low HDL C. IFCThigh WC. smoker. HTN or
with presence of other risk modifiers:
hsCRP>2.0 mg/L, CAC >0 AU. family history of
premature CAD, Lp(a)>_50 mg/dL(100 nmol/L)
See Landmark Endocrinology Trialsfar more
informal!on on the JUPITER trial.It details the effects
of statm treatment on cardiovascular events m
patients with elevated high -sensitivity CRP levels.
Statin thorapy notrecommondod for most
low risk individuals,oxcoptions includo:
a. LDL C >5.0 mmol/L lor ApoB >J 45 g/L or
non HDL C >4 2mmol/L) or
b. FRS is 5 9.9% with LDL C >3.5 mmol/L
(or non HDL C >4.2 mmol/Lor ApoB
>J .05 g/L),particularly with other CV
risk modifiers le.g.FHx,Lpla ) 50mg/dL
|or 100 nmol/Uor CAC >0 AU) as the
proportionalbenefitfrom statin therapy
may be similar to other treated groups
i
—H Discuss hoalth behaviouralmodifications
Initiate StatinTreatment
NO
HDL
^
?VS,
>m
2
oli/n
,
utLn?[,
^
,
f.52,80f
^
nun SiMindcS»
Honllh Behaviour Modifications:
•Smoking cessation
•Diet: itis recommended all individuals
adopt a healthy dietary pattern
•Exercise: itisrecommended adults
accumulate atleast 150 mirx/wk of
moderate vigorous intensity aerobic
physical activity
YES YES
-4*
Discuss add-on therapy withpatient:
Evaluate reductionin CVD risk vs. cost/access and side effects
r ~i
"- J /
NO Monitor
•Rosponsoto statinRx
•Response to add on lipid lowering Rx
•Health behaviour changes
ADD ON
YES Ezotiinibo as 1st line
(BAS as alternative)
+
Figure 3a. Treatment approach for primary prevention patients (without a statin indicated conditiont)
Adapted from 2021Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in
the Adult. Canadian Cardiovascular Society.
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E6 Endocrinology Toronto Notes 2023
Statin Indicated Conditions I
LDL>
_5.0mmol/L
•orApoB >1.4Sg/Loi
non-HDLC i5.8 mmol/L
•Familial hypoicholostorolomio or
gonotic dyslipidomio
Most potients withdiabotos:
•Ago £t0
•Ago >30 & 0Mx>_15 yrdurotion
•Microvasculor disoasu
Most patients withdiabotos:
•Ago >50 and oGFR <60ml/miiVt 73nf
or ACR >3mg/mmol
Atherosclerotic Cardiovascular
Disoaso:
•Myocardial infarction,ocuto coronary
syndromos
•Stable angina,documented coronary
artery disoaso by ongiography
•Stroke,TIA,document carotid disoaso
•Peripheral arterial disease,claudication
and/or ABI <0.9
•Abdominal aortic aneurysm
abdominal aorta >3.0 cm or previous
aneurysm surgery
Rcvicw/Discuss health behavioural modifications
I
Initiate StatinTreatment
ft If LDL- C £.5 mmol/L
(or <50% reduction)
orApoB 20.85 g/Lor
non HDL C 23 2 mmol/L
If LOL C .
^
2 0 mmol/L or
ApoB >0.80 g/Lor
non HDL C
^
2.6mmol/Lon
maximally tolerated statin dose
If LDLC>J.8 mmol/Lor
ApoB 21.70 g/Lor
DLC>2.4 mmol/Lon
NO NO
non H
maximally tolerated statin dose
J YES YES YES
Discuss add-on therapy with patient
Evaluoto reduction in CVD risk vs. cost/access and sido offocts
Discuss intensification of
therapy with patient
ADD ON ADD ON INTENSIFICATION
E/otimibo or Refer toFigure
PCSK9 inhibitor
Ezotimibcas 1st lino
IBAS as alternative add onto
othor diugs)
Treatment Intensification App
foi Potients with ASCVO
roach i
u.
un •
t
Monitor
•Rosponso to statinRx•Response to add on liprd lowering Rx *
Health behaviour modifications
Figure 3b. Treatment approach for patients with a statin indicated condition
Adopted horn 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipldemia lor the Prevention of Cardiovascular Disease in
the Adult. Canadian Cardiovascular Society.
I
Patients with Atherosclerotic Cardiovascular Disease
If LDLC >1.8mmol/Lor
ApoB.2).70 g/Lor
ifnon HDL C >2.4mmol/L
If TG >1.5 to5.6 mmol/L
A
LDL C 1.8 2.2 mmol/Lor
ApoB 0.70 0.80 g/Lor
non HDL C 2.4 2.9mmol/L
LDLC >2.2 mmol/Lor
ApoB>0.80 g/L or
non HDL C >2.9 mmol/Lor
high PCSK9i benefit patient
Consider
Icosapent ethyl 2000 mg BID
Consider
EzotimiboiPCSK9 inhibitor
Consider
PCSK9inhibitor ezotnmbo
Figure 3c. Treatment intensification approach for patients with atherosclerotic cardiovascular disease
(ASCVD)
Adapted horn 2021 Canadian Cardiovascular Society Guidelines lor the Management of Dyslipldemia lor the Prevention olCardiovascular Olscose In
the Adult. Canadian Cardiovascular Society.
r i
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E7 Endocrinology Toronto Notes 2023
Disorders of Glucose Metabolism
Overview of Glucose Regulation
•s \
Reduction of Cardiovascular Events with
Icosapent Ethyl Intervention Trill- REDUCE IT
HLIU 2019;580:11-22
Study Mjtticenter. nnUonned, double-blind,
bacebo co-tio led trial with S yr ot follow-up.
