Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome Dr. Amel Arnaout [email protected].

Back to Basics: Back to Basics: EndocrinologyEndocrinology

Diabetes, Obesity, Metabolic Diabetes, Obesity, Metabolic SyndromeSyndrome

Dr. Amel ArnaoutDr. Amel [email protected]@toh.on.ca

Which of the following Which of the following statements is true?statements is true?A.A. Type 1 diabetes is not diagnosed after age Type 1 diabetes is not diagnosed after age

5050

B.B. Type 2 diabetes is more strongly inherited Type 2 diabetes is more strongly inherited than type 1 diabetes.than type 1 diabetes.

C.C. The incidence and prevalence of DM-1 is on The incidence and prevalence of DM-1 is on the risethe rise

D.D. Gestational diabetes does not increase the Gestational diabetes does not increase the risk of developing diabetes in the future.risk of developing diabetes in the future.

E.E. People with type 2 diabetes never get DKAPeople 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 group and sex, 2008/09

Diabetes in Canada: Prevalence of Diagnosed Diabetes 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.

Pre

va

len

ce

(%

)

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 CanadaAge 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 prone to ketosis

Type 2 diabetes Diabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance

Gestational DiabetesMellitus

Glucose intolerance with onset or first recognition in pregnancy

Other types Variety of uncommon diseases, genetic forms, or diabetes associated with drug use.

TYPE 1 Diabetes

10%

Beta cell destruction (usually autoimmune)

Low or absent

Required for survival

Often <30 (but can occur at any age)

Usually lean

Smaller

Acute, severe

Yes

No

Proportion of diabetes cases

Pathogenesis

Endogenous insulin secretion

Need for insulin therapy

Age of onset

Body habitus

Genetic component

Symptoms at onset

Ketoacidosis

Long-term complications present at dx?

TYPE 2 Diabetes

90%

Insulin resistance, relative insulin deficiency

Variable

Required in <50%, to improve control rather than for survival

Often >40 but even in kids

Often obese

Very large

Often mild, slow onset

Rare

Retinopathy ~20%, CVD relatively common

Diminishedinsulin

Hyperglycemia

Liver

1. Insulin deficiency

2. Excess glucose output

3. Insulin resistance

Pancreas

Muscle and fat

Excess glucagon

Islet

Diminishedinsulin

α-cell produces excess glucagon

β-cell produces less insulin

The pathophysiology of T2DM The pathophysiology of T2DM includes includes

three main defectsthree main defects

Diabetes mellitus - Diabetes mellitus - complicationscomplications

Stroke

Cardiovascular Disease

Diabetic Neuropathy

Leading cause of non-traumatic lower extremity amputations5

Diabetic Retinopathy

Leading cause of blindness in

working-age adults1

Diabetic Nephropathy

Leading cause of end-stage renal

disease2

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: Diabetes Complications: MacrovascularMacrovascular

DM is a major risk factor for cardiac DM is a major risk factor for cardiac diseasedisease

Acute MI occurs 15-20 years earlier Acute MI occurs 15-20 years earlier in those with DMin those with DM

Heart disease accounts for Heart disease accounts for approximately 50% of all deaths approximately 50% of all deaths among people with diabetes in among people with diabetes in industrialized countries industrialized countries

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Several large epidemiological Several large epidemiological studies have found a strong studies have found a strong relationship between relationship between glucose level and subsequent coronary glucose level and subsequent coronary

events, even at ‘pre-diabetes’ levels events, even at ‘pre-diabetes’ levels (IGT and IFG)(IGT and IFG)

glucose levels that are only modestly glucose levels that are only modestly elevated place patients at risk. 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:Diabetes Complications: Cardiovascula diseaseCardiovascula disease

Diabetes….Diabetes…. Is the leading cause of non traumatic Is the leading cause of non traumatic

amputationamputation Increases the risk of amputation by 20 Increases the risk of amputation by 20

foldfold those living in the north or in low income those living in the north or in low income

neighborhoods and those with poor access neighborhoods and those with poor access to physician services are at particular risk to physician services are at particular risk for amputation.for amputation.

