Back to Basics: EndocrinologyDiabetes, Obesity, Metabolic SyndromeBack to Basics: EndocrinologyDiabetes, Obesity, Metabolic Syndrome
Dr. Amel ArnaoutDr. Amel Arnaout
aarnaout@toh.on.caaarnaout@toh.on.ca
Which of the following statements istrue?Which of the following statements istrue?
A.Type 1 diabetes is not diagnosed after age 50A.Type 1 diabetes is not diagnosed after age 50
B.Type 2 diabetes is more strongly inherited thantype 1 diabetes.B.Type 2 diabetes is more strongly inherited thantype 1 diabetes.
C.The incidence and prevalence of DM-1 is onthe riseC.The incidence and prevalence of DM-1 is onthe rise
D.Gestational diabetes does not increase the riskof developing diabetes in the future.D.Gestational diabetes does not increase the riskof developing diabetes in the future.
E.People with type 2 diabetes never get DKAE.People with type 2 diabetes never get DKA
AnswerAnswer
B and CB and C
Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age groupand sex, 2008/09
Diabetes in Canada: Prevalence of DiagnosedDiabetes by age and sex
Prevalence increased with age. The sharpest increase occurred after age 40 years.The highest prevalence was in the 75-79 year age group.
Prevalence (%)
0
10
15
25
30
1-19
5
20
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
≥85
Canada
Age group (years)
Females
Males
Total
Overall Prevalence
6.4%
7.2%
6.8%
Classification of DiabetesClassification of Diabetes
Type
Definition
Type 1 Diabetes
Diabetes due to pancreatic beta destruction and proneto ketosis
Type 2 diabetes
Diabetes that ranges from insulin resistance withrelative insulin deficiency to a predominant secretorydefect with insulin resistance
Gestational
Diabetes
Mellitus
Glucose intolerance with onset or first recognition inpregnancy
Other types
Variety of uncommon diseases, genetic forms, ordiabetes associated with drug use.
TYPE 1 Diabetes
10%
Beta cell destruction
(usually autoimmune)
Low or absent
Required for survival
Often <30 (but canoccur at any age)
Usually lean
Smaller
Acute, severe
Yes
No
Proportion of diabetescases
Pathogenesis
Endogenous insulinsecretion
Need for insulintherapy
Age of onset
Body habitus
Genetic component
Symptoms at onset
Ketoacidosis
Long-termcomplications present atdx?
TYPE 2 Diabetes
90%
Insulin resistance, relativeinsulin deficiency
Variable
Required in <50%, to improvecontrol rather than for survival
Often >40 but even in kids
Often obese
Very large
Often mild, slow onset
Rare
Retinopathy ~20%, CVDrelatively common
Diminishedinsulin
Hyperglycemia
Liver
1. Insulin deficiency
2. Excess glucose output
3. Insulin resistance
Pancreas
Muscle and fat
Excessglucagon
Islet
Diminishedinsulin
α-cell produces excessglucagon
β-cell producesless insulin
The pathophysiology of T2DM includesthree main defectsThe pathophysiology of T2DM includesthree main defects
Diabetes mellitus - complicationsDiabetes mellitus - complications
Stroke
CardiovascularDisease
Diabetic Neuropathy
Leading cause of non-traumatic lowerextremity amputations5
DiabeticRetinopathy
Leading cause ofblindness inworking-age adults1
DiabeticNephropathy
Leading cause ofend-stage renaldisease2
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 ofDiabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.
Diabetes Complications:MacrovascularDiabetes Complications:Macrovascular
DM is a major risk factor for cardiac diseaseDM is a major risk factor for cardiac disease
Acute MI occurs 15-20 years earlier in thosewith DMAcute MI occurs 15-20 years earlier in thosewith DM
Heart disease accounts for approximately 50%of all deaths among people with diabetes inindustrialized countriesHeart disease accounts for approximately 50%of all deaths among people with diabetes inindustrialized countries
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Several large epidemiological studies have founda strong relationship betweenSeveral large epidemiological studies have founda strong relationship between
glucose level and subsequent coronary events, evenat ‘pre-diabetes’ levels (IGT and IFG)glucose level and subsequent coronary events, evenat ‘pre-diabetes’ levels (IGT and IFG)
glucose levels that are only modestly elevated placepatients at risk.glucose levels that are only modestly elevated placepatients 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:Cardiovascula diseaseDiabetes Complications:Cardiovascula disease
Diabetes….Diabetes….
