ueda 2016 5-pharmacological management of diabetes - lobna el toony
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Pharmacological Management of Diabetes
UEDA Diabetes Mini-Course
Aswan Feb. 2016
Approaches To The Treatment Of T2DM
Diabetes Care. 2013 Aug;36 Suppl 2:S127-38. doi: 10.2337/dcS13-2011. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. DeFronzo RA, Eldor R, Abdul-Ghani M.
AAge
BBody
Weight
CComplicat
ions
DDuration
of Diabetes
EExpectancy
(Life)
EExpenses
•Long-term challenges:
• Prevent microvascular complications
• Prevent macrovascular complications
• Prevent long-term deterioration of glucose homeostasis
• Quality of life
Management of Diabetes ‘Glycemic control is fundamental to the management of diabetes’
American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S61
“Metabolic Memory”
Accumulating evidence suggests that achieving a normal HbA1c early in the course of type 2 diabetes
provides the best chance of reducing the risk of developing or advancing complications
JCEM. 2011;96:2367-2376.
The ProblemFor many individuals, achieving an adequate HbA1c
requires early intervention with insulin-based therapies which are often delayed due to physician and/or patient
resistance …
Hb
A1
C(%
)UKPDS: Long-term follow-up
Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.
Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
Differences in mean glycated
hemoglobin levels between the
intensive therapy group and the
conventional-therapy group
were lost by 1 year, with similar
glycated hemoglobin
improvements thereafter in all
groups (p= not significant)
P=0.71
Glucose similar
BUT CV
events now
better
Metformin group 21%33%27%
The Burden of Type 2 Diabetes Treatment Failure “Clinical Inertia”
Mea
n H
bA
1c
at L
ast
Vis
it*
(%)
8.2 Years
ADA Goal
Diet and Exercise
Years Elapsed Since Initial Diagnosis
Initiation of
insulin therapy
SU or metformin
Combination oral agents8.6%
8.9%
9.6%
7
8
9
10
2.5 Years 2.9 Years 2.8 Years
Brown JB et al., Diabetes Care. 2004;27:1535-1540
Oral Antidiabetic Drugs
OAD
UEDA Diabetes Mini-Course
Aswan Feb. 2016
Sites of Action of Metformin
Dose Effect: Metformin
-19
- 31
- 41
- 78
- 62
-80
-60
-40
-20
0
500 mg 1000 mg 1500 mg 2000 mg 2500 mgC
han
ge in
FP
G (
mg
/dL
)
Metformin Dose
Garber et al., Am J Med, 1997
Insulin SecretagoguesGlipizide, Glyburide, Glimepiride, Repaglinide and
Nateglinide
Action
• Releases insulin from pancreas in response to a glucose challenge
• Repaglinide and Nateglinide have a short half-life
Clinical Indicators
• Insulin deficiency
• Leaner patients
• High postprandial BG 200-300 mg/dL
Side effects
• Weight gain
• Hypoglycemia
Precautions and contraindications
• Kidney disease: use with caution
• Liver disease
• Pregnancy
Sulfonylureas
(su)
Sites of Action of Sulphonlyureas
Glinides Vs SUs
Short Acting, meal related, no meal no tablet
Better control of prandial glucose but less effective on
fasting
More flexibility fitting free life style
SUs
Glinides
DDP-4 inhibitors
Interfere with the degradation of GLP-1 by blocking the action of the DPP-4 enzyme and therefore raise GLP-1 levels 2- to 3-fold.
Sitagliptin, vildagliptin, saxagliptin & linagliptin are administered orally and is generally well tolerated, they lower A1C 0.5 to 0.8%, and more effective in combination with metformin.
DPP-4 Inhibitors: Physiologic Action
Blood
Glucose
Pancreas
β cellsα cells
Active
GLP-1 & GIP
Release of
Incretin Gut
Hormones
Ingestion of
Food
GI Tract
Glucagon from
α cells
(GLP-1)
Glucose-dependent
Insulin from β cells
(GLP-1 and GIP)
Glucose-dependent
Inactive GLP-1
and GIP
DPP-4
EnzymeXDPP-4
Inhibitor
Glucose
uptake by
muscles
Glucose
production
by liver
The α-Glucosidase Inhibitors:Effect on Postprandial Glucose
Dimitriadis, et al. Metabolism. 1982;31:841-843.
