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