Is the leading cause of non traumatic amputationIs the leading cause of non traumatic amputation
Increases the risk of amputation by 20 foldIncreases the risk of amputation by 20 fold
those living in the north or in low income neighborhoodsand those with poor access to physician services are atparticular risk for amputation.those living in the north or in low income neighborhoodsand those with poor access to physician services are atparticular risk for amputation.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:Peripheral vascular disease (Macro and microvasculardisease)Diabetes Complications:Peripheral vascular disease (Macro and microvasculardisease)
DiabetesDiabetes
Is a leading cause of adult-onset blindnessIs a leading cause of adult-onset blindness
Prevalence of diabetic retinopathy is ~ 70% inpersons with type 1 and 40% with person withtype 2 diabetes.Prevalence of diabetic retinopathy is ~ 70% inpersons with type 1 and 40% with person withtype 2 diabetes.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:Microvascular – RetinopathyDiabetes Complications:Microvascular – Retinopathy
DiabetesDiabetes
Is the leading cause of ESRDIs the leading cause of ESRD
Increases the risk of developing ESRD by up to 13-foldIncreases the risk of developing ESRD by up to 13-fold
Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &
Parchman ML, et al Medical Care 2002; 40(2):137-144.
Diabetes Complications:Microvascular - NephropathyDiabetes Complications:Microvascular - Nephropathy
DM-2 Risk FactorsDM-2 Risk Factors
Modifiable Risk FactorsModifiable Risk Factors
Physical ActivityPhysical Activity
Obesity Obesity
DietDiet
&&
Non-Modifiable Risk FactorsNon-Modifiable Risk Factors
EthnicityEthnicity
Family HistoryFamily History
AgeAge
Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.
Diabetes Risk Factors:ModifiableDiabetes Risk Factors:Modifiable
The Epidemic:Ethnic Groups at High Risk for DMThe Epidemic:Ethnic Groups at High Risk for DM
AboriginalAboriginal
LatinoLatino
South AsianSouth Asian
AsianAsian
African DescentAfrican Descent
Prevention strategiesPrevention strategies
Primary PreventionPrimary Prevention
Prevent diabetes through reduction of modifiablerisk factors in general populationPrevent diabetes through reduction of modifiablerisk factors in general population
Secondary PreventionSecondary Prevention
Screening those at high-risk for diabetesScreening those at high-risk for diabetes
Tertiary PreventionTertiary Prevention
Upon diagnosis of diabetes, prevention ofcomplications morbidity, and mortalityUpon diagnosis of diabetes, prevention ofcomplications morbidity, and mortality
REF: Diabetes Blueprint
Primary Prevention ModelPrimary Prevention Model
GoalGoal
Reducing modifiable risk factors for diabetesReducing modifiable risk factors for diabetes
TargetTarget
General population & high-risk groupsGeneral population & high-risk groups
MessagesMessages
Healthy lifestyle choicesHealthy lifestyle choices
Current Delivery Models of Primary PreventionCurrent Delivery Models of Primary Prevention
Population HealthPopulation Health
Primary CarePrimary Care
REF: Health Canada
Primary Prevention Model:Population Health – NationalPrimary Prevention Model:Population Health – National
CDS
Health Canada
NADA
GoalGoal
Early identification of those with dysglycemiaEarly identification of those with dysglycemia
TargetTarget
High-risk individuals and groupsHigh-risk individuals and groups
MessagesMessages
Diabetes awarenessDiabetes awareness
Current delivery model of secondary preventionrelies on primary careCurrent delivery model of secondary preventionrelies on primary care
Secondary PreventionSecondary Prevention
Secondary Prevention:Is It Effective?Secondary Prevention:Is It Effective?
Yes….Yes….
Patients diagnosed with IGT can be prevented fromprogressing to type 2 diabetesPatients diagnosed with IGT can be prevented fromprogressing to type 2 diabetes
58% reduction with lifestyle changes (DPP, DPS)58% reduction with lifestyle changes (DPP, DPS)
30% reduction with medication (DPP, Stop NIDDM)30% reduction with medication (DPP, Stop NIDDM)
Tertiary Prevention:Is it Effective?Tertiary Prevention:Is it Effective?
Yes…Yes…
Strong evidence for tertiary prevention particularlyfor microvascular diseaseStrong evidence for tertiary prevention particularlyfor microvascular disease
DCCT, UKPDSDCCT, UKPDS
And for macrovascular as legacy effect (UKPDS andEDIC follow up studies)And for macrovascular as legacy effect (UKPDS andEDIC follow up studies)
How to translate this evidence into practice?How to translate this evidence into practice?