Population:81)9 patients with established CUD or
with diabetes and other risk lactors,who hadbeen
relentingstatin therapy arid who had a fastingID
revet of 135-459 ragfdLard a LDL level of 41-100
mgidL
Intervention:Randomly assigned to receive 2 gof
icosapent ethyl BID or placebo.
Primary Outcome:Composite ol cardiovascular
death,nonlatal HI.nonlatal stroke,coronary
revascolariiation or unstable angina.
Desalts 4 pnmatyendpoint event occurred in t)
.2%
ot the patientsinthe icosapent ethyl groupiompared
to 22\of the patients In the placebo group (HR-0.7S.
95%Ct 0.68-0.83,P
‘
0.001). The rates of additional
ischemic eod points weresignificantly lower in the
icosapentethyl groupthan in the placehogroup.
induingthe rate of cardiovascular death.A larger
percentage of patientsin the icosapent ethyl group
thaninthe placebn group ware hospitaliied for atrial
fibrii’ation or flutter (P*0.004|and serious bleeding
occurledin 2.1% of the patients in the icosapent
ethylgroup as compared to 2.1% in the placebo group
(P-0.06)
Conclusions Among patients with elevated16 levels
despite statin therapy, the risk of cardiovascular
events wassigrufrcanlly lower in the group who
received 2 gof icosapent ethyl BIO compared to those
whoreceived placebo.
See trralfor more details,outlining specdie emboints
and results.
gills of the pancreas
stimulated to roloaso
insulininto the blood S Insulin stream (A
• -
Body colls take
up more glucose /
• Liver takesup
excess glucose and
stones itas
glycogen
Increase inblood
glucose levels
Blood Glucose Level Decrease inblood
glucoso levels
Liver breaks down
glycogen stores and
rclcascsglucosc
into the blood
Glucagon
stimulated torelease
a culls glucagoninto the blood
Figure 4. Blood glucose regulation
Pre-Diabetes (Impaired Glucose Tolerance/Impaired Fasting
Glucose)
• 1-5% per yr go on to develop DM
• 50-80% revert to normal glucose tolerance
• weight loss may improve glucose tolerance (5-10% of body weight)
• increased risk of developing niacrovascular complications
• lifestyle modifications decrease progression to DM by 58%
Diagnostic Criteria (Diabetes Canada 2018 Guidelines) (any of the following)
• ll-G: I PG 6.1-6.9 mmol/L
•1GT:2 h 75 g OGTT 7.8-11.0 mmol/L
• Ale:6.0-6.4%
Diabetes Mellitus
Definition
• DM is a heterogeneous metabolic disorder characterized by the presence of hyperglycemia
• chronic hyperglycemia of diabetes is associated with relatively specific long-term microvascular
complications affecting the eyes, kidneys, and nerves, as well as an increased risk for macrovascular
complications such as CVD,stroke, and peripheral vascular disease. Diabetes also increases the risk of
heart failure
See Landmark Endocrinology Trials
foe more information on the 4T trial.It
details the efficacy of complex insulin
regimen for patients with T2DM.
Diagnostic Criteria (as per Diabetes Canada 2018 Clinical Practice Guidelines)
• any one of the following is diagnostic:
See Landmark Endocrinology Trials for
more information on the UKPDS trial.
It compares the safety and efficacy of
intensive blood-glucose control with
sulphonylurea or insulin vs. conventional
treatment on the risk of complications
in T20M.
Table 4. Diagnosis of Diabetes
FPGs7.0 mmoDl
Fasting - no caloric intake lor at least 8 h
or
A1c »6.5% (inadults)
Hot lor diagnosis ol suspected MOM.children,adolescents, or pregnant women 1
or L J
2hPG in a 75 g OGTT >11.1mmol/L
See Landmark Endocrinology Trials for
more information on the DCCT trial.
It details the use of intensive insulin
injection therapy for the treatment of
T1DM in patients with no cardiovascular
history or severe diabetic complications.
