing DM
relative risk
2
1.5
1
0.5
0
5
4
3
2
1
quintiles based on fat/fibre content
Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.
Diabetes Risk Factors:
Modifiable
Obesity:
Relative Risk For Developing DM
Relative Risk
40
30
20
10
0
<23 23-25 25-30 30-35 <35
BMI = wt/(ht) 2
Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.
Diabetes Risk Factors:
Modifiable

Relative risk for developing type 2 is cumulative.





A physically inactive individual (less than 30 min/wk of
exercise)
who consumes an unhealthy diet
and is modestly overweight (BMI 25-30)
would have a 30-fold increased (1.8*2*8) risk of developing
type 2 DM compared to the general population,
which would translate to a lifetime risk of nearly 100%
REF: Atlas of Diabetes 2nd Ed, Part 2, JS Sklyer, Editor
Run away from diabetes
The Epidemic:
Non-Modifiable Risk
Factors
Ethnicity
Age
Family History / Genetics
The Epidemic:
Ethnic Groups at High Risk
for DM
Aboriginal
Latino
South East Asian
Asian
African Descent
Diabetes Risk Factors: Non-Modifiable
Other High-risk Groups in Canada

77.1% of Canada’s immigrant population are
coming from populations which from high risk
ethnic groups



7.3% Latinos
 Central and South America, 7.3%
57.0% Asian
12.8% African Decent
 Caribbean and Bermuda, 5.5%
 Africa, 7.3%
REF: Statistics Canada, 1996 Census
Type 2 Diabetes is NOT a Mild
Disease
Diabetic
Retinopathy
Leading cause of
blindness in
working-age adults1
Stroke
2- to 4-fold increase in
cardiovascular mortality
and stroke3
Cardiovascular
Disease
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease2
8/10 diabetic patients
die from CV events4
Diabetic Neuropathy
Leading cause of nontraumatic lower
extremity amputations5
1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S102. 2. Molitch ME et al. Diabetes Care 2003; 26
(Suppl 1):S94-S98. 3. Kannel WB et al. Am J Heart 1990; 120:672-6. 4. Gray RP and Yudkin JS. In: Textbook of
Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.
Diabetes Complications:
Macrovascular



DM is a major risk factor for cardiac disease
Acute MI occurs 15-20 years earlier in those
with DM
Heart disease accounts for approximately 50%
of all deaths among people with diabetes in
industrialized countries
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Macrovascular

Several large epidemiological studies have found
a strong relationship between
glucose level and subsequent coronary events, even
at ‘pre-diabetes’ levels (IGT and IFG)
 glucose levels that are only modestly elevated place
patients at risk.

REF: Coutiho M. et al Diabetes Care 1999;22:233-240.
& DECODE Study Group. Arch Intern Med 2001;161:397-404.
Diabetes Complications: Macrovascular
Relationship between FPG and CHD
Metaregression - 20 prospective studies
n = 95,783 - follow-up 12.4 yrs
FPG > 6 mmol/L: RR 1.38 (1.06-1.67)
Relative Risk
2.5
2
1.5
1
4
5
6
7
Fasting glucose (mmol/L)
REF: Coutinho et al. Diabetes Care 1999;22:233-40.
8
9
Diabetes Complications:
Microvascular – Amputation

Diabetes….
Is the leading cause of non traumatic amputation
 Increases the risk of amputation by 20 fold


those living in the north or in low income neighborhoods
and those with poor access to physician services are at
particular risk for amputation.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Microvascular – Retinopathy
Diabetes
 Is a leading cause of adult-onset blindness
 Prevalence of diabetic retinopathy is ~ 70% in
persons with type 1 and 40% with person with
type 2 diabetes.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Microvascular - Nephropathy

Diabetes
Is the leading cause of ESRD
 Increases the risk of developing ESRD by up to 13fold

Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &
Parchman ML, et al Medical Care 2002; 40(2):137-144.
Prevention strategies

Primary Prevention


Secondary Prevention


Prevent diabetes through reduction of modifiable
risk factors in general population
Screening those at high-risk for diabetes
Tertiary Prevention

Upon diagnosis of diabetes, prevention of
complications morbidity, and mortality
REF: Diabetes Blueprint
Primary Prevention Model

Goal

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Target


General population & high-risk groups
Messages


Reducing modifiable risk factors for diabetes
Healthy lifestyle choices
Current Delivery Models of Primary Prevention


Population Health
Primary Care
Primary Prevention Model:
Population Health – National
CDS
Health Canada
NADA
REF: Health Canada
Secondary Prevention

Goal


Target


High-risk individuals and groups
Messages


Early identification of those with dysglycemia
Diabetes awareness
Current delivery model of secondary prevention
relies on primary care
Secondary Prevention:
Is It Effective?