Tertiary PreventionTertiary Prevention
GoalsGoals
Glucose, blood pressure, and lipid control to reducethe development of complicationsGlucose, blood pressure, and lipid control to reducethe development of complications
Complication screening for early identification andmanagementComplication screening for early identification andmanagement
OBESITYOBESITY
Why are Obesity and Type 2 DMIncreasing in Frequency?
More sedentary lifestylesMore sedentary lifestyles
Worldwide changes in urbanization and nutritionWorldwide changes in urbanization and nutrition
Aging population due to demographic growth rates (babyboomers) and increased life expectancyAging population due to demographic growth rates (babyboomers) and increased life expectancy
www.who.int and www.idf.org accessed March 16, 2006
ObesityObesity
The most common metabolic condition inindustrialized nationsThe most common metabolic condition inindustrialized nations
Statistics Canada: 48% of Canadians between ages 20-64 yr are overweight (BMI>25), about 25% are obeseStatistics Canada: 48% of Canadians between ages 20-64 yr are overweight (BMI>25), about 25% are obese
Associated with dyslipidemia, impaired glucosetolerance and insulin resistanceAssociated with dyslipidemia, impaired glucosetolerance and insulin resistance
Risk factor for developing metabolic syndrome, type 2Dm, cardiovascular diseaseRisk factor for developing metabolic syndrome, type 2Dm, cardiovascular disease
Huge economic costsHuge economic costs
METABOLICSYNDROMEMETABOLICSYNDROME
Metabolic SyndromeMetabolic Syndrome
A constellation of risk factorsA constellation of risk factors
Significantly increased CVD risksSignificantly increased CVD risks
Significantly increased risks for type 2diabetesSignificantly increased risks for type 2diabetes
Definition of Metabolic Syndrome – need central obesity plus 2others for diagnosis
Clinical Features of the MetabolicSyndromeClinical Features of the MetabolicSyndrome
Abdominal obesityAbdominal obesity
HyperglycemiaHyperglycemia
Atherogenic dyslipidemiaAtherogenic dyslipidemia
HypertensionHypertension
Proinflammatory stateProinflammatory state
Prothrombotic stateProthrombotic state
Metabolic SyndromeMetabolic Syndrome
A common condition associated with increasedcardiovascular disease risksA common condition associated with increasedcardiovascular disease risks
Treatment is aimed at lifestyle modification toachieve desirable body weight and reduceabdominal obesityTreatment is aimed at lifestyle modification toachieve desirable body weight and reduceabdominal obesity
Multiple medical therapy may be required toachieve metabolic targets (lipids, glucose and BP)Multiple medical therapy may be required toachieve metabolic targets (lipids, glucose and BP)
Lifestyle modification benefits everyone!Lifestyle modification benefits everyone!
DIABETESDIABETES
FPG ≥7.0 mmol/L
Fasting = no caloric intake for at least 8 hours
or
A1C ≥6.5% (in adults)
Using a standardized, validated assay, in the absence of factors that affect theaccuracy of the A1C and not for suspected type 1 diabetes
or
2hPG in a 75-g OGTT ≥11.1 mmol/L
or
Random PG ≥11.1 mmol/L
Random= any time of the day, without regard to the interval since the last meal
2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose
Diagnosis of DiabetesDiagnosis of Diabetes
2013
Diagnosis of Prediabetes*Diagnosis of Prediabetes*
Test
Result
Prediabetes Category
Fasting PlasmaGlucose
(mmol/L)
6.1 - 6.9
Impaired fasting glucose(IFG)
2-hr Plasma Glucose ina 75-g Oral GlucoseTolerance Test (mmol/L)
7.8 – 11.0
Impaired glucose tolerance(IGT)
Glycated
Hemoglobin
(A1C) (%)
6.0 - 6.4
Prediabetes
* Prediabetes = IFG, IGT or A1C 6.0 - 6.4% high risk of developing T2DM
2013
Definitions of Impaired Fasting Glucose (IFG)and Impaired Glucose Tolerance (IGT) andDiabetes
Fasting Glucose (mmol/L)
3.5
4.5
5.5
6.5
7.5
8.5
3
4
6
8
10