Normal absorption of CHO
Without Acarbose
With Acarbose
Acarbose blocks proximal absorption
DuodenumJejunum Ileum
Time (min)
140
–30 0 60 120 180 240
120
100
80
*
*
MealPlacebo
Acarbose
* P <.05
Pla
sma
Glu
cose
(mg
/dL
)
α-Glucosidase Inhibitors
• Action
– Delays breakdown of
carbohydrates in the
small intestine
• Clinical Indicators
– Elevated postmeal
BG
• Side effects
– Nausea, vomiting,
diarrhea, and flatulence
• Precautions and
Contraindications
– Gastrointestinal disease
– Pregnancy (Category C)
SGLT2 Inhibition: A Novel Approach to Reduce Hyperglycaemia
SGLT2 inhibition decreases plasma glucose by increasing urinary glucose excretion Canagliflozin is a potent inhibitor of SGLT2
Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors
Provide insulin-independent glucose lowering by
blocking glucose reabsorption in the proximal
renal tubule by inhibiting SGLT2.
These agents provide modest weight loss and
blood pressure reduction.
They are not yet available in the Egyptian Market.
Traditional current oral therapies do not address all islet cell dysfunction
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitusAdapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
Pancreatic Islet Dysfunction
Inadequate glucagon
suppression(-cell
dysfunction)
Progressivedecline of β-cell
function
Insufficient Insulin secretion
(β-celldysfunction)
Sulfonylureas
Glinides
TZDsMetformin
Insulin Resistance(Impaired insulin action)
Traditional current oral therapies do not address all islet cell dysfunction
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitusAdapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
Pancreatic Islet Dysfunction
Inadequate glucagon
suppression(-cell
dysfunction)
Progressivedecline of β-cell function
Insufficient Insulin
secretion (β-cell
dysfunction)
Insulin Resistance(Impaired insulin action)
GLP-1DPP-4 inhibitors
GLP-1DPP-4 inhibitors
GLP-1DPP-4 inhibitors
Sulfonylureas
Glinides
TZDsMetformin
Treatment Algorithm
3rd Agent
2nd Agent
1st Agent Metformin
SU
TZD or DDP-4 or GLP-1 or
insulin
TZD
SU or DPP-4 or GLP-1 or
insulin
DPP-4 inhibitor
SU or TZD or insulin
GLP-1 agonist
SU or TZD or insulin
Insulin (usu. Basal)
TZD or DPP-4 or GLP-1
Healthy eating, weight control, increased physical activity & diabetes education
Metformin high low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
high low risk
gain
edema, HF, fxs
low
Thiazolidine- dione
intermediate low risk
neutral
rare
high
DPP-4 inhibitor
highest high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-dione
+ SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high low risk
loss
GI
high
GLP-1 receptor agonist
Sulfonylurea
high moderate risk
gain
hypoglycemia
low
SGLT2 inhibitor
intermediate low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor agonist
+
SGLT-2 Inhibitor +
SU
TZD
Insulin§
Metformin +
Metformin +
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono- therapy
Efficacy* Hypo risk
Weight
Side effects
Costs
Dual therapy†
Efficacy* Hypo risk
Weight
Side effects
Costs
Triple therapy
or
or
DPP-4 Inhibitor
+ SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin +
Combination injectable therapy‡
GLP-1-RA Mealtime Insulin
HbA1c≥9%
Me orminintoleranceorcontraindica on
Uncontrolledhyperglycemia
(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Insulin Therapy
UEDA Diabetes Mini-Course
Aswan Feb. 2016
Indications of insulin
Continuous Use* Type 1 Diabetes * Type 2 Diabetes with OHA failure
- Primary - Secondary
Intermittent Use* Type 2 diabetes during
- major surgery- pregnancy, labour and delivery- myocardial infarction- acute infections- Hypergycemic emergencies: DKA & HHS
* GDM
Life-saving in T1DMEssential in T2DM
Insulin
Which has no dose limit, is inexpensive, and improves the lipid profile, particularly triglycerides.
However, it requires injections, capillary glucose monitoring and may be associated with hypoglycaemia and weight gain.
Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 U or 0.1–0.2 U/kg, depending on the degree of hyperglycemia.
Basal insulin is usually prescribed in conjunction with metformin and possibly one additional noninsulin agent. If basal insulin has been titrated to an acceptable fasting blood glucose level, but A1C remains above target, consider advancing to multiple insulin injection therapy.
Insulin has the advantage of being effective where other agents
may not be and should be considered as part of any
combination regimen when hyperglycemia is severe, especially
if symptoms are present or any catabolic features (weight loss,
ketosis) are in evidence.
Consider initiating combination insulin injectable therapy when
blood glucose is ≥ 300–350 mg/Dl and/or A1C is ≥10–12%. As
the patient’s glucose toxicity resolves, the regimen can,
potentially, be subsequently simplified.