Yes….

Patients diagnosed with IGT can be prevented from
progressing to type 2 diabetes
58% reduction with lifestyle changes (DPP, DPS)
 30% reduction with medication (DPP, Stop NIDDM)

Tertiary Prevention:
Is it Effective?

Yes…

Strong evidence for tertiary prevention particularly
for microvascular disease


DCCT, UKPDS
How to translate this evidence into practice?
Tertiary Prevention

Goals
Glucose, blood pressure, and lipid control to reduce
the development of complications
 Complication screening for early identification and
management

Why are Obesity and Type 2 DM
Increasing in Frequency?

More sedentary lifestyles

Worldwide changes in urbanization and nutrition

Aging population due to demographic growth rates (baby
boomers) and increased life expectancy
www.who.int and www.idf.org accessed March 16, 2006
Obesity by Province: BMI 30
1985
1990
1996
< 10%
< 10% - 14.9%
> 15%
No data
Source: Katzmarzyk PT, CMAJ Apr. 16, 2002; 166 (8)
1994
1998
Obesity


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

The most common metabolic condition in
industrialized nations
Statistics Canada: 48% of Canadians between ages 2064 yr are overweight (BMI>25)
Associated with dyslipidemia, impaired glucose
tolerance and insulin resistance
Risk factor for developing metabolic syndrome, type 2
Dm, cardiovascular disease
Huge economic costs
Obesity in Canada: 1978/79 to
2004
Quick Facts:
% of obese children
increased from 3% to 8%
Among adults, the
increase was even more
dramatic: from 14% to
23%, a total of 5.5 million
people
About 30% of baby
boomers (aged 45 to 64)
are obese
Data from Canadian Community Health Survey
www.statcan.ca/Daily/English/050706/d050706a.htm
Canada’s Food guide to healthy
eating


Promote a diet with 30% or less energy from fat,
15-20% energy from protein and 50-55% from
complex carbohydrates
Despite a decrease from 40% of energy from fat
in U.S. diet in 1965 to 34% in 1991, incidence of
obesity increased
Why is it Important to Recognize
the
Metabolic Syndrome?
A prevalent condition associated with:
 Significantly increased CVD risks
 Significantly increased risks for type 2 diabetes
It is treatable and preventable
Clinical Features of the Metabolic
Syndrome

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Abdominal obesity
Hyperglycemia
Atherogenic dyslipidemia
Hypertension
Proinflammatory state
Prothrombotic state
IDF Classification of the
Metabolic Syndrome
Risk Factors
Central obesity
 Europids, Mid-east
 S. Asians, Chinese
 Japanese
Cut Points
Men
Waist C.
Women
 94 cm (37 in)
 80 cm (31.5 in)
 90 cm (35 in)
 80 cm (31.5 in)
 85 cm (33 in)
 90 cm (35 in)
Plus any 2 of the following for diagnosis:
Triglycerides
HDL cholesterol
 Men

Women
 1.7
 0.90
 1.10
Blood pressure
 130 Syst. or diast.  85 mm Hg or Rx
Fasting glucose
 5.6 mmol/L
Inadequate evidence to recommend routine measurement of insulin resistance (e.g., plasma insulin),
proinflammatory state, or prothrombotic state in the diagnosis of the metabolic syndrome
Metabolic Syndrome




A common condition associated with increased
cardiovascular disease risks
Treatment is aimed at lifestyle modification to
achieve desirable body weight and reduce
abdominal obesity
Multiple medical therapy may be required to
achieve metabolic targets (lipids, glucose and BP)
Lifestyle modification benefits everyone!
Therapeutic strategies for
the management of type
2 diabetes.
Targets for Metabolic Control:
Glucose Control (2003 CDA
Guidelines)
Normal Range
(consider if can be
achieved safely)
Target for Most
Patients
 6.0
 7.0
Preprandial
4.0 – 6.0
4.0 – 7.0
2 h Postprandial
5.0 – 8.0
5.0 – 10.0
A1C
Risk categories and target lipid levels
III-9
Achieve Target A1C within 6–12
Months
Clinical assessment and initiation of nutrition and physical activity
A1C ≥9%
A1C <9%
BMI ≥25
Metformin (first-line)
TZD
Secretagogue
Insulin
Acarbose
BMI <25
Metformin
TZD
Secretagogue
Insulin
Acarbose
2 agents:
Metformin
TZD
Secretagogue
Insulin
Acarbose
Timely adjustments/additions should be made to attain
target A1C within 6–12 months.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2003;27(Suppl 2):S1–152.
Insulin
Oral Medications to
Treat Type 2 Diabetes
Oral Medications to
Treat Type 2 Diabetes
Major Classes of Medications
1. Drugs that sensitize the
body to insulin and/or
control hepatic glucose
production
Thiazolidinediones
Biguanides
2. Drugs that stimulate the
pancreas to make more
insulin
Sulfonylureas
Meglitinides
3. Drugs that slow the
absorption of starches
Alpha-glucosidase
inhibitors
Thiazolidinediones