12
14
2-h Post-load Glucose (mmol/L)
Diabetes
IFG + IGT
Normal
Glucose
IGT
IFG
6.1
6.9
7.8
11.1
* 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
5.6*
Recognize pitfalls of A1C:conditions that can affectvalueRecognize pitfalls of A1C:conditions that can affectvalue
Factors affectingA1C
Increased A1C
Decreased A1C
Variable Change inA1C
Erythropoiesis
B12/Fe deficiencyDecreased erythropoiesis
Use of EPO, Fe, or B12
Reticulocytosis
Chronic liver Dx
Alteredhemoglobin
Fetal hemoglobinHemoglobinopathiesMethemoglobin
Altered glycation
Chronic renal failure
(use of EPO decreasesA1C)
ASA, vitamin C/E
Hemoglobinopathies
↑ erythrocyte pH
Erythrocytedestruction
Splenectomy
Hemoglobinopathies
Chronic renal failure
Splenomegaly
Rheumatoid arthritis
HAART meds, Ribavirin
Dapsone
Assays
Hyperbilirubinemia
Carbamylated Hb
ETOH
Chronic opiates
Hypertriglyceridemia
Pros and Cons of Diagnostic TestsPros and Cons of Diagnostic Tests
Test
Advantages
Disadvantages
FPG
Established standard
Fast and easy
Single Sample
Sample not stable
Day-to-day variability
Inconvenient to fast
Glucose homeostasis in single time point
2hPG in75 gOGTT
Established standard
Sample not stable
Day-to-day variability
Inconvenient, Unpalatable
Cost
A1C
Convenient
Single sample
Low day-to-day variability
Reflects long term [glucose]
$$$
Affected by medical conditions, aging,ethnicity
Standardized, validated assay required
Not used for age <18, pregnant womenor suspected T1DM
Treatment of Diabetes –Target A1CTreatment of Diabetes –Target A1C
Individualizing A1C TargetsIndividualizing A1C Targets
which must bebalanced againstthe risk ofhypoglycemia
Consider 7.1-8.5% if:
2013
DCCTn=1441 T1DMIntensive(≥ 3injections/dayor CSII)vsConventional(1-2 injectionsper day)DCCTn=1441 T1DMIntensive(≥ 3injections/dayor CSII)vsConventional(1-2 injectionsper day)
Reduction in Retinopathy
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
Primary Prevention
Secondary Intervention
76% RRR
(95% CI 62-85%)
54% RRR
(95% CI 39-66%)
RRR = relative risk reduction CI = confidence interval
DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653.
DCCT/EDIC: Early intensive therapy reduced the risk ofnonfatal MI, stroke or death from CVD
57% risk reduction(P=0.02; 95% CI: 12–79%)
MI, stroke or CV death
Conventionaltreatment
Intensivetreatment
01234567891011121314151617 18 19 20 21
Years since entry
0.12
0.10
0.08
0.06
0.04
0.02
0.00
UKPDS: N = 3867 T2DMUKPDS: N = 3867 T2DM
0
6
8
9
0
3
6
9
12
15
A1C (%)
Conventional
7.9%
Intensive
7.0%
7
UKPDS Study Group. Lancet 1998:352:837-53.
Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.
UKPDS: decreased risk of diabetes-related complicationsassociated with a 1% decrease in A1CUKPDS: decreased risk of diabetes-related complicationsassociated with a 1% decrease in A1C
UKPDS: decreased risk of diabetes-related complicationsassociated with a 1% decrease in A1CUKPDS: decreased risk of diabetes-related complicationsassociated with a 1% decrease in A1C
Percentage decrease in relative riskcorresponding to a 1% decrease in HbA1C
**
Anydiabetes-
related
endpoint
21%
**
Diabetes-
related
death
21%
**
Allcausemortality
14%
*
Stroke
12%
**
Peripheralvasculardisease†
43%
**
Myocardial
infarction
14%
**
Micro-
vascular
disease
37%
**
Cataractextraction
19%
Observational analysis from UKPDS study data
†Lower extremity amputation or fatal peripheral vascular disease
*P = 0.035; **P < 0.0001
After median 8.5 years post-trial follow-up
Aggregate Endpoint 19972007
Any diabetes related endpointRRR:12%9%
P: 0.029 0.040
Microvascular diseaseRRR: 25%24%
P: 0.00990.001
Myocardial infarctionRRR:16%15%
P: 0.0520.014
All-cause mortalityRRR:6%13%
P: 0.440.007
Legacy Effect of Earlier GlucoseControl
Holman R, et al. N Engl J Med 2008;359.
Therapeutic strategies forthe management of type2 diabetes.Therapeutic strategies forthe management of type2 diabetes.