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Diabetes Complications: Diabetes Complications: Peripheral vascular disease (Macro and Peripheral vascular disease (Macro and

microvascular disease) microvascular disease)

DiabetesDiabetes Is a leading cause of adult-onset Is a leading cause of adult-onset

blindnessblindness Prevalence of diabetic retinopathy is ~ Prevalence of diabetic retinopathy is ~

70% in persons with type 1 and 40% 70% in persons with type 1 and 40% with person with type 2 diabetes. with person with type 2 diabetes.

REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

Diabetes Complications: Diabetes Complications: MicrovascularMicrovascular – Retinopathy– Retinopathy

Diabetes Diabetes Is the leading cause of ESRDIs the leading cause of ESRD Increases the risk of developing ESRD Increases the risk of developing ESRD

by up to 13-foldby 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: Diabetes Complications: MicrovascularMicrovascular - - NephropathyNephropathy

DM-2 Risk FactorsDM-2 Risk Factors

Modifiable Risk FactorsModifiable Risk FactorsPhysical Activity Physical Activity

Obesity Obesity DietDiet

&&

Non-Modifiable Risk FactorsNon-Modifiable Risk FactorsEthnicityEthnicity

Family HistoryFamily HistoryAgeAge

0

10

20

30

40

Rela

tive R

isk

<23 23-25 25-30 30-35 <35

BMI = wt/ (ht)2

Obesity: Relative Risk For Developing DM

Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.

Diabetes Risk Factors:Diabetes Risk Factors:ModifiableModifiable

The Epidemic: The Epidemic: Ethnic Groups at High Risk Ethnic Groups at High Risk

for DM for DM Aboriginal Aboriginal

LatinoLatino

South AsianSouth Asian

AsianAsian

African DescentAfrican Descent

Prevention strategiesPrevention strategies

Primary PreventionPrimary Prevention Prevent diabetes through reduction of Prevent diabetes through reduction of

modifiable risk factors in general modifiable risk factors in general populationpopulation

Secondary PreventionSecondary Prevention Screening those at high-risk for diabetesScreening those at high-risk for diabetes

Tertiary PreventionTertiary Prevention Upon diagnosis of diabetes, prevention of Upon diagnosis of diabetes, prevention of

complications morbidity, and mortalitycomplications morbidity, and mortality

REF: Diabetes Blueprint

Primary Prevention Primary Prevention ModelModel

GoalGoal Reducing modifiable risk factors for diabetesReducing modifiable risk factors for diabetes

Target Target General population & high-risk groups General population & high-risk groups

MessagesMessages Healthy lifestyle choicesHealthy lifestyle choices

Current Delivery Models of Primary Current Delivery Models of Primary PreventionPrevention Population HealthPopulation Health Primary CarePrimary Care

REF: Health Canada

Primary Prevention Model: Primary Prevention Model: Population HealthPopulation Health – National – National

CDS

Health Canada

NADA

GoalGoal Early identification of those with Early identification of those with

dysglycemia dysglycemia Target Target

High-risk individuals and groups High-risk individuals and groups MessagesMessages

Diabetes awarenessDiabetes awareness Current delivery model of secondary Current delivery model of secondary

prevention relies on primary careprevention relies on primary care

Secondary PreventionSecondary Prevention

Secondary Prevention: Secondary Prevention: Is It Effective?Is It Effective?

Yes….Yes…. Patients diagnosed with IGT can be Patients diagnosed with IGT can be

prevented from progressing to type 2 prevented from progressing to type 2 diabetes diabetes 58% reduction with lifestyle changes (DPP, 58% reduction with lifestyle changes (DPP,

DPS) DPS) 30% reduction with medication (DPP, Stop 30% reduction with medication (DPP, Stop

NIDDM) NIDDM)

Tertiary Prevention: Tertiary Prevention: Is it Effective?Is it Effective?