or
Random PG»11.1mmol/L
Random - any lime of the day.without regard to the interval since last meal
+
• in the presence of hyperglycemia symptoms (polyuria, polydipsia, polyphagia, weight loss, blurry
vision ), a confirmatory test is not required
• in the absence of hyperglycemia symptoms, a repeat confirmatory test (IPti, A Ic, 2hP(i in a 75 g
OGTT) on another day is required for diagnosis of diabetes
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E8Endocrinology Toronto Notes 2023
Etiology and Pathophysiology
Table 5. Etiologic Classification of Diabetes Mellitus
Diabetes Canada 2018 Clinical
I.T1DM immune-med ated or idiopathic Practice Guidelines ^
cell destruction,usually leading to absolute insulin deficiency (includes latent autoimmune diabetes in
adults (LADA))
II.T2DM occurs when the pancreas does notproduce enoughinsulin or when thebody does not effectively use the insulin that is produced
III.Other Specific Causes of DM
a. Genetic defects of 8 cell function (e.g.Maturity-Onset Oiabetes of the Young(MOOY;also knownas monogenic diabetes)) or insulin action
b. Diseases of the exocrine pancreas:
Pancreatitis,pancreatectomy,neoplasia,cystic fibrosis,hemochromatosis Tbronrediabetes")
c. Endocrinopathies:
Acromegaly.Cushing's syndrome,glucagonoma.pheochromocytoma.hyperthyroidism
d. Drug-induced:
Glucocorticoids,thyroidhormone.8-adrenerg.c agonists,thiazides,phenytoin.antipsychotics
e. Infections:
Congenitalrubella.CMV.coxsackie
f. Genetic syndromes associated with DM:
Down's syndrome.Klinefelter's syndrome,turner'
s syndrome
IV.Gestational Diabetes Mellitus|seeObstetrics.0B29)
target
<1.0% (most adults)
4-7 mmolI
A1c
Fasting plasma
glucose
2h post-prandial
glucose
5-10 mmol/L
5-8mmoLl if not
meeting target A1c
and can be safely
achieved
Lipids
Blood pressure
LDL <2.0 or 50%
<130/80
Table 6. Comparison of Type 1 and Type 2 Diabetes Mellitus
Type 1 Type 2
Usually <30 yrolage Usually >40 yr of age
Increasing incidence inpaediatric population 2" to obesity
More common in Black. Hispanic.Indigenous,and Asian populations
Accounts for >90% of all DM
Onset
Epidemiology traditionally more common inEuropean populations
less common m Asian.Hispanic.Indigenous,andBlack populabons
Accounts for 5-10% of all DM
Autoimmune or idiopathic
Monozygotic twin concordance ts 30-40%
Associated with HLA class IIDR3 and DR4.with either allelepresent inup to 95% of T1DM
Certain DO alleles also confer a risk
Etiology
Genetics
Complex and multifactorial
Greater herilability than T1DM
Monozygotic twin concordance is 70-90%
Polygenic
Kon-HLA associated
Impairment of insulin secretion,excess glucose production by the liver,insulin resistance
in fat and muscle,impaired renal handling of glucose|SGLT2i).impaired incretin activity
(decreased insulin production, excess glucagon production,enhanced carbohydrate
absorption in the gut and increased appetite from the hypothalamus)
Pathophysiology Synergistic effects of genetic,immune,and environmental factors that cause 3cell
destruction resulting in impaired insulin secretion
Autoimmune process is believed to be triggered by environmental factors (e.g.viruses,
bovine milk protein,urea compounds)
Pancreatic cells are infiltrated with lymphocytes resulting m islet cell destruction
80% of 8 cell mass is destroyed before features of DM present
Natural History
glucose insulin resistance glucose
^
(3 cell function
. *
N
'
'vt
/AiAA-'
'
'
.
v insulin
insulin
I
0 cell defect I I
honeymoon period (3 cell failure
time
(S coll
decompensation
After initial presentation,honeymoon periodoften occurs where gtycemic control can
be achieved withlittle or noinsulin treatment as residual cellsare still able to produce
insulin
Once thesecells are destroyed,thereiscompleteinsulin deficiency
Early on.glucose tolerance remains normal despite insulin resistanceas 8 cells
compensate with increased insulin production
As insulin resistance and compensatory hyperinsulinemia continue, the 8 cells are unable
to maintain the hyperinsulinemic state whichresults in glucose intolerance and DM
Circulating Islet cell Ab present in up to 60-85%
Autoantibodies Most common islet cell Ab is against glutamic acid decarboxylase|GA0)
Up to 60% have Ab against insulin
Risk Factors Personal history of other auto rrune diseases includingGraves'disease,myasthenia
gravis,autoimmune thyroid disease,celiac disease,and perniciousanemia
Family history of auto mmune diseases
<10%
Age >40 yr
Schizophrenia
Abdominal obesity/overweight
Fatty liver
First-degree relative with DM
Hyperuricemia
Race/ethnicity (Black.Indigenous.Hispanic,Asian-American.Pacific Islander)
HxoflGTorlFG
HIM
Dyslipidemia
Medications e.g.2nd generation antipsychotics
PC0S
Hx of gestational DM or macrosomic baby (>9 lb or >4 kg)
Typically overweight with increased central obesity
lifestyle modification
Non-insulin antihyperglycemic agents •unless contraindicated,metformin shouldbe the
initial antihyperglycemic agent of choice.Additional agents to be selected on the basis of
clinically relevant issues, such as CV risk,eGFR.glucose-lowering effectiveness,risk of
hypoglycemia,and effect on body weight
Insulin therapy
Body Habitus
Treatment
Normal to thin
Insulin
Acute HHS
Complications
Screening
DKA
DKA +
Subdimcal prodrome can be detected nfirst and second-degree relabves of those with
T1DM by the presence of pancreatic islet autoantibodies
Screen individuals with risk factors
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E9 Endocrinology Toronto Notes 2023