Start metformin immediately
Consider initial combination withanother antihyperglycemic agent
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin
A1C <8.5%
Symptomatic hyperglycemia withmetabolic decompensation
A1C 8.5%
Initiateinsulin +/-
metformin
If not at glycemictarget (2-3 mos)
Start / Increasemetformin
If not at glycemic targets
L
I
F
E
S
T
Y
L
E
Add an agent best suited to the individual:
Patient Characteristics
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
Comorbidities (renal, cardiac, hepatic)
Preferences & access to treatment
Other
See next page…
AT DIAGNOSIS OF TYPE 2 DIABETES
Agent Characteristics
BG lowering efficacy and durability
Risk of inducing hypoglycemia
Effect on weight
Contraindications & side-effects
Cost and coverage
Other
2013
Oral Medications toTreat Type 2 DiabetesOral Medications toTreat Type 2 Diabetes
Major Classes of MedicationsMajor Classes of Medications
1. Drugs that sensitize thebody to insulin and/orcontrol hepatic glucoseproduction1. Drugs that sensitize thebody to insulin and/orcontrol hepatic glucoseproduction
2. Drugs that stimulate thepancreas to make moreinsulin2. Drugs that stimulate thepancreas to make moreinsulin
3. Drugs that slow the3. Drugs that slow the
absorption of starches absorption of starches
Thiazolidinediones
Biguanides
Sulfonylureas
Meglitinides
Alpha-glucosidaseinhibitors
New Class of MedicationsNew Class of Medications
IncretinsIncretins
Derived from gut hormone GLP-1Derived from gut hormone GLP-1
Glucagon like peptide 1Glucagon like peptide 1
GLP-1 Effects in Humans: UnderstandingGlucoregulatory Role of IncretinsGLP-1 Effects in Humans: UnderstandingGlucoregulatory Role of Incretins
Adapted from Flint A, et al. J Chin Invest. 1998;101:515-520; Larsson H, et al. ActaPhysiol Scand. 1997;160:413-422; Nauck MA, et al. Diabetologia. 1996;39:1546-1553;Drucker DJ. Diabetes. 1998;47:159-169.
ThiazolidinedionesThiazolidinediones
Thiazolidinediones decrease insulin resistance by making muscleand adipose cells more sensitive to insulin. They also suppresshepatic glucose production.Thiazolidinediones decrease insulin resistance by making muscleand adipose cells more sensitive to insulin. They also suppresshepatic glucose production.
EfficacyEfficacy
Decrease fasting plasma glucose ~1.9-2.2 mmol/LDecrease fasting plasma glucose ~1.9-2.2 mmol/L
Reduce A1C ~0.5-1.0%Reduce A1C ~0.5-1.0%
6 weeks for maximum effect6 weeks for maximum effect
Other EffectsOther Effects
Weight gain, edemaWeight gain, edema
Hypoglycemia (if taken with insulin or agents that stimulate insulin release)Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
Contraindicated in patients with abnormal liver function or CHFContraindicated in patients with abnormal liver function or CHF
Improves HDL cholesterol and plasma triglycerides; usually LDL neutralImproves HDL cholesterol and plasma triglycerides; usually LDL neutral
Medications in this Class: pioglitazone (Actos), rosiglitazone(Avandia),Medications in this Class: pioglitazone (Actos), rosiglitazone(Avandia),
BiguanidesBiguanides
Biguanides decrease hepatic glucose production and increaseinsulin-mediated peripheral glucose uptake.Biguanides decrease hepatic glucose production and increaseinsulin-mediated peripheral glucose uptake.
EfficacyEfficacy
Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%
Other EffectsOther Effects
Diarrhea and abdominal discomfortDiarrhea and abdominal discomfort
Risk of Lactic acidosis in those at risk (renal failure, CHF)Risk of Lactic acidosis in those at risk (renal failure, CHF)
Cause small decrease in LDL cholesterol level and triglyceridesCause small decrease in LDL cholesterol level and triglycerides
No specific effect on blood pressureNo specific effect on blood pressure
No weight gain, with possible modest weight lossNo weight gain, with possible modest weight loss
Contraindicated in patients with impaired renal function (eGFR<33 ml/min)Contraindicated in patients with impaired renal function (eGFR<33 ml/min)
Medications in this Class: metformin (Glucophage), metforminhydrochloride extended release (Glumetza)Medications in this Class: metformin (Glucophage), metforminhydrochloride extended release (Glumetza)
SulfonylureasSulfonylureas
Sulfonylureas increase endogenous insulin secretionSulfonylureas increase endogenous insulin secretion
EfficacyEfficacy
Decrease fasting plasma glucose 3.3-3.9 mmol/LDecrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C by 1.0-2.0%Reduce A1C by 1.0-2.0%
Other EffectsOther Effects
HypoglycemiaHypoglycemia
Weight gainWeight gain
No specific effect on plasma lipids or blood pressureNo specific effect on plasma lipids or blood pressure
Generally the least expensive class of medicationGenerally the least expensive class of medication
Medications in this Class:Medications in this Class:
glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)
MeglitinidesMeglitinides
Meglitinides stimulate insulin secretion (rapidly and for ashort duration) in the presence of glucose.Meglitinides stimulate insulin secretion (rapidly and for ashort duration) in the presence of glucose.