Yes…Yes… Strong evidence for tertiary prevention Strong evidence for tertiary prevention

particularly for microvascular diseaseparticularly for microvascular disease DCCT, UKPDSDCCT, UKPDS And for macrovascular as legacy effect And for macrovascular as legacy effect

(UKPDS and EDIC follow up studies)(UKPDS and EDIC follow up studies) How to translate this evidence into How to translate this evidence into

practice?practice?

Tertiary PreventionTertiary Prevention

GoalsGoals Glucose, blood pressure, and lipid Glucose, blood pressure, and lipid

control to reduce the development of control to reduce the development of complicationscomplications

Complication screening for early Complication screening for early identification and managementidentification and management

OBESITYOBESITY

Why are Obesity and Type 2 DM

Increasing in Frequency? More sedentary lifestyles More sedentary lifestyles Worldwide changes in urbanization and nutritionWorldwide changes in urbanization and nutrition Aging population due to demographic growth rates Aging population due to demographic growth rates

(baby boomers) and increased life expectancy (baby boomers) and increased life expectancy

www.who.int and www.idf.org accessed March 16, 2006

ObesityObesity The most common metabolic condition in The most common metabolic condition in

industrialized nationsindustrialized nations Statistics Canada: 48% of Canadians Statistics Canada: 48% of Canadians

between ages 20-64 yr are overweight between ages 20-64 yr are overweight (BMI>25), about 25% are obese(BMI>25), about 25% are obese

Associated with dyslipidemia, impaired Associated with dyslipidemia, impaired glucose tolerance and insulin resistanceglucose tolerance and insulin resistance

Risk factor for developing metabolic Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular syndrome, type 2 Dm, cardiovascular diseasedisease

Huge economic costsHuge economic costs

METABOLIC METABOLIC SYNDROMESYNDROME

Metabolic SyndromeMetabolic Syndrome

A constellation of risk factors A constellation of risk factors Significantly increased CVD Significantly increased CVD

risksrisks Significantly increased risks for Significantly increased risks for

type 2 diabetestype 2 diabetes

Definition of Metabolic Syndrome – need central obesity plus 2 others for diagnosis

Clinical Features of the Clinical Features of the Metabolic SyndromeMetabolic Syndrome

Abdominal obesityAbdominal obesity HyperglycemiaHyperglycemia Atherogenic dyslipidemiaAtherogenic dyslipidemia HypertensionHypertension Proinflammatory stateProinflammatory state Prothrombotic stateProthrombotic state

Metabolic SyndromeMetabolic Syndrome

A common condition associated with A common condition associated with increased cardiovascular disease risksincreased cardiovascular disease risks

Treatment is aimed at lifestyle Treatment is aimed at lifestyle modification to achieve desirable body modification to achieve desirable body weight and reduce abdominal obesityweight and reduce abdominal obesity

Multiple medical therapy may be Multiple medical therapy may be required to achieve metabolic targets required to achieve metabolic targets (lipids, glucose and BP)(lipids, glucose and BP)

Lifestyle modification benefits Lifestyle modification benefits everyone!everyone!

DIABETESDIABETES

FPG ≥7.0 mmol/LFasting = 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 the

accuracy of the A1C and not for suspected type 1 diabetes

or

2hPG in a 75-g OGTT ≥11.1 mmol/Lor

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 Diabetes2013

Diagnosis of Prediabetes*Diagnosis of Prediabetes*

Test Result Prediabetes Category

Fasting Plasma Glucose(mmol/L)

6.1 - 6.9

Impaired fasting glucose (IFG)

2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)

7.8 – 11.0 Impaired glucose tolerance (IGT)

GlycatedHemoglobin(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) and Diabetes