Treatment of Diabetes
Who
$
should receive statins (regardless
of LDL-C level)
. Clinical CVD
. Age >40 yr
. Microvascular complications or
• Diabetes >15 yr duration and age
>30 yr
. Warrants therapy based on the 2016
Canadian Cardiovascular Society
Guidelines for the Diagnosis and
Treatment of Dyslipidemia
Glycemic Targets
Ale reflects glycemic control over 3 mo and is a measure of long-term glycemic control
Ale is recommended to be measured once every 3-6 mo and personalized Ale targetsshould be set for
patients based on their frailty'or functional dependence and life expectancy
therapy for most individuals living with T1DM orT2DM (especially younger patients) should be
targeted to achieve an A lc 57.0% in order to reduce the risk of microvascular and, if implemented
early in the course of disease, macrovascular complications
more intensive glucose control, Ale <6.5%, maybe targeted to further reduce risk of nephropathy and
retinopathy, provided this does not result in a significant increase in hypoglycemia
lessstringent Ale targets (7.1-8.5%) may be more appropriate in patients with limited life expectancy,
higher level of functional dependency, a history of recurrent severe hypoglycemia, multiple
comorbidities, extensive CAD,or a failure to achieve an Ale <70% despite intensified basal and bolus
insulin therapy
there may be harm associated with strategy to target Ale <6.0% (see ACCORD Trial,E63)
Ale can be slightly increased in iron deficiency, vitamin B12 deficiency, alcoholism,CKD, independent
of glycemic status
Ale can be slightly decreased in chronic liver disease, reticulocytosis, ingestion of ASA, vitamin C or
E, and splenomegaly, independent of glycemic status
timing and frequency of self-monitored blood glucose is determined by the type of diabetes,
treatment,and the individual’
s capacity to use the information
flash glucose monitoring and continuous glucose monitoring devices may be suggested for some
people living with diabetes to optimize their diabetesseif-management
Who should receive ACEI/ARB
(regardless of baseline BP)
. Clinical CVD
• Age >55 years with an additional
CV risk factor or end organ damage
(albuminuria,retinopathy,left
ventricular hypertrophy)
• Microvascular complications
:•
ABCDES
*
of Diabetes Care
Ale targets (<7.0%)
Blood pressure (<130/80)
Cholesterol (LDL-C <2.0mmolfl)
Drugs for CVD risk reduction
Exercise goals and healthy eating
Smoking cessation
Screening for complications
Stress management
Diet
nutritional therapy can reduce Ale by 1-2%
it is recommended to intake 45-60% carbohydrates, 15-20% protein, and <35% fats as a percentage of
total daily energy
it is recommended to intake <7% ofsaturated fats and <10% of polyunsaturated fats as a percentage of
total daily calories
it is recommended to replace high-glycemic-index carbohydrates with low-glycemic-index
carbohydrates and increase fibre intake
limitsodium,alcohol, and caffeine intake
people with diabetesshould adopt dietary patternsthat result in the greatest adherence based on their
values and preferences
type 1: carbohydrate counting is used to titrate prandial insulin dose
type 2: weight reduction to help control blood glucose levels
Cloud-Loop Insulin Delivery for Elyceinic Control
inMoncriticalCare
HEJM 2018:379:547-556
Purpose:lo determine if a closed-loop delivery
system (artificial pancreas) can impioit glycemic
controlinpatients with T2DM rtcening noncribcal
care.
Methods:Patients|n=136)retentd either cloudloopinsulin delivery or cnnventionalsubcutaneous
insulin therapy.The percentage of timethe sensor
glucose measurement waswithinS.6to10.0mmol/L
was measured.
Results:Closed-loop Insulin detnrety was more
effective at mainlainlngglucou within tlu target
range (95% Cl:18.6-30.0:P<0.D01|.Patients on
closed-loop insulin therapy hadlower mean glucose
levels|P<0.001|.There wasno difference in duration
of hypoglycemia or amount of insolindelivered
between groups.
Conclusions:The use of an automated,closed-loop
msuim-deiivery system (artificial pantreasl resulted
in signitcantly better glycemic controlamong
inpatientswithT2DM receiving oooaitical care.
Lifestyle
losing 5-10% of the initial body weight can improve insulin sensitivity, glycemic control, hypertension,
and dyslipidemia in people with T2DM
regular physical exercise can improve insulin sensitivity, lower lipid concentrations, and control blood
pressure. At least 150 min per wk of moderate-vigorous aerobic exercise and at least 2 sessions per wk
of resistance exercise are recommended
smoking cessation,referral to diabetes education clinic, psychosocialsupport
Medical Treatment: Non-Insulin Antihyperglycemic Agents (T2DM)
initiate non-insulin antihyperglycemic therapy (generally metformin first line) within 3 mo if lifestyle
management does not result in adequate glycemic control
if the initial Ale value is more than 1.5% higher than the patient’
s personalized Ale target, initiate
pharmacologic therapy with metformin immediately, and consider insulin or a combination of
therapies
if presenting in metabolic decompensation, begin with insulin therapy immediately
adjust dose or add additional pharmacologic therapy in a timely fashion to achieve target Ale within
3-6 mo of diagnosis
see Common Medications, E57 for details on antihyperglycemic agents
Clotrt-laopinsulin delivery usingMartificial
pancreas bus also shown promise m patientswith
BDM (MEJM 2019:381:1797-17).