Thiazolidinediones decrease insulin resistance by making muscle
and adipose cells more sensitive to insulin. They also suppress
hepatic glucose production.
Efficacy




Other Effects





Decrease fasting plasma glucose ~1.9-2.2 mmol/L
Reduce A1C ~0.5-1.0%
6 weeks for maximum effect
Weight gain, edema
Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
Contraindicated in patients with abnormal liver function or CHF
Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
Medications in this Class: pioglitazone (Actos), rosiglitazone
(Avandia),
Biguanides


Biguanides decrease hepatic glucose production and increase
insulin-mediated peripheral glucose uptake.
Efficacy



Other Effects







Decrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%
Diarrhea and abdominal discomfort
Risk of Lactic acidosis in those at risk (renal failure, CHF)
Cause small decrease in LDL cholesterol level and triglycerides
No specific effect on blood pressure
No weight gain, with possible modest weight loss
Contraindicated in patients with impaired renal function (eGFR<33 ml/min)
Medications in this Class: metformin (Glucophage), metformin
hydrochloride extended release (Glumetza)
Sulfonylureas


Sulfonylureas increase endogenous insulin secretion
Efficacy



Other Effects





Decrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C by 1.0-2.0%
Hypoglycemia
Weight gain
No specific effect on plasma lipids or blood pressure
Generally the least expensive class of medication
Medications in this Class:

glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)
Meglitinides


Meglitinides stimulate insulin secretion (rapidly and for a
short duration) in the presence of glucose.
Efficacy




Other Effects





Decreases peak postprandial glucose
Decreases plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%
Hypoglycemia (although may be less than with sulfonylureas if patient has a
variable eating schedule)
Weight gain
No significant effect on plasma lipid levels
Safe at higher levels of serum Cr than sulfonylureas
Medications in this Class: repaglinide (Gluconorm),
nateglinide (Starlix)
Alpha-glucosidase Inhibitors


Alpha-glucosidase inhibitors block the enzymes that
digest starches in the small intestine
Efficacy




Other Effects





Decrease peak postprandial glucose 2.2-2.8 mmol/L
Decrease fasting plasma glucose 1.4-1.7 mmol/L
Decrease A1C 0.5-1.0%
Flatulence or abdominal discomfort
No specific effect on lipids or blood pressure
No weight gain
Contraindicated in patients with inflammatory bowel disease or
cirrhosis
Medications in this Class: acarbose (Glucobay)
Treatment of Type 2 Diabetes
Diagnosis
Therapeutic Lifestyle Change
Monotherapy
Combination Therapy - Oral Drugs Only
Combination Therapy - Oral Drug with Insulin
Insulin Therapy
Normal Pancreatic Function
Basal: Beta cells secrete
small amounts of insulin
throughout the day.
Bolus: At mealtime, insulin
is rapidly released in
response to food.
Bolus Insulin
Basal Insulin
Meal
•
Meal
Meal
Expected insulin changes during the day for
individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Action Profiles of Bolus & Basal
Insulins
lispro/aspart 4–6 hours
regular 6-10 hours


BOLUS INSULINS
BASAL INSULINS
NPH 12–20 hours
detemir ~ 6-23 hours (dose dependant)
glargine ~ 20-26 hours
Hours
Note: action curves are approximations for illustrative purposes. Actual patient response will vary.
Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491
Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12
Therapy Compared to Normal Physiology
Basal needs: NPH
Bolus needs: Regular
Meal
•
•
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data
Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500
Multiple Daily Injections (MDI) –
Strive to Mimic Normal Physiology
MDI insulin therapy addresses:
Basal needs: Glargine, Detemir
Bolus needs: Lispro, Aspart
Meal
•
•
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Insulin Regimens
Type 2

Usually – a single bedtime injection of basal
insulin added to OAD.

Occasionally - twice daily injections of basal
insulin with OAD.

Twice daily injection of “pre-mixed” insulin (split
mix without mixing).