Fas

ting

Glu

cose

(mm

ol/

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

NormalGlucose

IGT

IFG6.1

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: Recognize pitfalls of A1C: conditions that can affect conditions that can affect

valuevalueFactors affecting A1C

Increased A1C Decreased A1C Variable Change in A1C

Erythropoiesis B12/Fe deficiency Decreased erythropoiesis

Use of EPO, Fe, or B12Reticulocytosis Chronic liver Dx

Altered hemoglobin

Fetal hemoglobin Hemoglobinopathies Methemoglobin

Altered glycation Chronic renal failure (use of EPO decreases A1C)

ASA, vitamin C/E Hemoglobinopathies ↑ erythrocyte pH

Erythrocyte destruction

Splenectomy HemoglobinopathiesChronic renal failureSplenomegalyRheumatoid arthritisHAART meds, RibavirinDapsone

Assays HyperbilirubinemiaCarbamylated HbETOHChronic opiates

Hypertriglyceridemia

Pros and Cons of Diagnostic TestsPros and Cons of Diagnostic TestsTest Advantages Disadvantages

FPG Established standardFast and easySingle Sample

Sample not stableDay-to-day variabilityInconvenient to fastGlucose homeostasis in single time point

2hPG in 75 g OGTT

Established standard Sample not stableDay-to-day variabilityInconvenient, UnpalatableCost

A1C ConvenientSingle sampleLow day-to-day variabilityReflects long term [glucose]

$$$Affected by medical conditions, aging, ethnicityStandardized, validated assay requiredNot used for age <18, pregnant women or suspected T1DM

Treatment of Diabetes – Treatment of Diabetes – Target A1CTarget A1C

Individualizing A1C Individualizing A1C TargetsTargets

which must be balanced against the risk of hypoglycemia

Consider 7.1-8.5% if:

2013

DCCDCCTT

n=1441 n=1441 T1DMT1DM

IntensiveIntensive(≥ 3 (≥ 3

injections/dinjections/day or CSII) ay or CSII)

vs vs ConventionConvention

alal (1-2 (1-2 injections injections per day)per 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 of nonfatal MI, stroke or death from CVD

57% risk reduction(P=0.02; 95% CI: 12–79%)

MI,

stro

ke

or

CV

de

ath

Conventionaltreatment

Intensivetreatment

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years since entry

0.12

0.10

0.08

0.06

0.04

0.02

0.00

UKPDS: UKPDS: N = 3867 T2DMN = 3867 T2DM

06

8

9

0 3 6 9 12 15

A1C

(%

)

Conventional7.9%

Intensive7.0%

7

UKPDS Study Group. Lancet 1998:352:837-53.

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040

Microvascular disease RRR: 25% 24% P: 0.0099 0.001

Myocardial infarction RRR: 16% 15% P: 0.052 0.014

All-cause mortality RRR: 6% 13% P: 0.44 0.007

Legacy Effect of Earlier Glucose Control

Holman R, et al. N Engl J Med 2008;359.

Therapeutic Therapeutic strategies for the strategies for the management of management of type 2 diabetes.type 2 diabetes.

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5%Symptomatic hyperglycemia with

metabolic decompensationA1C 8.5%

Initiate insulin +/-metformin

If not at glycemic target (2-3 mos)

Start / Increase metformin

If not at glycemic targets

LIFESTYLE

Add an agent best suited to the individual:

Patient CharacteristicsDegree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityComorbidities (renal, cardiac, hepatic)Preferences & access to treatmentOther

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Agent CharacteristicsBG lowering efficacy and durabilityRisk of inducing hypoglycemiaEffect on weightContraindications & side-effectsCost and coverageOther

2013

Oral Medications Oral Medications to Treat Type 2 to Treat Type 2

DiabetesDiabetes

Major Classes of Major Classes of MedicationsMedications

1. Drugs that sensitize 1. Drugs that sensitize the body to insulin the body to insulin and/or control hepatic and/or control hepatic glucose productionglucose production