Medical Treatment:Insulin
used for TT DM at onset, may be used in T2DM at any point in treatment
routes of administration:subcutaneous injections, continuous subcutaneous insulin infusion pump,
IV infusion (regular insulin only)
basal insulin:to control blood sugar (produced by liver) during periods of fasting;slow onset of action,
long-acting
bolus insulin: required to dispose of glucose from a meal or BG correction; rapid onset of action,
short
-acting
estimated total daily insulin requirement:often start with 0.3-0.5 units/kg/d (see Table 7, Ell )
See landmark Endocrinology Trials for
more information on the ACCORD trial.
It details the effects of intensive glucose
control in patients with T2DM and
cardiovascular risk factors.
n
L J
for
See
mmore
landmark
information
Endocrinology
on the ACCORD
Trials +
Trial-Blood Pressure Control.It details
the effects of intensive blood pressure
control for patients with T2DM.
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E10 Endocrinology Toronto Notes 2023
Kidneys
Increased Glucose
I Resorption rt
Pancreas Muscle
DecreasedGlucose
. Uptake
DecieasedInsulin
Secretion
1 r l Islet acoll Brain
r
•
Hyperglycemia —
Increased Glucagon
Secretion
Neurotransmitter
Dystunction
i \
Intestines
r
tu
1 Adipose tissue '
”,
£
Increased Hepatic Decreased M
Glucose Production IncretinEffect
Increased Lipofysis s
Figure 5. Ominous octet: factors leading to hyperglycemia
Kidneys
Pancreas Muscle
t urinary / SGLT2 inhibitors +
DPP- 4
inhibitors glucose
GLP secretion -1 analoguos
Insulin t/Biguanidu
secretagogue
Circulatory system
T- Glucose
T- FFA letease
Intestinal lipase
Biguanide W inhibitor
FFA release
Corbohydratos ,
t
TZD s
Intestines
Adipose tissue
Figure 6. Antihyperglycemic agents
r T
+
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Ell Endocrinology Toronto Notes 2023
Healthy eating, weight control, increased activity
INITIALDRUG Metformin
MONOTHERAPY
Elticacyl
-tHbAlc) High
Hypoglycemia LowRisk
Weight Neulral/Loss
Side elfectls) 61/Lactic Acidosis
Costs Low
See Landmark Endocrinology Trials for
more information on the ACCORD TrialCombination Lipid Therapy.It details the
effects of combinational lipid therapy for
patients with T2DM.
Alter
-3months:it needed to reach individualized HbAIc target,proceed totwo-drug combination
Iorder not meant to denote any speciiic preference!
TWO-DRUG A Metformin Metformin
COMBINATIONS
Metfoimm Metformin Metformin See Landmark Endocrinology Trials for
more information on thePREDIMED trial.
It details the effects of a Mediterranean
diet on reducing major cardiovascular
events in patients with T2DM or other
high cardiovascular risk factors.
+ + + +
Sulfonylurea GLP-IReceptor
Agonist
Insulin (usually
basal)
Thiazolidinedione DPP-4 Inhibitor
Efficacy (J.HbAlc)
Hypoglycemia
Weight
Major side ef fect(s)
Costs
High Intermediate
Low risk
Neutral
Edema,HE,Fx's Rare
High High Highest
Moderate risk Low risk Low risk Low risk
Gain Gain Loss Gain
Hypoglycemia Gl Hypoglycemia
Low High High High Variable
Alter -3months: ilneeded to reach individualized HbAlc target, proceed to three-drug combination
Iorder not meant to denote any speciiic preference)
Metformin
Sick Day Management
If patient is ill and is unable to maintain
adequate fluid intak e, or has an acute
decline in renal function,they should
hold the following medications:
THREE-DRUG Metformin Metformin Metformin Metformin
COMBINATIONS
’ '
+ + + +
Sulfonylurea
+ one of:
Thiazolidinedione DPP-4 Inhibitor
+ one of:
GLP-IReceptor
Agonist
+ one of:
Insulin (usually
basall
+ one of:
+ one of:
SAD MANS
Sulfonylureas
ACEIs
Diuretics and direct renin inhibitors
Metformin
ARBs
NSAIDs
SGLT2!