EfficacyEfficacy
Decreases peak postprandial glucoseDecreases peak postprandial glucose
Decreases plasma glucose 3.3-3.9 mmol/LDecreases plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%Reduce A1C 1.0-2.0%
Other EffectsOther Effects
Hypoglycemia (although may be less than with sulfonylureas if patient has avariable eating schedule)Hypoglycemia (although may be less than with sulfonylureas if patient has avariable eating schedule)
Weight gainWeight gain
No significant effect on plasma lipid levelsNo significant effect on plasma lipid levels
Safe at higher levels of serum Cr than sulfonylureasSafe at higher levels of serum Cr than sulfonylureas
Medications in this Class: repaglinide (Gluconorm),nateglinide (Starlix)Medications in this Class: repaglinide (Gluconorm),nateglinide (Starlix)
Alpha-glucosidase InhibitorsAlpha-glucosidase Inhibitors
Alpha-glucosidase inhibitors block the enzymes thatdigest starches in the small intestineAlpha-glucosidase inhibitors block the enzymes thatdigest starches in the small intestine
EfficacyEfficacy
Decrease peak postprandial glucose 2.2-2.8 mmol/LDecrease peak postprandial glucose 2.2-2.8 mmol/L
Decrease fasting plasma glucose 1.4-1.7 mmol/LDecrease fasting plasma glucose 1.4-1.7 mmol/L
Decrease A1C 0.5-1.0%Decrease A1C 0.5-1.0%
Other EffectsOther Effects
Flatulence or abdominal discomfortFlatulence or abdominal discomfort
No specific effect on lipids or blood pressureNo specific effect on lipids or blood pressure
No weight gainNo weight gain
Contraindicated in patients with inflammatory bowel disease orcirrhosisContraindicated in patients with inflammatory bowel disease orcirrhosis
Medications in this Class: acarbose (Glucobay)Medications in this Class: acarbose (Glucobay)
2013
guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
Insulin TherapyInsulin Therapy
Types of InsulinTypes of Insulin
Types of Insulin (continued)
Normal Pancreatic FunctionNormal Pancreatic Function
Meal
Meal
Meal
Bolus: At mealtime, insulinis rapidly released inresponse to food.
Basal: Beta cells secretesmall amounts of insulin
throughout the day.
Basal Insulin
Bolus Insulin
•Expected insulin changes during the day forindividuals with a healthy pancreas.•Expected insulin changes during the day forindividuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Action Profiles of Bolus & BasalInsulinsAction Profiles of Bolus & BasalInsulins
Plasma Insulin levels
Hours
Note: action curves are approximations for illustrative purposes. Actual patient response will vary.
regular 6-10 hours
NPH 12–20 hours
lispro/aspart 4–6 hours
BASAL INSULINS
detemir ~ 6-23 hours (dose dependant)
glargine ~ 20-26 hours
Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491
Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12
BOLUS INSULINS
•Expected insulin changes during the day•Expected insulin changes during the day
•for individuals with a healthy pancreas.•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
BID NPH and Regular InsulinTherapy -Compared to Normal PhysiologyBID NPH and Regular InsulinTherapy -Compared to Normal Physiology
Bolus needs: Regular
Basal needs: NPH
Meal
Meal
Meal
•Expected insulin changes during the day•Expected insulin changes during the day
•for individuals with a healthy pancreas.•for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Multiple Daily Injections (MDI) –Strive to Mimic Normal PhysiologyMultiple Daily Injections (MDI) –Strive to Mimic Normal Physiology
MDI insulin therapy addresses:
Bolus needs: Lispro, Aspart
Basal needs: Glargine, Detemir
Meal
Meal
Meal
Insulin RegimensType 2Insulin RegimensType 2
Usually – a single bedtime injection of basalinsulin added to OAD.Usually – a single bedtime injection of basalinsulin added to OAD.
Occasionally - twice daily injections of basalinsulin with OAD.Occasionally - twice daily injections of basalinsulin with OAD.
Twice daily injection of “pre-mixed” insulinTwice daily injection of “pre-mixed” insulin
Intensive insulin – basal/bolus (THE ONLYRECOMMENDED OPTION FOR DM TYPE 1)Intensive insulin – basal/bolus (THE ONLYRECOMMENDED OPTION FOR DM TYPE 1)
40% basal/20% mealtime with each meal40% basal/20% mealtime with each meal
Case 1Case 1
Breakfast Lunch Dinner Bedtime
9.5 7.5 7.1 7.0
Is this patient well controlled?