2. Drugs that stimulate 2. Drugs that stimulate the pancreas to make the pancreas to make more insulinmore insulin

3. Drugs that slow the3. Drugs that slow the absorption of starchesabsorption of starches

ThiazolidinedioneThiazolidinedioness

BiguanidesBiguanides

SulfonylureasSulfonylureasMeglitinidesMeglitinides

Alpha-glucosidase Alpha-glucosidase inhibitorsinhibitors

New Class of New Class of MedicationsMedications

IncretinsIncretins Derived from gut hormone GLP-1 Derived from gut hormone GLP-1 Glucagon like peptide 1Glucagon like peptide 1

GLP-1 Effects in Humans: GLP-1 Effects in Humans: Understanding Glucoregulatory Understanding Glucoregulatory

Role of IncretinsRole of Incretins

Adapted from Flint A, et al. J Chin Invest. 1998;101:515-520; Larsson H, et al. Acta Physiol 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 Thiazolidinediones decrease insulin resistance by

making muscle and adipose cells more sensitive to making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose insulin. They also suppress hepatic glucose production.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, edema Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate Hypoglycemia (if taken with insulin or agents that stimulate

insulin release)insulin release) Contraindicated in patients with abnormal liver function or Contraindicated in patients with abnormal liver function or

CHFCHF Improves HDL cholesterol and plasma triglycerides; usually Improves HDL cholesterol and plasma triglycerides; usually

LDL neutralLDL neutral Medications in this Class: pioglitazone (Actos), Medications in this Class: pioglitazone (Actos),

rosiglitazone (Avandia), rosiglitazone (Avandia),

BiguanidesBiguanides Biguanides decrease hepatic glucose production and Biguanides decrease hepatic glucose production and

increase insulin-mediated peripheral glucose uptake.increase insulin-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 Contraindicated in patients with impaired renal function

(eGFR<33 ml/min)(eGFR<33 ml/min) Medications in this Class: metformin (Glucophage), Medications in this Class: metformin (Glucophage),

metformin hydrochloride extended release metformin hydrochloride extended release (Glumetza)(Glumetza)

SulfonylureasSulfonylureas Sulfonylureas increase endogenous insulin Sulfonylureas increase endogenous insulin

secretionsecretion 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 gain Weight 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 glyburide (DiaBeta), glimepiride (Amaryl), gliclizide

(Diamicron)(Diamicron)

MeglitinidesMeglitinides Meglitinides stimulate insulin secretion Meglitinides stimulate insulin secretion

(rapidly and for a short duration) in the (rapidly and for a short duration) in the presence of glucose.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 Hypoglycemia (although may be less than with

sulfonylureas if patient has a variable eating schedule)sulfonylureas if patient has a variable eating schedule) Weight gain Weight 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 Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)(Gluconorm), nateglinide (Starlix)

Alpha-glucosidase Alpha-glucosidase InhibitorsInhibitors Alpha-glucosidase inhibitors block the Alpha-glucosidase inhibitors block the

enzymes that digest starches in the small enzymes that digest starches in the small intestineintestine

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 discomfort Flatulence 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 Contraindicated in patients with inflammatory bowel

disease or cirrhosisdisease or cirrhosis Medications in this Class: acarbose Medications in this Class: acarbose

(Glucobay)(Glucobay)

2013

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

Insulin TherapyInsulin Therapy

Types of Insulin Types of Insulin

Types of Insulin (continued)

Normal Pancreatic Normal Pancreatic FunctionFunction

Meal Meal Meal

Bolus: At mealtime, insulin is rapidly released

in response to food.

Basal: Beta cells secrete small amounts of insulinthroughout the day.

Basal Insulin

Bolus Insulin

• Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreasfor individuals with a healthy pancreas..