TZD TZD TZD TZD TZD
DPP-4-i
GLP-l-RA
Insulin :
DPP-4-i
GLP-l-RA
Insulin
DPP-4-i
GLP-l-RA
Insulin
DPP-4-i
GLP-l-RA
Insulin :
DPP-4-i
GLP-l-RA
Insulin :
£
S3
Alter -3-6months: il combination therapy that includes basal insulin tails to achieve HbAIc 5
y j
Proceed to complex insulinstrategy,usually in combination with one or twononinsulinagents:
Insulin (multiple daily doses)
C
I
More complex
insulin strategies
:;. i
Figure 7. Management of hyperglycemia in T2DM
Adapted fiom Canadian Journal of Diabetes.Volume42,Lipscombe L.Booth Gillian.Butalia S. et al.Pharmacologic Gtycemic Management of Type 2
Diabetes in Adults. Page S92.Copyright (2020).with permission from Elsevier
Table 7. Available Insulin Formulations Conversion Chart
for Porcontago HbAlc
to Avorago Blood Sugar Control
Average blood
sugar level
(mmol/LI
Insulin Type (trade name) Onset Peak Duration
PRANDIAL (BOLUS) INSULINS
Rapid-acting insulin analogues
Insulin aspatl(NovoRapld -)
Insulin faster aspait (Hasp )
Insulin lispro (Humalog '
.Humalog 200 units/mL)
Insulin glulisine (Apidra - )
Short-acting Insulins
Kumulin R;
Hovolin Toronto*
Hemoglobin Ate
(% HbAlc)
10-15 min 3- 5 h
4min
10-15 min
10-15 min
1-1.5 h
1h 3- 4h
1-2 h 3.5- 4.75 h 17 — 12% I
16 —Inadequatel_
n%
Control
1-1.5 h 3-5 h
30 min 2-3 h 6.5 h
j— 10%
L- 9%
'
0 —Suboptumil '
I4 -,
12 —
BASAL INSULINS
Intermediate-acting
Humulin N1
Hovolin NPH •
long-acting basal insulin analogues
Insulin detemir (Leveniir
*
)
Insulin glargine100 units/ml (Lantus '
/Basaglar - )
Insulin glargine 300 unitsr'mL (Toujeo -)
Insulin glargine (Basaglar r
j
Insulin degludec (Tresiba *
)
1
8 7% - 3 h 5-8 h Up to 18 h
6
_ Optimal _ 6%
COUVMMMIdulladupli
-d liom Nalhun DM.«1<1.Ike
dmedrVoimeonvalue ol aglycosylated hvmogloOie
90 min euy.NUM 1984:310:341-346
90 min
Up to 6 h
90 min
60 min
Up to 24 h (detemir 16-24 h)
Up to 24h(glargine 24 h)
Up to 30h
Up to 24h(glargine 24 h)
Ultralong acting (42 h)
Hot applicable
The 81’
sPrecipitating DKA
Infection
Ischemia or Infarction
Iatrogenic (glucocorticoids)
Intoxication
Insulin missed
Initial presentation
Intra-abdominal process (e.g.
pancreatitis,cholecystitis)
Intraoperative/perioperative stress
PRE-MIXED INSULINS
Premixed regular insulin- NPH
Humulin 30/70 '
Hovolin30/70'
Premixed insulin analogues
Biphasic insulinaspart (NovoMix 30'
I
Insulin lispro/lispro protamine
(Humulin 30/70.Nowlin 30/70. Novomix 30 and Humalog
Mix 25)
A single vial or cartridge contains a fixed ratio olinsulin
(% olrapid-acting or short-acting insulin to % olintermediate- acting insulin)
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El2 Endocrinology Toronto Notes 2023
.Lispro/Aspart/Glulisinc
Activity
Rcgular/Toranto NPH
GlargineyOetemir
\ 1 1
Breakfast Lunch Dinner Bed
Figure 8.Duration of activity of different insulins
Table 8. Insulin Regimens for T2DM and T1DM
Regimen Administration
Basal-bolus (multiple daily injections (MDI|) Estimated total insulinrequirement is 0.5-0.7 U/kg
40% is given as basal insulin atbedtime
20% is given as bolus insulin before breakfast,lunch, and dinner
Estimated total insulinrequirement is 0.5-0.7 U/kg
2/3 dose is given as pre-ruiedinsulin before breakfast
1/3 dose is given as pre-maed insulin before dinner
Titrate up by1unit until EPG <7.0 mmol/L
T1DM
Premiied
T2DM Non* insulin antihyperglycemic agent*
basal insulin
'Bolus insulin:Aspart.Gfulisine.lispro:'Basal insulin:Glargire.Detemir.NPH:'Pre-rrued insulin:Humdin 30/70.Novolin 30/70.Novomix 30.and
HumalogMu2
Table 9. Titrating Insulin Doses
Hyperglycemic Reading Insulin Correction
High AM sugar
High lunchsugar
High suppersugar
High bedtime sugar
Increase bedtime basal insulin
Increase AM rapid/regular insulin
Increase lunch rapid/regular insulin or increase AM basal insulin
Increase supper rapid/regular insulin
Insulin Dose Schedules
Table 10.Insulin Titration and Titration Suggestions for T2DM (as per Diabetes Canada 2018 Clinical Practice Guidelines)
BasalInsulin Only -Add-on to Anti-hyperglycemic Agents
See above summary for Ale.BE targets
Most patients wdl need 40-50 units/d to achieve target but there is no maximum dose
Start at a lour dose of 10 U at bedtime (lower for lean patients <50 kg)
Titrate dose accord -gky until fasting BG target is achieved (see CDA guidelines for appropriate titration)
If fasting hypoglycemia,dose of bedtime basal should be reduced
If daytime hypoglycemia,reduce dose of oral antihyperglycemic agents (especially secrelagogues)
Dosing and Titration Examp/e
Starling dose — 10 U at bedtime
Increase dose by1U every1night until fasting BG has reached
target of 4-7 mmolTl
Basal-Bolus Insulins
When addition of basal insulin toanti-hyperglycemic agents is insufficient to reach target BG.bolus (prandial) insulin should be
added before meals
Option exrsts lo only add bolus insulin tothe meal with the highest postprandial BG as a startingpoint
Insulin secretogogues typically stopped when bolus (prandial)insulin added:metformin is continued