Intensive insulin – basal/bolus

40% basal/20% mealtime with each meal
Case 1
55
year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 7.5%
On metformin, glyburide, TZD (thiazolidinedione)
Breakfast
Lunch
Dinner
Bedtime
9.5
7.5
7.1
7.0
 Is this patient well controlled?
 Does this patient require insulin?
If “yes”…
 How would you start insulin here?
 How do you titrate the insulin dose?
 What do you do with the oral agents?
Case 1 - Bedtime Insulin
55
year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 7.5%
On metformin, glyburide, TZD
Breakfast



Lunch
-
Dinner
-
Bedtime
NPH, Glargine or
Detemir - 10 units
Start with 10 units1, or use 0.1- 0.2 units/kg and titrate2
Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units
Continue metformin, glyburide. Continuing TZD would be
off-label in Canada
1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-86
2 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135
Dosage Initiation & Titration for
Once-Daily Insulin Regimens
Initial dose of insulin at bedtime (Glargine, Detemir, NPH)
 - Safe starting dose should equal fasting blood glucose
in mmol/L. For example: Fasting glucose = 10 mmol/L
Starting Insulin Dose = 10 units

Self-adjustment of insulin doses
 - Measure fasting glucose daily during first weeks or
months; after reaching target, frequency of testing can
reduce to once a week

- If fasting glucose exceeds 5.5 mmol/L on three
consecutive FPG measurements, increase bedtime insulin
dose by 2 units

Yki-Jarvinen, H., Diabetes Care 2001, 24(4): 758-67
Hypoglycemia – Recognition

Hypoglycemia = development of symptoms or a plasma glucose
<4.0 mmol/L.
Symptoms of hypoglycemia
Autonomic
Trembling
Palpitations
Sweating
Anxiety
Neuroglycopenic
Hunger
Nausea
Tingling
Difficulty concentrating
Vision changes
Difficulty speaking
Headache
Dizziness
Confusion
Weakness
Drowsiness
Tiredness
Severity of hypoglycemia
Mild: Autonomic symptoms are present. The individual is able to self-treat.
Moderate: Autonomic and neuroglycopenic symptoms are present. The
individual is able to self-treat.
Severe: Individual requires assistance of another person. Unconsciousness may
occur. Plasma glucose is typically <2.8 mmol/L.
CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43
Type 2 Diabetes and Dyslipidemia
Dyslipidemic Profile in Type 2
Diabetes
Type 2 diabetes is associated with a lipid profile that
increases CV risk:






Low levels of HDL cholesterol
Elevated triglycerides
Raised concentrations of free fatty acids
Increased small, dense, and more atherogenic
LDL particles
Total LDL levels remain relatively unchanged
Raised total cholesterol / HDL cholesterol ratio
Pyorala K, et al. Diabetes Care. 1997;20:614-620.
Paolisso G, Howard BV. Diabet Med 1998;15:360-366.
Haffner SM, et al. Diabetes Care. 1999;22:562-568.
LDL Atherogenicity in Type 2
Diabetes


Total LDL cholesterol concentrations similar to
those in nondiabetic controls, BUT…
Important qualitative changes in LDL



Shift in LDL subfraction distribution to smaller
denser particles (pattern B)
Increased susceptibility to oxidation
Glycation of LDL apo B
Adapted from Chait A, Bierman EL. Joslin's Diabetes Mellitus 13th ed. Philadelphia: Lea & Febiger; 1994:648-664.
Haffner SM. Diabetes Care. 1998;2:160-178.
Treatment options

Reduce LDL-C to target for high risk patients
mmol/L)
(< 2.0

Combinations of lipid-lowering medications can and should be
used to achieve lipid targets
Statin + cholesterol absorption inhibitors
Statin + fibrates
Statin + niacin
Cholesterol absorption inhibitors + fibrates
Vascular Protection Through a
Multifaceted Approach
For ALL High-risk Patients with Diabetes
• ACEI
• ASA (clopidogrel if intolerance)
• Lifestyle management: No smoking, healthy diet / weight, physical activity
Lipid Control
Blood Pressure Control
High
CV risk
Aim for BP < 130/80 mm Hg
If BP >130/80 mm Hg despite ACEI:
Treat as per hypertension
recommendations (CHEP/CHS)
Aim for
LDL ≤ 2.0 and
TC:HDL < 4.0
When monotherapy fails to achieve lipid
targets, the addition of a second drug
from another class should be considered
Renal Protection
•Treat as per nephropathy
recommendations (CDA)
Adapted from Can J Diabetes. 2003;27:S58-S65.
Glycemic Control
Aim for A1C < 7.0%
(< 6.0% if achievable safely)
If AIC > 7%: Treat as per glycemia
recommendations (CDA)
Smoking Cessation advice.
Diabetic
Nephropathy
Diabetic Nephropathy