Does this patient require insulin?
55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,On metformin, glyburide,
Case 1 - Bedtime InsulinCase 1 - Bedtime Insulin
Breakfast Lunch Dinner Bedtime
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 beoff-label in Canada
NPH, Glargine or
Detemir - 10 units
55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,On metformin, glyburide,
- - -
1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-86
2 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135
Hypoglycemia – RecognitionHypoglycemia – Recognition
Hypoglycemia = development of symptoms or a plasma glucose<4.0 mmol/L.Hypoglycemia = development of symptoms or a plasma glucose<4.0 mmol/L.
Symptoms of hypoglycemiaSymptoms of hypoglycemia
AutonomicAutonomic
NeuroglycopenicNeuroglycopenic
TremblingTrembling
PalpitationsPalpitations
SweatingSweating
AnxietyAnxiety
HungerHunger
NauseaNausea
TinglingTingling
Difficulty concentratingDifficulty concentrating
Vision changesVision changes
Difficulty speakingDifficulty speaking
HeadacheHeadache
DizzinessDizziness
ConfusionConfusion
WeaknessWeakness
DrowsinessDrowsiness
TirednessTiredness
Severity of hypoglycemiaSeverity of hypoglycemia
Mild: Autonomic symptoms are present. The individual is able to self-treat.Mild: Autonomic symptoms are present. The individual is able to self-treat.
Moderate: Autonomic and neuroglycopenic symptoms are present. Theindividual is able to self-treat.Moderate: Autonomic and neuroglycopenic symptoms are present. Theindividual is able to self-treat.
Severe: Individual requires assistance of another person. Unconsciousness mayoccur. Plasma glucose is typically <2.8 mmol/L.Severe: Individual requires assistance of another person. Unconsciousness mayoccur. Plasma glucose is typically <2.8 mmol/L.
CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43
Diabetic ketoacidosisDiabetic ketoacidosis
Diagnostic criteria Diagnostic criteria
HyperglycemiaHyperglycemia
Glucose >11.1 mmol/l; usually > 15 mmol/lGlucose >11.1 mmol/l; usually > 15 mmol/l
Metabolic acidosis (increased anion gap)Metabolic acidosis (increased anion gap)
pH < 7.35pH < 7.35
decreased bicarbonate <15 (best estimation with venous)decreased bicarbonate <15 (best estimation with venous)
Positive serum ketonesPositive serum ketones
Urine ketones: may be absent in early stagesUrine ketones: may be absent in early stages
Insulin deficiencyInsulin deficiency
Decreased peripheral glucose utilizationDecreased peripheral glucose utilization
increased glucose productionincreased glucose production
liver - gluconeogenesis (from aminoacids, glycerol),glycogenolysisliver - gluconeogenesis (from aminoacids, glycerol),glycogenolysis
increased ketogenesisincreased ketogenesis
increased lipolysis in adipocytes - provides free fattyacids for ketones and glycerol for gluconeogenesisincreased lipolysis in adipocytes - provides free fattyacids for ketones and glycerol for gluconeogenesis
1
Clinical featuresClinical features
Hyperglycemia: thirst, polyuria, circulatorycollapseHyperglycemia: thirst, polyuria, circulatorycollapse
Ketosis: “acetone breath’Ketosis: “acetone breath’
Acidosis/ compensatory respiratory alkalosis:tachypneaAcidosis/ compensatory respiratory alkalosis:tachypnea
Consequences of DKAConsequences of DKA
HyperglycemiaHyperglycemia
osmotic diuresisosmotic diuresis
dehydrationdehydration
loss of K, Na, HCO3 in urineloss of K, Na, HCO3 in urine
hyperosmolar statehyperosmolar state
increase free water into blood hyponatremia, cerebraldehydration decreased level of consciousnessincrease free water into blood hyponatremia, cerebraldehydration decreased level of consciousness
acidosisacidosis
compensatory respiratory alkalosiscompensatory respiratory alkalosis
K shifts (hyperkalemia)K shifts (hyperkalemia)
Laboratory Calculations fordiagnosis and treatmentLaboratory Calculations fordiagnosis and treatment
Serum osmolalitySerum osmolality
2(Na + K) + glucose +BUN2(Na + K) + glucose +BUN
serum Naserum Na
for each 3-4 mmol/l increase in glucose, Na should decreaseby 1for each 3-4 mmol/l increase in glucose, Na should decreaseby 1
anion gapanion gap
Na -(Cl+HCO3)Na -(Cl+HCO3)
compensation for metabolic acidosiscompensation for metabolic acidosis