Maintain thebasal dose and add bolus insulin with each meal at a dose equivalent to10% of basal dose
Total Daily Insulin (TOI)
- 0.3-0.5 U/kg:40% TDI
- basal.20% TDI prandial(bolus) prior lo each meal
Adyust basal insulin to achieve target fasting BG. bolus insulin to achieve postprandial BG levels (5-10 mmol/L).or preprandial BG
levels for subsequent meal (4-7mmol/L)
Dosing and Titration Examp'
e
TDI
- 0.5 U/kg:0.5 x 100 kg - 50U
Basal insulin - 40% of TDI
40% x 50 U - 20 U:basal bedtime - 20 U
Bolus insulin -60% of TDI
60% x 50 U - 30 U:10 U dosed with each meal
Premiied InsulinBefore Breakfast and Before Dinner
Target fasting and pre-dinner BG levels of 4-7 mmol/L
Most patients with T20M need40-50 U BID to achieve target,but no maximum dose
Start atalow dose of 5-10 U BID (beforebreakfast and before dinner)
Patients can self bbate by increasing insulin dose by1U/d unlit pre -dinner (breakfast dose) or fasting BG (dinner dose) at target
Continuemetforminand consider slopping secretagogne
Dosing and Titration Example
10 U before breakfast.10 U before dinner
Increase breakfast doseby1U/d until pre-dinner BG has reached
target
Increase dinner dose by1U/d unbi fasting 3G has reached target
• Correction f actor (Cl ) = 100/Tota) Daily Dose of insulin (TDD)
= change in blood glucose per unit
insulin
• BG <4 mmol/L:call physician and give 15 gof rapid-acting carbohydrates and recheck in 15 min
• BG between 4 to 8: no additional insulin
• BG between 8 to (8 + CF):give one additional unit
• BG between (8 + CT) to (8 + 2CF):give two additional units
BG between (8 + 2CF) to (8 + 3CF): give three additional units
Insulin Pump Therapy:Continuous Subcutaneous Insulin Infusion (CSII)
• external battery-operated device provides continuous basal dose of rapid-acting insulin analogue
(aspart,glulisine,orlispro) through small subcutaneous catheter
• at meals, patient programs pump to deliver insulin bolus based on carbohydrate:insulin ratios
• presides improved quality of life and flexibility
• risk of DKA if pump is inadvertently disconnected or pump malfunctions
• cos’erage for insulin pumps for individuals with T1D.\l varies by province
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E13 Endocrinology Toronto Notes 2023
Acute Complications
Table 11. Acute Complications of Diabetes Mellitus:Hyperglycemic Comatose States
Diabetic Ketoacidosis (DKA) Hyperosmolar Hyperglycemic State (HHS)
Occurs in T 2DM
Often precipitated by sepsis,stroke. Ml. CHF.renal failure, trauma,drugs
(glucocorticoids,immunosuppressants,phenyloin. diuretics),dialysis,tecenl
surgery,burns
Partial or relativeinsulin deficiency decreases glucose utilization in muscle,fat. and
liver whileinducing hyperglucagonemia and hepatic glucose production
Presence of a small amount of insulin prevents the development of ketosis by
inhibiting lipolysis
Characterized by hyperglycemia,hyperosmolality.and dehydration without ketosis
More severe dehydration compared to OKA due to mote gradual onset and
duration of metabolic decompensation plus impaired fluid intake whichis common
in bedridden or elderly
Volume contraction -*
renal insufficiency*
t hyperglycemia. » osmolality -*
shift of
fluid from neurons toECF ->mental obtundation and coma
• Onset is insidious -*
preceded by weakness,polyuria,polydipsia
History of decreased fluid intake
History ol ingesting large amounts olglucose containing fluids
Dehydration (orthostatic changes)
*
IOC » lethargy,confusion,comatose due to high serum osmolality
Kussmaul's respiration is absent unless theunderlying precipitant has also caused
a metabolic acidosis
t BG (typically 44.4-133.2 mmol/l)
In mild dehydration,may have hyponatremia(spurious 2"
to hyperglycemia •
*
for
every « in BG by 10 mmol/lthere is a a in Ha*
by 3 mmol/l)
-if dehydration progresses, may get hypernatremia
Ketosis usually absent or mild if starvation occurs
« osmolality
Pathophysiology • Usually occurs in T10M
• Insulin deficiency with » counlerregulatory hormones (glucagon,cortisol,
catecholamines.OH)
• Can occur withlack of insulin (non-adherence,inadequate dosage,1st
presentation) or increased stress (surgery,infection,exercise)
• Unopposed hepatic glucoseproduction
*
hyperglycemia -•osmotic diuresis -»
dehydration and electrolyte disturbance
* *
Na+ (water shift to ECF causing
pseudohyponatremia)
• Fat mobilization »» FFA »ketoaods
*
metabolic acidosis
• Severe hyperglycemia exceeds Iherenal threshold lor glucose and ketone
reabsorption •
*
glucosuria and ketonuria
• Total body K*
depletion but serum K* may be normal or elevated,2"
to shift from
ICF to ECF due to lack of insulin,t plasma osmolality
ClinicalFeatures • Hyperglycemia (polyuria,polydipsia,weakness)
• Acidosis (air hunger,nausea, vomiting,abdominal pain. Kussmaul's respiration,
acetone- odoured breath)
• Precipitating conditions (insulin omission,new diagnosis of diabetes,infection.