Insulin
Normal Insulin Secretion
Mealtime (bolus) insulin needs ~ 50%
Background (Basal) Insulin Needs ~ 50%
Kruszynska et al. Diabetologia 30: 16-21, 1987Polonsky et a. J. Clin. Invest. 81: 442-48, 1988
Time
The Role of Insulin Therapy
Relative InsulinDeficiency
Pre-diabetes and Type 2 Diabetes
InsulinResistance
Incretin DysfunctionInsulin
Deficiency
Type 1 Diabetes
Critical role in both Type 1 and Type 2 diabetes
Greatest potency of available therapies
Demonstrated benefit – multiple clinical trials
Insulin Therapy Nomenclature
Basal insulin – long-acting insulin that is used to provide a
background level of insulin throughout the day and night
Bolus insulin – short- or rapid-acting insulin that is used to
provide an increased level of insulin for a short period
Correction insulin - bolus insulin administered to lower a high
blood glucose level
Pre-mixed (or Biphasic) insulin- combination of short- or rapid-
acting and intermediate or long-acting insulin used to try to
cover both fasting and prandial insulin needs
Insulin Therapy Options
Basal insulin only
Bolus (Prandial) only
Premixed
Basal plus limited-meal bolus (‘Basal plus’)
Basal-Bolus (i.e. multiple daily injections - MDI)
Basal-Bolus (i.e. continuous subcutaneous
insulin infusion [CSII], “Insulin Pump”)
Action Profiles of Injectable Insulins in T2DM Patients
Barriers to Initiation of Insulin Therapy
Heath care providers
• Lack of consensus
• Limited local
resources
• Inconsistent training
• Self-monitoring
Patient challenges
• Hypoglycemia
• Weight gain
• Self-monitoring
• Complexity of TTT
• Injection technique
• Perceived ‘failure’
Barriers to Insulin Therapy in Type 2 DM
Patient, Physician, and Society
Challenges in the Management of Type 2 Diabetes: Insulin Therapy & Strategies
Why start
When to start
How to start
When is Insulin the Preferred Treatment ?
There are several conditions when insulin may be the
preferred choice including:
(1) current glucose levels are too far above target for
non-insulin therapies to be effective;
(2) non-insulin therapies alone and in combination have
failed to achieve target;
(3) the preference of the individual with diabetes and/or
clinician is to restore normal glucose profiles using
insulin to potentially benefit from metabolic memory;
(4) Attempt to “induce” clinical remission
Principles to Follow for Individuals Concomitantly Treated with Non-insulin Agents
1) Metformin, DPP-4 inhibitor, GLP-1 receptor agonist and/orα-glucosidase inhibitors are usually maintained at usualdose although they need careful monitoring;
2) Insulin secretagogue dose is often reduced or stopped dueto risk of hypoglycemia and/or excessive weight gain;
3) TZD dose is often reduced or stopped due to risk ofhypoglycemia, excessive weight gain, edema, and/or heartfailure.
Glargine and Detemir:• Lasts up to 24 hours; BID dosing may be required (less
common in T2DM vs. T1DM) • Decreases risk of hypoglycemia (especially nocturnal)• Less weight gain• Less variability in effect
Neutral Protamine Hagedorn (NPH):• Lasts 10–16 hours• Peaks 8–10 hours• Less expensive• May partly cover meal (e.g., breakfast if taken in morning)
but can result in later hypoglycemia (e.g., early afternoon)
Riddle et al. Diabetes Care. 26:3080-3086; 2003Raskin et al Diabetes Care. 28:260-265; 2005
Basal Insulin Options
The most convenient strategy is with a single injection ofbasal insulin administered before the evening meal or atbedtime, at an initial dose of 0.1units/kg. This will ensurethat changes in blood glucose levels will be gradual.
Under special conditions, such as significant hyperglycemia(HbA1c ≥9%) and/or obesity, a starting dose of 0.2 units/kgmay be used.
An alternative, non-weight-based option is to start mostindividuals empirically with 10 units, or in obesity up to 20units, of basal insulin (i.e., long-acting or intermediate-acting).
Initiating Basal Insulin
Advancing Basal Insulin
If most AM fasting BG >120 mg/dL(>6.7 mmol/L)
Titrate until fasting glucose at target BG
• Increase 2 units [or 4 units if FBG >180 mg/dl or 10 mmol/L] every 3 days
• If dose reaches ~0.5 units/kg body weight, consider adding mealtime insulin
If most AM fasting BG <120 mg/dL(<6.7 mmol/L) and A1C remains above target
Test pre–evening meal and bedtime (or 2-hour post–evening meal) and consider need for mealtime insulin
If hypoglycemia or FPG < 70 mg/dL
Reduce insulin dose by 3 units or 10%, whichever is greater
Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range but HbA1c ≥7%, check blood glucose before lunch, dinner, and bed and add a second injection:
• If pre-lunch blood glucose is out of range,
– add rapid-acting insulin at breakfast
• If pre-dinner blood glucose is out of range,
– add NPH insulin at breakfast or rapid-acting insulin at lunch
• If pre-bed blood glucose is out of range,
– add rapid-acting insulin at dinner
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
A basal/bolus insulin regimen can be considered atdiagnosis when rapid achievement of glucose control isdesired (e.g., symptomatic, or to induce “clinicalremission,” see Module 2).