Over 40% of new cases of endstage renal disease (ESRD) are
attributed to diabetes.
In 2001, 41,312 people with
diabetes began treatment for endstage renal disease in U.S.
In 2001, it cost $22.8 billion in
public and private funds to treat
patients with kidney failure.
Minorities experience higher than
average rates of nephropathy and
kidney disease
Incidence of ESRD
Resulting from Primary
Diseases (1998)
19%
3%
43%
12%
23%
Diabetes
Hypertension
Glomerulonephritis
Cystic Kidney
Other Causes
Screening for Diabetic
Nephropathy
Test
When
Normal Range
Blood
Pressure1
Each office visit
<130/80 mm/Hg
Urinary
Albumin1
Type 2: Annually
beginning at diagnosis
Type 1: Annually, 5-years
post-diagnosis
<30 mg/day
30 mg/mgcreatinine
1American
ACR </= 2.8 for women
ACR </= 2.0 for men
Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes
Care 27 (Suppl.1): S79-S83, 2004
Treatment of Diabetic
Nephropathy

Hypertension Control - Goal: lower blood
pressure to <130/80 mmHg

Antihypertensive agents

Angiotensin-converting enzyme (ACE) inhibitors


Angiotensin receptor blocker (ARB) therapy


captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril,
quinapril, perindopril, trandolapril, moexipril
candesartan cilexetil, irbesartan, losartan potassium,
telmisartan, valsartan, esprosartan
Beta-blockers
Treatment of Diabetic
Nephropathy (cont.)

Glycemic Control
Preprandial plasma glucose 90-130 mg/dl
 A1C <7.0%
 Peak postprandial plasma glucose <180 mg/dl
 Self-monitoring of blood glucose (SMBG)
 Medical Nutrition Therapy


Restrict dietary protein to RDA of 0.8 g/kg
body weight per day
Treatment of End-Stage Renal
Disease (ESRD)
There are three primary treatment options for
individuals who experience ESRD:
1. Hemodialysis
2. Peritoneal Dialysis
3. Kidney Transplantation
How Can You Prevent Diabetic
Kidney Disease?






Maintain blood pressure <130/80 mm/Hg
Maintain preprandial plasma glucose 4-7
mmol/L
Maintain postprandial plasma glucose <10
mmol/L
Maintain A1C <7.0%
Use ACE inhib or ARB if ACR is elevated even
if normotensive
Use antiplatelet therapy
Diabetic Retinopathy
Diabetic Retinopathy
• Diabetic retinopathy is the
most common cause of new
cases of blindness among
adults 20-74 years of age.
• During the first two decades
of disease, nearly all patients
with type 1 diabetes and over
60% of patients with type 2
diabetes have retinopathy
Risks of Diabetic Retinopathy
Related Vision Loss

Duration of diabetes disease





type 1 patients experience a 25% rate of retinopathy after 5
years of disease, and 80% at 15 years of disease1
Up to 21% of newly diagnosed type 2 patients have some
degree of retinopathy at time of diagnosis1
Puberty
Pregnancy
Lack of appropriate ophthalmic examination
1American
Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1):
S84-S87, 2004
Retinopathy Screening





Type 1 diabetes - screen within 3-5 years of
diagnosis after age 101
Type 2 diabetes - screen at time of diagnosis1
Pregnancy - women with preexisting diabetes
should be screened prior to conception and during
first trimester1
Follow-up annually; less frequent exams (2-3 yrs)
may be considered1
Examination Methods - Dilated indirect
ophthalmoscopy coupled with biomicroscopy and
seven-standard field steroscopic 30° fundus
photography1
1American
Diabetes Association: Retinopathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1):
S84-S87, 2004
Natural History of Diabetic
Retinopathy
Mild nonproliferative diabetic
retinopathy (NPDR)
 Moderate NPDR
 Severe NPDR
 Very Severe NPDR
 Proliferative diabetic
retinopathy (PDR)

Diabetic ketoacidosis
TYPE 1 Diabetes
TYPE 2 Diabetes
10%
90%
Pathogenesis
Beta cell destruction
(usually autoimmune)
Insulin resistance, relative
insulin deficiency
Endogenous insulin
secretion
Low or absent
Variable
Need for insulin
therapy
Required for survival
Required in <50%, to improve
control rather than for survival
Age of onset
Often <30 (but can
occur at any age)
Often >40
Body habitus
Usually lean
Often obese
Genetic component
Smaller
Very large
Symptoms at onset
Acute, severe
Often mild, slow onset
Ketoacidosis
Yes
Rare
Proportion of diabetes
cases
Long-term
No
complications present at
dx?
Retinopathy ~20%, CVD
relatively common
Diagnostic criteria

Hyperglycemia


metabolic acidosis (increased anion gap)



Glucose >11.1 mmol/l; usually > 15 mmol/l
pH < 7.35
decreased bicarbonate <15 (best estimation with venous)
positive serum ketones

Urine ketones: may be absent in early stages
Insulin deficiency


Decreased peripheral glucose utilization
increased glucose production


liver - gluconeogenesis (from aminoacids, glycerol),
glycogenolysis
increased ketogenesis

increased lipolysis in adipocytes - provides free fatty
acids for ketones and glycerol for gluconeogenesis
Clinical features