If suspect other causes for acidosis; meausre serumlactate and salicylateIf suspect other causes for acidosis; meausre serumlactate and salicylate
TreatmentTreatment
GOAL:GOAL:
replace volume loss (with normal saline)replace volume loss (with normal saline)
stop ketone production (with insulin)stop ketone production (with insulin)
replace K loss (K initially high but falls rapidly withtreatment)replace K loss (K initially high but falls rapidly withtreatment)
lower serum glucoselower serum glucose
*Need to correct INSULIN DEFICIENCY*Need to correct INSULIN DEFICIENCY
*Look for precipitating cause and treat*Look for precipitating cause and treat
FluidFluid
NS 1L per hour first 2 hours, then 1L over 4 hrsNS 1L per hour first 2 hours, then 1L over 4 hrs
NS until glucose < 15NS until glucose < 15
then D5/NS or D5 depending if still replacing volumethen D5/NS or D5 depending if still replacing volume
insulininsulin
intravenousintravenous
50 units regular in 500 normal saline (0.1U/ml)50 units regular in 500 normal saline (0.1U/ml)
Bolus 0.1 unit per kg body weight (IM/IV)Bolus 0.1 unit per kg body weight (IM/IV)
Infusion 0.1 unit/kg/hourInfusion 0.1 unit/kg/hour
Glucoscans q1h, adjust IV rate and IV D5Glucoscans q1h, adjust IV rate and IV D5
* Do not stop insulin infusion until acidosis/ AG corrected* Do not stop insulin infusion until acidosis/ AG corrected
bicarbonate generally avoidedbicarbonate generally avoided
potassiumpotassium
start when K 3.3-5.5, 20 mmol/L (hold insulin if K is<3.3 and give 40 meq/hstart when K 3.3-5.5, 20 mmol/L (hold insulin if K is<3.3 and give 40 meq/h
Hyperosmolar non-ketotic stateHyperosmolar non-ketotic state
Severe hyperglycemia generally in DM type 2Severe hyperglycemia generally in DM type 2
dehydrationdehydration
serum hyperosmolalityserum hyperosmolality
lack of significant ketosis (still some circulating insulin)lack of significant ketosis (still some circulating insulin)
* takes less insulin to prevent ketosis than to stophyperglycemia* takes less insulin to prevent ketosis than to stophyperglycemia
Stressor - increased insulin resistanceStressor - increased insulin resistance
relative insulin deficiencyrelative insulin deficiency
increased glucose production, decreasedutilizationincreased glucose production, decreasedutilization
reduced renal excretion of glucosereduced renal excretion of glucose
secondary to renal disease, aging kidneyssecondary to renal disease, aging kidneys
Treatment of HONKTreatment of HONK
Correct increased serum osmolalityCorrect increased serum osmolality
Blood glucose will fall in response to fluidrepletionBlood glucose will fall in response to fluidrepletion
If Na>155 mmol/L, start 0.45% NS as initialfluidIf Na>155 mmol/L, start 0.45% NS as initialfluid
Insulin infusion only if persistent hyperglycemiaafter fluid repleteInsulin infusion only if persistent hyperglycemiaafter fluid replete
SCREENING AND PREVENTIONOF COMPLICATIONSSCREENING AND PREVENTIONOF COMPLICATIONS
≥40 yrs old or≥40 yrs old or
Macrovascular disease orMacrovascular disease or
Microvascular disease orMicrovascular disease or
DM >15 yrs duration and age >30 yearsorDM >15 yrs duration and age >30 yearsor
Warrants therapy based on the 2012Canadian Cardiovascular Society lipidWarrants therapy based on the 2012Canadian Cardiovascular Society lipid
Among women with childbearing potential, statins should onlybe used in the presence of proper preconception counseling &reliable contraception. Stop statins prior to conception.
2013
Who Should Receive Statins?Who Should Receive Statins?
Who Should Receive ACEi or ARBTherapy?Who Should Receive ACEi or ARBTherapy?
≥55 years of age or≥55 years of age or
Macrovascular disease orMacrovascular disease or
Microvascular diseaseMicrovascular disease
At doses that have shown vascular protection [perindopril 8mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mgdaily (ONTARGET)]
Among women with childbearing potential, ACEi or ARB should onlybe used in the presence of proper preconception counseling & reliablecontraception. Stop ACEi or ARB either prior to conception orimmediately upon detection of pregnancy
2013
EUROPA Investigators, Lancet 2003;362(9386):782-788.
HOPE study investigators. Lancet. 2000;355:253-59.
ONTARGET study investigators. NEJM. 2008:358:1547-59