Ml.thyrotoxicosis,drugs)
Serum • » BG (typically 14 55 mmol/l,
*
Na -(2’
lo hyperglycemia -*
foi every *
in BG by
10 mmol/lthere is a « in Na* by 3 mmol/l)
• Normal or t K •, a HCOJ-,
*
BUN. t Cr,ketonemia,» P0«J-
• t osmolality
• corrected sodium * currentsodium *
(0.3 x (current glucose -5)]
• Be aware of possible euglycemic DKA (with near normal sugars) in pregnancy and
with those who use SGIT2 inhibitors
• Anion gap metabolic acidosis with possible 2“
respiratory alkalosis
• If severe vomiting/dehydration there may also be a metabolic alkalosis
• +ve lor glucose and ketones
ABG Metabolic acidosis absent unless underlying piccipitant leads to acidosis (c.g. lactic
acidosis in Ml)
•ve for ketones unless there is starvation ketosis
Glycosuria
Urine
• ABCs are First priority
• Monitor degree of ketoacidosis with AG.not BG or serum ketone level
• NOIE: AG is the most important endpoint used to monitor the resolution ol the
metabolic acidosis
• Dehydration
- 500 ml/h x4 h,then 250 mL/h x4 h NS if mild- moderate deficit,1-2l/h HS il
severe deficit(shock)
- Switch to 0.45% NaCI once euvolemic (continue NS if corrected (Na *)is low or . K replacement
rate of fall of plasma osmolality >3 mosm/kg/h)
- Once BG reaches14.0 mmol/ladd D5W or D10W to maintain BG of 12-14 mmol/l
• Insulin therapy
- Critical to resolve acidosis,not hyperglycemia
- Do not use with hypokalemia (see below), until serum K'
is corrected to >3.3
mmol/
Same resuscitation and emergency measures as DKA
Dehydration
-IV fluids:IlfhHSinitially
- Evaluate corrected scrurn Na'
-If corrected serum Na'high or normal,switch to 0.45% HaCI (4 14 ml/kg/h)
-If corrected serum Na'
low,maintain HS (4-14 ml/kg/h)
- When serum BG reaches13.9mmol/L (250 mg/dl|switch to D5W
Treatment
-less severe K'deplelion compared to OKA
-If serum Kv3.3 mmol/l, give 40 mEq/ lK 'replacement andhold insulin until|K'
|
:3.3mmol/l
- When K 3.3 5.0 mmol/L add KCL 10- 40 mEq/L to keep K 1n therange of 3.5-5
mEq/l
-If serum K>5.5 mmol/L,checkK "every 2 h
• Search for precipitatingevent
• Insulin therapy
- Achieved by monitoring plasma osmolality,adding glucose lo infusions once BG
reaches 14 mmol/ .using correct concentration of saline
-Switch lo 0.45% HaCI once euvolemic as unnar y loss of electrolytes in osmotic
diuresis are usually hypotonic
-Increase saline concentration if falling too rapidly
- Maintain on 0.1U/kg/h insulin R infusion
- Check serum glucose hourly
• K '
replacement
- With insulin administration,hypokalemia may develop
-If serum K'
*3.3 mmol/l,give 40 mEq/lK'replacement and hold insulin until
|IC ] »3.3mmol/L
-When K "3.3-5.0 mtnol/L add KC110- 40 mEq/L to keep K '
in the range of 3.5-5
mEq/ L
. HCOJ -
-If pH <7.0 or ilhypotension,arrhythmia,or coma is present give HCOJ'1
ampoule (50mmol) in 200ml D5W (or sterile water ilavailable) over 1h.
repeated q1-2 h until pH >7.0
- Oo not give if pH >7.1(risk olmetabolic alkalosis)
- Can give in case of life-threatening hyperkalemia
• <1-3.3% mortality in developed countries
• Serious morbidity from sepsis,hypokalemia,respiratory complications,
thromboembolic complications,and cerebral edema (the latter inchildren)
• Mortality rates between12-17%.but studies looking at this included mixed DKA/
HHS stale
Prognosis
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EM Endocrinology Toronto Notes 2023
Macrovascular Complications $
Laboratory Testing: Ketones
• The nitroprusside test for
ketones identifies acetone and
acetoacetate but does NOT detect
p hydroxybutyrate (BHB).the ketone
most frequently in excess in DKA.
This hastwo clinical consequences:
• Be wary of a patient with a clinical
picture of DKA but negative serum or
urinary ketones. These could be false
negatives because of the presence
of BHB
• As DKA istreated. BHB is converted
to acetone and acetoacetate. Serum
or urinary ketones may therefore
rise,falsely suggesting that the
patient is worsening when in fact
they are improving
• increased risk of CAD, ischemic stroke, and peripheral arterial disease secondary to accelerated
atherosclerosis
• CAD (see Cardiology and Cardiac Surgery.C30)
risk of Ml is 3-5x higher in those with DM compared to age-matched controls
CAD is the leading cause of death in T2DM
• most patients with DM are considered "
high-risk"
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