Hyperglycemia: thirst, polyuria, circulatory
collapse
Ketosis: “acetone breath’
Acidosis/ compensatory respiratory alkalosis:
tachypnea
DKA: Precipitating Causes
Consequences of DKA

Hyperglycemia

osmotic diuresis



hyperosmolar state


dehydration
loss of K, Na, HCO3 in urine
increase free water into blood hyponatremia, cerebral
dehydration  decreased level of consciousness
acidosis


compensatory respiratory alkalosis
K shifts (hyperkalemia)
Laboratory Calculations for
diagnosis and treatment

Serum osmolality


serum Na



for each 3-4 mmol/l increase in glucose, Na should decrease
by 1
anion gap


2(Na + K) + glucose +BUN
Na -(Cl+HCO3)
compensation for metabolic acidosis
If suspect other causes for acidosis; meausre serum
lactate and salicylate
Treatment

GOAL:
replace volume loss
 stop ketone production
 replace K loss (K initially high but falls rapidly with
treatment)
 lower serum glucose
*Need to correct INSULIN DEFICIENCY
*Look for precipitating cause and treat


Fluid




NS 1L per hour first 2 hours, then 1L over 4 hrs
NS until glucose < 15
then D5/NS or D5 depending if still replacing volume
insulin
intravenous
 50 units regular in 500 normal saline (0.1U/ml)
 Bolus 0.1 unit per kg body weight (IM/IV)
 Infusion 0.1 unit/kg/hour
 Glucoscans q1h, adjust IV rate and IV D5
* Do not stop insulin infusion until acidosis/ AG corrected



bicarbonate generally avoided
potassium

start when K 4.5-5.0, 20 mmol/L
Hyperosmolar non-ketotic state





Severe hyperglycemia generally in DM type 2
dehydration
serum hyperosmolality
lack of significant ketosis (still some circulating insulin)
* takes less insulin to prevent ketosis than to stop
hyperglycemia




Stressor - increased insulin resistance
relative insulin deficiency
increased glucose production, decreased
utilization
reduced renal excretion of glucose

secondary to renal disease, aging kidneys
Treatment of HONK




Correct increased serum osmolality
Blood glucose will fall in response to fluid
repletion
If Na>155 mmol/L, start 0.45% NS as initial
fluid
Insulin infusion only if persistent hyperglycemia
after fluid replete
Thyroid
Thyroid Gland
Average weight 20 gms (~0.7 ounces)
Thyroid Hormone Review

Tetraiodothyronine (T4)
and triiodothyronine (T3)
released from thyroid gland
in ratio 20:1

T3 is the active form or
thyroid hormone

20% of T3 from thyroid
gland, 80% from extrathyroidal conversion by
5’deiodinase enzyme
Thyroid Review cont…

T4 converted to T3 by
5’deiodinase enzyme in target
tissues

5’deiodinase also converts T4 to
rT3 (inactive form)

rT3 production upregulated (at
the expense of T3) in acute or
chronic illness

Thyroid hormones exert a variety
of effects including inotropic and
chronotropic effects on the heart
(direct and permissive via
upregulation of B-adrenergic
receptors), vasodilation, increased
heat production.
Review: Hypothalamic-Pituitary
Axis
What can go wrong?



Functional

Hypothyroidism

Hyperthyroidism
Structural

Nodules

Cancer
Both
Hypothyroidism

Can exacerbate preexisting medical
conditions.

Fatigue
Slow heart rate
Constipation
Menstrual Irregularities
Dry Skin, Coarse Hair
Cold Intolerance





Signs of Hypothyroidism

Pseudomyotonic reflexes (95%)

Hypothermia or cold skin (83%)

Skin changes (79%) – nonpitting waxy dry edema,
dependant edema (30%)

Coarse hair (76%), loss of axillary and pubic hair
(30%), loss of scalp and facial hair (18%)

Pallor (24%)

Abdominal distension (18%)

Goiter (16%)