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

Action Profiles of Bolus Action Profiles of Bolus & Basal Insulins& Basal Insulins

Pla

sm

a In

sulin

lev

els

HoursNote: 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 BID NPH and Regular Insulin Therapy - Insulin Therapy -

Compared to Normal Compared to Normal PhysiologyPhysiology

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 Multiple Daily Injections (MDI) – (MDI) –

Strive to Mimic Normal Strive to Mimic Normal PhysiologyPhysiology

MDI insulin therapy addresses:

Bolus needs: Lispro, Aspart Basal needs: Glargine, Detemir

Meal Meal Meal

Insulin RegimensInsulin RegimensType 2Type 2

Usually – a single bedtime injection of Usually – a single bedtime injection of basal insulin added to OAD. basal insulin added to OAD.

Occasionally - twice daily injections of Occasionally - twice daily injections of basal insulin with OAD.basal insulin with OAD.

Twice daily injection of “pre-mixed” Twice daily injection of “pre-mixed” insulin insulin

Intensive insulin – basal/bolus (THE Intensive insulin – basal/bolus (THE ONLY RECOMMENDED OPTION FOR DM ONLY RECOMMENDED OPTION FOR DM TYPE 1)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 be

off-label in Canada

NPH, Glargine or Detemir - 10 units

55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% 8.5% On metformin, glyburide, On metformin, glyburide,

- - -

1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-862 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135

Hypoglycemia – Hypoglycemia – RecognitionRecognition

Hypoglycemia = development of symptoms or a plasma Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L.glucose <4.0 mmol/L.

Symptoms of hypoglycemiaSymptoms of hypoglycemia

AutonomicAutonomic NeuroglycopenicNeuroglycopenicTremblingTremblingPalpitationsPalpitationsSweatingSweatingAnxietyAnxiety

HungerHungerNauseaNauseaTinglingTingling

Difficulty Difficulty concentrating concentrating Vision changesVision changesDifficulty speakingDifficulty speakingHeadacheHeadacheDizzinessDizziness

ConfusionConfusionWeaknessWeaknessDrowsinessDrowsinessTirednessTiredness

Severity of hypoglycemiaSeverity of hypoglycemiaMild: Mild: Autonomic symptoms are present. The individual is Autonomic symptoms are present. The individual is able to self-treat.able to self-treat.Moderate: Moderate: Autonomic and neuroglycopenic symptoms are Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.present. The individual is able to self-treat.Severe: Severe: Individual requires assistance of another person. Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L. <2.8 mmol/L.

CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43

Diabetic Diabetic ketoacidosisketoacidosis

Diagnostic criteriaDiagnostic criteria

HyperglycemiaHyperglycemia Glucose >11.1 mmol/l; usually > 15 mmol/lGlucose >11.1 mmol/l; usually > 15 mmol/l

Metabolic acidosis Metabolic acidosis (increased anion gap)(increased anion gap) pH < 7.35pH < 7.35 decreased bicarbonate <15 (best estimation decreased bicarbonate <15 (best estimation

with venous)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 Decreased peripheral glucose utilizationutilization

increased glucose productionincreased glucose production liver - gluconeogenesis (from liver - gluconeogenesis (from

aminoacids, glycerol), glycogenolysisaminoacids, glycerol), glycogenolysis increased ketogenesisincreased ketogenesis

increased lipolysis in adipocytes - increased lipolysis in adipocytes - provides free fatty acids for ketones and provides free fatty acids for ketones and glycerol for gluconeogenesisglycerol for gluconeogenesis

1

Clinical featuresClinical features

Hyperglycemia: thirst, polyuria, Hyperglycemia: thirst, polyuria, circulatory collapsecirculatory collapse

Ketosis: “acetone breath’Ketosis: “acetone breath’ Acidosis/ compensatory respiratory Acidosis/ compensatory respiratory

alkalosis: tachypneaalkalosis: 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 state hyperosmolar state increase free water into blood increase free water into blood hyponatremia, hyponatremia,

cerebral dehydration cerebral dehydration decreased level of decreased level of consciousnessconsciousness

acidosisacidosis compensatory respiratory alkalosiscompensatory respiratory alkalosis K shifts (hyperkalemia)K shifts (hyperkalemia)

