Ueda 2016 5-pharmacological management of diabetes - lobna el toony

1. Pharmacological
Management of Diabetes
UEDA Diabetes Mini-Course
Aswan Feb. 2016

2. 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.
A
Age
B
Body
Weight
C
Complicat
ions
D
Duration
of
Diabetes
E
Expectancy
(Life)
E
Expenses

6. •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

7. “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 Problem
For many individuals, achieving an adequate HbA1c
requires early intervention with insulin-based therapies
which are often delayed due to physician and/or patient
resistance …

8. HbA1C(%)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 group21%33%27%

9. The Burden of Type 2 Diabetes Treatment
Failure “Clinical Inertia”MeanHbA1catLastVisit*
(%)
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

10. Oral Antidiabetic Drugs
OAD
UEDA Diabetes Mini-Course
Aswan Feb. 2016

11. Sites of Action of Metformin

13. Dose Effect: Metformin
-19
- 31
- 41
- 78
- 62
-80
-60
-40
-20
0
500 mg 1000 mg 1500 mg 2000 mg 2500 mgChangeinFPG(mg/dL)
Metformin Dose
Garber et al., Am J Med, 1997

14. Insulin Secretagogues
Glipizide, 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

15. Sulfonylureas
(su)
Sites of Action of Sulphonlyureas

16. 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

20. 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.

21. DPP-4 Inhibitors: Physiologic Action
Blood
Glucose
Pancreas
β cells
α 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
Enzyme
X
DPP-4
Inhibitor
Glucose
uptake by
muscles
Glucose
production
by liver

24. 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
Duodenum Jejunum Ileum
Time (min)
140
–30 0 60 120 180 240
120
100
80
*
*
Meal
Placebo
Acarbose
* P <.05
PlasmaGlucose
(mg/dL)

25. 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)

26. 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.

27. 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.

29. Traditional current oral therapies do
not address all islet cell dysfunction
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis.
2003; 3 (Suppl 1): S24–S40.
Pancreatic Islet Dysfunction
Inadequate
glucagon
suppression
(-cell
dysfunction)
Progressive
decline of β-cell
function
Insufficient
Insulin secretion
(β-cell
dysfunction)
Sulfonylureas
Glinides
TZDsMetformin
Insulin Resistance
(Impaired insulin action)

30. Traditional current oral therapies do
not address all islet cell dysfunction
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
Pancreatic Islet Dysfunction
Inadequate
glucagon
suppression
(-cell
dysfunction)
Progressive
decline of β-
cell function
Insufficient
Insulin
secretion
(β-cell
dysfunction)
Insulin Resistance
(Impaired insulin action)
GLP-1
DPP-4 inhibitors
GLP-1
DPP-4 inhibitors
GLP-1
DPP-4 inhibitors
Sulfonylureas
Glinides
TZDsMetformin

31. 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

32. 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-RAMealtime Insulin
HbA1c
≥9%
Me ormin
intolerance or
contraindica on
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

35. Insulin Therapy
UEDA Diabetes Mini-Course
Aswan Feb. 2016

37. 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 T1DM
Essential in T2DM

38. 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.

39.  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

40. Normal Insulin Secretion
Mealtime (bolus)
insulin needs ~ 50%
Background (Basal) Insulin Needs ~ 50%
Kruszynska et al. Diabetologia 30: 16-21, 1987
Polonsky et a. J. Clin. Invest. 81: 442-48, 1988
Time

41. The Role of Insulin Therapy
Relative Insulin
Deficiency
Pre-diabetes and
Type 2 Diabetes
Insulin
Resistance
Incretin Dysfunction
Insulin
Deficiency
Type 1 Diabetes
Critical role in both Type 1 and Type 2 diabetes
 Greatest potency of available therapies
 Demonstrated benefit – multiple clinical trials

42. 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

43. 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”)

44. Action Profiles of Injectable Insulins in
T2DM Patients

45. 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’

46. 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

47. 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

48. Principles to Follow for Individuals Concomitantly
Treated with Non-insulin Agents
1) Metformin, DPP-4 inhibitor, GLP-1 receptor agonist and/or
α-glucosidase inhibitors are usually maintained at usual
dose although they need careful monitoring;
2) Insulin secretagogue dose is often reduced or stopped due
to risk of hypoglycemia and/or excessive weight gain;
3) TZD dose is often reduced or stopped due to risk of
hypoglycemia, excessive weight gain, edema, and/or heart
failure.

49. 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; 2003
Raskin et al Diabetes Care. 28:260-265; 2005
Basal Insulin Options

50.  The most convenient strategy is with a single injection of
basal insulin administered before the evening meal or at
bedtime, at an initial dose of 0.1units/kg. This will ensure
that 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/kg
may be used.
 An alternative, non-weight-based option is to start most
individuals empirically with 10 units, or in obesity up to 20
units, of basal insulin (i.e., long-acting or intermediate-
acting).
Initiating Basal Insulin

51. 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

53. 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.

54.  A basal/bolus insulin regimen can be considered at
diagnosis when rapid achievement of glucose control is
desired (e.g., symptomatic, or to induce “clinical
remission,” see Module 2).
 Basal/bolus regimens can also be considered when the
combination of basal or premixed insulin and non-
insulin therapies are no longer effective.
 The minimal starting total daily dose is 0.2 units/kg
divided as 50% long- or intermediate-acting and 50%
short- or rapid-acting insulin.
Initiating Basal-Bolus Insulin
Regimen

55. 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, 2010
International Diabetes Center
Initiating Basal-Bolus Insulin
Regimen

56. 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

57. Starting Premixed Insulin

58.  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

59.  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

60.  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

61. 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-RAMealtime Insulin
HbA1c
≥9%
Me ormin
intolerance or
contraindica on
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

63. Proposed progressive insulin strategies in type 2
diabetes.
*Log = rapid-acting insulin analogues (lispro, aspart, glulisine

64. 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