Basal/bolus regimens can also be considered when thecombination of basal or premixed insulin and non-insulin therapies are no longer effective.
The minimal starting total daily dose is 0.2 units/kgdivided as 50% long- or intermediate-acting and 50%short- or rapid-acting insulin.
Initiating Basal-Bolus Insulin Regimen
A1C <9% A1C ≥9%
Basal-Bolus insulin
0.2 units/kg/ day
Basal 0.1 units/kg
+
Mealtime 0.1 units/kg
0.4 units/kg/day
Basal 0.2 units/kg
+
Mealtime 0.2 units/kg
Stop or reduce insulin secretagogue
TZDs are often reduced or stopped due to risk of hypoglycemia,
excessive weight gain, edema, and/or heart failure
Select and calculate starting dose
Divide 50% background, 50% mealtime
Mazze R, et al. Staged Diabetes Management Adult Quick Guide, 5th Edition Revised, 2010International Diabetes Center
Initiating Basal-Bolus Insulin Regimen
Calculating Basal + Mealtime Insulin Doses
Insulin dose =
Weight in kg 80 x units/kg 0.4 = 32 units / Day
16 Units Long Acting + 16 Units Rapid Acting
Example: T2DM Patient (80 kg) with A1C of 9.6% on metformin and insulin secretagogue
Plan Insulin AM Noon PM Bed
LA 16
RA 5 6 5
Total starting dose = 0.4 units/kg
Starting Premixed Insulin
If the HbA1c is ≥9%, the starting dose of premixed
insulin is 0.2 units/kg before the morning and evening
meals (total daily dose 0.4 units/kg).
If the HbA1c is <9%, the starting dose is 0.1 units/kg
before the morning and evening meals (total daily dose
0.2 units/kg).
Based on glucose monitoring, premixed insulin
adjustments of 2 units is typically recommended.
Initiating Premixed Insulin
Most insulin regimens take into account the
individual’s weight at initiation because doing so will
help prevent adverse reactions caused by over-
insulinization (most notably hypoglycemia and weight
gain).
When using premixed insulin, insulin secretagogues
are often discontinued and other non-insulin therapies
should be reconsidered.
The effectiveness of these medications should be
reconsidered in light of the action of the premixed
insulin.
Initiating Premixed Insulin
Relatively easy to use
Covers insulin requirements
through most of day
Not very physiological
Less flexibility than
basal(±bolus)
Greater likelihood of
hypoglycemia
More weight gain than basal
Emerging evidence supports
better A1C reduction with
basal/bolus
Premixed Insulin Therapy
Supporting Evidence Non-supporting Evidence
Healthy eating, weight control, increased physical activity & diabetes education
Metformin high low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
high low risk
gain
edema, HF, fxs
low
Thiazolidine- dione
intermediate low risk
neutral
rare
high
DPP-4 inhibitor
highest high risk
gain
hypoglycemia
variable
Insulin (basal)
Metformin +
Metformin +
Metformin +
Metformin +
Metformin +
Basal Insulin +
Sulfonylurea
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
or
or
or
or
Thiazolidine-dione
+ SU
DPP-4-i
GLP-1-RA
Insulin§
TZD
DPP-4-i
GLP-1-RA
high low risk
loss
GI
high
GLP-1 receptor agonist
Sulfonylurea
high moderate risk
gain
hypoglycemia
low
SGLT2 inhibitor
intermediate low risk
loss
GU, dehydration
high
SU
TZD
Insulin§
GLP-1 receptor agonist
+
SGLT-2 Inhibitor +
SU
TZD
Insulin§
Metformin +
Metformin +
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Mono- therapy
Efficacy* Hypo risk
Weight
Side effects
Costs
Dual therapy†
Efficacy* Hypo risk
Weight
Side effects
Costs
Triple therapy
or
or
DPP-4 Inhibitor
+ SU
TZD
Insulin§
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin +
Combination injectable therapy‡
GLP-1-RA Mealtime Insulin
HbA1c≥9%
Me orminintoleranceorcontraindica on
Uncontrolledhyperglycemia
(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
Proposed progressive insulin strategies in type 2 diabetes.
*Log = rapid-acting insulin analogues (lispro, aspart, glulisine
)
Lastly we hope that course will achieve
its goals and help you all in getting the
best of the forthcoming conference
UEDA Board
UEDA Diabetes Mini-Course
Aswan Feb. 2016