Laboratory Calculations Laboratory Calculations for diagnosis and for diagnosis and

treatmenttreatment 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 for each 3-4 mmol/l increase in glucose, Na

should decrease by 1should decrease by 1 anion gapanion gap

Na -(Cl+HCO3)Na -(Cl+HCO3) compensation for metabolic acidosiscompensation for metabolic acidosis If suspect other causes for acidosis; If suspect other causes for acidosis;

meausre serum lactate and salicylatemeausre serum lactate and salicylate

TreatmentTreatment

GOAL: GOAL: replace volume loss (with normal replace volume loss (with normal

saline)saline) stop ketone production (with insulin)stop ketone production (with insulin) replace K loss (K initially high but falls replace K loss (K initially high but falls

rapidly with treatment)rapidly with treatment) lower serum glucoselower serum glucose

**Need to correct INSULIN DEFICIENCYNeed 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 < 15 NS until glucose < 15 then D5/NS or D5 depending if still replacing then D5/NS or D5 depending if still replacing

volumevolume 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 * Do not stop insulin infusion until acidosis/ AG

correctedcorrected bicarbonate generally avoidedbicarbonate generally avoided potassiumpotassium

start when K 3.3-5.5, 20 mmol/L (hold insulin if K start when K 3.3-5.5, 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/his <3.3 and give 40 meq/h

Hyperosmolar non-Hyperosmolar non-ketotic stateketotic state

Severe hyperglycemia generally in DM Severe hyperglycemia generally in DM type 2type 2

dehydrationdehydration serum hyperosmolalityserum hyperosmolality lack of significant ketosis (still some lack of significant ketosis (still some

circulating insulin)circulating insulin)

* takes less insulin to prevent ketosis than * takes less insulin to prevent ketosis than to stop hyperglycemiato stop hyperglycemia

Stressor - increased insulin Stressor - increased insulin resistanceresistance

relative insulin deficiencyrelative insulin deficiency increased glucose production, increased glucose production,

decreased utilizationdecreased utilization reduced renal excretion of glucose reduced renal excretion of glucose

secondary to renal disease, aging secondary to renal disease, aging kidneyskidneys

Treatment of HONKTreatment of HONK

Correct increased serum osmolality Correct increased serum osmolality Blood glucose will fall in response to Blood glucose will fall in response to

fluid repletionfluid repletion If Na>155 mmol/L, start 0.45% NS If Na>155 mmol/L, start 0.45% NS

as initial fluidas initial fluid Insulin infusion only if persistent Insulin infusion only if persistent

hyperglycemia after fluid repletehyperglycemia after fluid replete

SCREENING AND SCREENING AND PREVENTION OF PREVENTION OF COMPLICATIONSCOMPLICATIONS

≥≥40 yrs old 40 yrs old oror Macrovascular disease Macrovascular disease oror Microvascular disease Microvascular disease oror DM >15 yrs duration and age >30 years DM >15 yrs duration and age >30 years

oror Warrants therapy based on the 2012 Warrants therapy based on the 2012

Canadian Cardiovascular Society lipid Canadian Cardiovascular Society lipid

Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling &

reliable contraception. Stop statins prior to conception.

2013

Who Should Receive Who Should Receive Statins? Statins?

Who Should Receive ACEi or ARB Who Should Receive ACEi or ARB Therapy?Therapy?

≥≥55 years of age 55 years of age or or Macrovascular disease Macrovascular disease or or Microvascular disease Microvascular disease

At doses that have shown vascular protection [perindopril 8 mg daily (EUROPA),

ramipril 10 mg daily (HOPE), telmisartan 80 mg daily (ONTARGET)]

Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception counseling & reliable contraception.

Stop ACEi or ARB either prior to conception or immediately 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