Pericardial effusion, dull facial expression,
unsteady gait, husky voice, periorbital puffiness,
bradycardia, narrow pulse pressure, macroglossia,
CTS, thyroidectomy scar
Labs – macrocytic anemia, hyponatremia, elevated
CPK, AST, LDH dyslipidemia, low FT4
LEVOTHYROXINE
•T4 preparation exact chemical structure of human thyroxine
• stable, cheap, widely available
• one of the most commonly prescribed drugs
•half life is ~ 7 days
DOSAGE ADJUSTMENT
• evaluate clinical response
• measure TSH ~ 6 weeks after change
in dose
• adjust dose by 0.025 mg (0.012 mg)
• once TSH is in target range, repeat annually
RISKS OF OVER TREATMENT
WITH THYROID HORMONES
• induce symptoms of hyperthyroidism
• may accelerate bone loss in those at risk
• exacerbate angina
• risk of atrial fibrillation
• increased heart rate and myocardial contractility
•Important to keep the T3 level in the target range
THYROID HORMONE REPLACEMENT
IN PREGNANCY
• requirements can increase by 25 - 50%
• must monitor TSH every 8 weeks and
and 6 weeks after dosage adjustment
• target TSH in normal range
• post pregnancy - requirements return to
pre-pregnancy dose
THYROIDITIS
Thyroiditis with pain and tenderness:
• acute infectious (rare)
• subacute granulomatous thyroiditis
(common, viral)
SUBACUTE GRANULOMATIS
THYROIDITIS
• subacute thyroiditis or DeQuervains’
thyroiditis, likely viral
• three phases:
hyperthyroid,
hypothyroid
recovery phase
• treatment: NSAID or prednisone,
• b-blocker for hyperthyroid symptoms
L-T4 not usually necessary
POST-PARTUM THYROIDITIS
• lymphocytic thyroiditis up to 1 year
post-partum, usually 6 weeks after
delivery
• usually mild phases of hyper/hypothyroidism
• anti-thyroid peroxidase antibodies elevated
• usually resolves but can recur after
future pregnancies
HYPERTHYROIDISM
Symptoms
Signs
Nervousness
Restlessness
Heat intolerance
Warm, moist skin
Insomnia
Tremor
Sweating
Diffuse goitre
Diarrhea
Bruit
OTHER MANIFESTATIONS

dermopathy

spider angiomata

onycholysis

myopathy

gynecomastia

periodic paralysis

palmar erythema

vitiligo
HYPERTHYROIDISM MOST COMMON CAUSES
• Graves’ Disease
• Toxic nodular goitre
solitary nodular or multinodular
• hyperthyroid phase of subacute thyroiditis
• excessive administration of thyroid hormone
HYPERTHYROIDISM UNCOMMON CAUSES
• choriocarcinoma or hydatidiform moles (HCG)
• thyroid carcinoma
 toxic carcinomatous nodule
 from widespread metastasis
• struma ovarii
• associated with acromegaly
• related to polyostotic fibrous dysplasia
• induced by iodine
• TSH-producing pituitary adenoma
• T3 toxicosis
LABORATORY TESTING
Graves’
FT4
FT3
TSH
RAIU
Toxic
nodular
Toxic
nodule
Thyroiditis
ETIOLOGY OF GRAVES
DISEASE
• autoimmune disorder
• TSI bind to hTSH-R
TSH
or Ab
GRAVES’ DISEASE
• most common cause of hyperthyroidism
• females 4: males 1
• autoimmune disorder
• thyroid stimulating immunoglobulin (TSI)
• genetic factors
AUTOIMMUNE DISEASES ASSOCIATED WITH
GRAVES’ AND HASHIMOTO’S DISEASES
Graves’ disease
Hashimoto’s thyroiditis
• Hashimoto’s thyroiditis
• Pernicious anemia
• Addison’s disease
• Diabetes mellitus
• Vitiligo
• Myasthenia gravis
• Rheumatoid arthritis
• Idiopathic thrombocytopenic
purpura
• Graves’ disease
• Pernicious anemia
• Sjögren’s syndrome
• Addison’s disease
• Rheumatoid arthritis
GRAVES’ DISEASE MANIFESTATIONS
• hyperthyroidism
• ophthalmopathy
• “pretibial myxedema”
Graves Dermopathy



Accumulation of
polysaccharides –
glycosaminoglycans
Usually on anterior tibia
Can be painful, usually
has red appearance
Graves’ Ophthalmopathy




Thyroid stare
chemosis
Proptosis
Improves with treatment
of hyperthyroidism
GRAVES’ DISEASE - TREATMENT
• antithyroid drugs
 propylthiouracil
 methimazole
• radioactive iodine
Complications:
 recurrence
 hypothyroidism
• subtotal thyroidectomy
Complications:
 recurrence
 hypothyroidism
 vocal cord palsy
 hypoparathyroidism
Hyperthyroidism and pregnancy
•Start propylthiouraci if needed,
(methimazole is second choice).
•Target free T4 and free T3 to the upper range
of normal
•Refer to Endocrinology
•Ensure women with history of Graves’ disease
inform their doctor’s with each pregnancy.
Subclinical Hyperthyroidism
40 y.o woman c/o fullness in neck, otherwise will




TSH is <0.1 mU/L
fT4 is 18 pmol/L, fT3 is 4.8 pmol/L
no palpable nodule, slight goitre
Do you need to do more? Only if becomes
symptomatic or is high risk for atrial fib. or
osteoporosis
Subclinical Hyperthyroidism
• Increase risk of atrial fibrillation
• May have mild symptoms of hyperthyroidism
• increased risk of bone loss
• Treat if symptoms or has other risk factors for
AF or osteoporosis
• Most cases of subclinical hyperthyroidism
resolve within 1 year without treatment
THYROID NODULAR DISEASE
Prevalence of thyroid nodules
 4% on palpation (most are 2cm)
 67% by ultrasound
 50% by autopsy
 ~30,000 palpable nodules found annually
 Rarely malignant, ~5%
CAUSES OF THYROID NODULES
• Common causes:
 colloid nodule (nodular goitre)
 cyst
 benign neoplasm
 papillary carcinoma
Uncommon causes:
 granulomatous thyroiditis
 infections
 cancer: follicular, medullary, anaplastic,
metastatic (breast, renal, GI), lymphoma
Thyroid Nodule or Nodules
Fine Needle Aspiration Biopsy
Benign solid Thyroid Nodule
Observation for 1 Year
Thyroid Ultrasonography
Size Decreased
Size Unchanged
Continue Observation
Size Increased
Fine Needle
Aspiration Biopsy
Malignant or
Suspicious Nodule
Benign Nodule
L-Thyroxine Suppressive
Therapy for 1 Year
Surgery
Thyroid Ultrasonography
Size decreased or
Size Increased
unchanged
Surgery
Continue L-Thyroxine
Therapy
Decision making for treatment of patients with benign thyroid nodules
Ultrasonography-guided fine-needle aspiration with needle tip accurately placed
in the nodule
Castro, M. R. et. al. Ann Intern Med 2005;142:926-931
TREATMENT OF THYROID
NODULES
Toxic Nodule
Nontoxic Nodule
• antithyroid drugs
• observation
• radioactive iodine
• surgery
• Ethanol injection
• thyroxine suppression
• surgery
Thyroid Cancer Update
Outline

What types?

How common?

Treat?

Follow-up?
Question 1
Thyroid cancer is the most rapidly increasing
cancer among Canadians age 20-44.
True
False
Question 2
One is considered “cured” after being
disease-free for 10 years and no further
follow-up is required.
True
False
Thyroid Cancer

Differentiated

Papillary (83%)

Follicular (9%)

Medullary (2%)

Anaplastic

Lymphoma
“Cancer Care Ontario: Cancer in Young Adults in Canada, May 2006
How common?

~3400 cases in Canada in 2006

3rd most common in young adults

Most rapidly growing

2-3 times more prevalent in women
“Cancer Care Ontario: Cancer in Young Adults in Canada, May 2006
“Cancer Care
Ontario:
Cancer in
Young Adults
in Canada,
May 2006
Prognosis = good!

Age at diagnosis (<45 yrs)

Tumour size

Recurrence

Metastases

Pathologic features
Cumulative Recurrence
and Cancer Death After Initial Therapy
Cumulative percent
40
Recurrence
At 30 years:
30
Recurrence
30%
20
Cancer death
8%
Cancer death
10
0
0
10
20
30
40
Years after initial therapy
Patients at risk
(n)
1355
1075
568
185
10
Mazzaferri. Am J Med. 1994; 97:418–428.
Therefore …

Thyroid cancer prevalence is increasing –
particularly in young adults

Prognosis is generally good

Death from thyroid cancer is uncommon

Recurrence can happen even years after
diagnosis
Treatment
Treatment
1. THYROIDECTOMY

To remove the cancer and the rest of the
thyroid

To provide information about the cancer
(size etc)
Treatment
2.
RADIOIODINE REMNANT ABLATION

Iodine is taken up by thyroid cells

Radioiodine in large dose will destroy any remaining
thyroid cells (normal and cancer)

Works better when cells are “hungry” for iodine

Must have a high TSH (means hypothyroid)

Withdrawal of hormone is usual for treatment

Whole body scan 1 week later
Treatment
3. THYROID REPLACEMENT (Thyroxine)

To replace missing thyroid hormone

Give a little “extra” to push down TSH to not
stimulate any remaining cells (thyroid
hormone suppression therapy)
Treatment
3. THYROID REPLACEMENT

Target TSH to <0.5 mIU/L for most

May consider TSH 0.3 – 2 long term in some
cases
Thyroid Cancer






Ensure suppressed TSH
Follow thyroglobulin as tumor marker
Periodic CXR, US neck
Stimulated thyroglobulin levels
raise TSH by hypothyroidism or Thyrogen
(rhTSH injection)
Iodine body scans (not always used)
Question 1
Thyroid cancer is the most rapidly increasing
cancer among Canadians age 20-44.
True
False
Question 2
One is considered “cured” after being diseasefree for 10 years and no further follow-up is
required.
True
False
Thank you!