Diabetes revised march 2013

Diabetes Mellitus
By
Farid Fawzy, MD, PhD
Prof. of Internal Medicine ,Diabetes & Endocrinology
Zagazig University, Egypt


INTRODUCTION

DEFINITION

CLASSIFICATION

Clinical Findings

DIAGNOSIS

PREVALENCE

PATHOGENESIS

TREATMENT

ACUTE COMPLICATIONS

CHRONIC COMPLICATIONS


One of the most common non-communicable
diseases globally.

Diabetes kills: 1 person every 8 seconds
4 million people a year

Diabetes doesn't discriminate: all ages
all countries
rich and poor


Accordingly Diabetes mellitus is a major
health problem worldwide, both in developed
and more so in developing countries.

Acknowledging this fact, the United Nations
(UN) has recognized the 14th of November
each year as the National Diabetes Day.


2010 2030
Total world population (billions) 7.0 8.4
Adult population(20-79ys, billions) 4.3 5.6
Diabetes
Global prevalence (%) 6.6 7.8
Number with diabetes (millions) 285 438

Mean health expenditure per person with diabetes (USD),
2010

Definition

A syndrome with disordered metabolism
and inappropriate hyperglycemia due to
either :
- Absolute deficiency of insulin secretion
- or
- Reduction in its biologic effectiveness

Clinical Definition

A syndrome characterized by :
Polyphagia
Polydypsia
Polyurea
Weight loss
Inappropriate hyperglycemia

Classification Of Diabetes Mellitus

The WHO classification (1979):
- IDDM
- NIDDM
- Gestational Diabetes mellitus [GDM]
- Malnutrition-related Diabetes
- Impaired Glucose Tolerance (IGT)
- Other types

(1)
IDDM Type 1 diabetes
NIDDM Type 2 diabetes

(2)
Malnutrition-related diabetes mellitus
→
Diseases of the exocrine pancreas

(3)
IGT
↓
Pre-diabetes (IGT+IFG)
↓
Categories of increased risk
(IGT+IFG+Abnormal A1C)

Current Classification of DM (ADA,1996 & 2010)

Type 1 Diabetes Mellitus


High risk categories (IFG,IGT & abnormal
A1c)

Gestational Diabetes Mellitus (GDM)

Other specific types of Diabetes.

Remarks on classification

Assigning a type of Diabetes to an individual
often depends on the circumstances present
at the time of diagnosis.

Many diabetic individuals do not easily fit
into a single class.


For example, a person with GDM may
continue to be hyperglycemic after delivery
and may be determined to have, in fact, type
1 or type 2 Diabetes Mellitus.


Alternatively, a person who acquires diabetes
because of large doses of exogenous
steroids may become normoglycemic once
the glucocorticoids are discontinued, but
then may develop diabetes many years later
after recurrent episodes of pancreatitis.


Another example would be a person treated
with thiazides who later develops diabetes.

Because thiazides in themselves seldom cause
severe hyperglycemia, such individuals
probably have type 2 Diabetes that is
exacerbated by the drug.

Type 1 Diabetes Mellitus:
- Immune-mediated
- Idiopathic

Immune-mediated Type 1 Diabetes.

Cellular-mediated autoimmune destruction of the
β-cells of the pancreas.

Markers of the immune destruction of the β-cell
include:
- islet cell autoantibodies (ICAs)
- insulin autoantibodies (IAAs)
- glutamic acid decarboxylase Ab’s (GAD65)
- tyrosine phosphatase autoantibodies (IA-2)


One and usually more of these auto-antibodies
are present in 85-90% of individuals when
fasting hyperglycaemia is initially detected.

Severity of the disease is correlated with the
number of autoantibodies

Type 1 DM has strong HLA associations.


The rate of B-cell destruction is quite variable.

Some patients, mainly children and adolescents,
may present with ketoacidosis

Others have modest fasting hyperglycemia that
can rapidly change to severe hyperglycemia or
ketoacidosis.

Still others, particularly adults, may retain
residual β-cell function sufficient to prevent
ketoacidosis for many years.


Immune-mediated DM commonly occurs in
childhood and adolescence, but it can occur at
any age, even in the 8th and 9th
(LADA)

Although patients are rarely obese when they
present with type 1 of Diabetes, the presence of
obesity is not incompatible with the diagnosis.


Autoimmune destruction of ß-cells has
multiple genetic predispositions and is also
related to environmental factors that are still
poorly defined.


Patients with autoimmune type 1 DM are
also prone to other autoimmune disorders:
- Graves' disease
- Hashimoto's thyroiditis
- Addison's disease
- vitiligo
- Pernicious anaemia.

Idiopathic Type 1 Diabetes
CHARACTERISTICS:

Strongly inherited

Lacks immunological evidence for β -cell
autoimmunity

Not HLA associated.

An absolute requirement for insulin in
affected patients may come and go.

Type 2 Diabetes

Previously referred to as non-insulin-
dependent or adult-onset diabetes

Describes individuals with insulin resistance
and usually have relative insulin deficiency.

At least initially, and often for lifetime, these
individuals do not need insulin to survive.

Type 2 Diabetes(Cont.)

There are probably many different causes of this form of
diabetes

It is likely that the proportion of patients in this category
will decrease in the future as identification of specific
pathogenic processes and genetic defects permits a
definitive classification.

Type 2 Diabetes(Cont.)

Type 2 DM frequently goes undiagnosed for
many years.

Nevertheless, such patients are at increased
risk of developing macro-vascular and
micro-vascular complications.

Risk Factors for Type 2 Diabetes
- Age
- Obesity
- lack of physical activity
- Women with prior GDM
- Individuals with hypertension or dyslipidemia
- Certain racial/ethnic subgroups.
- Associated conditions (Acanthosis nigricans,
POS)

Type 2 Diabetes (Cont.)

It is often associated with a strong genetic
predisposition

The genetic basis of type 2 is more evident
than in type 1

The genetics of this form of diabetes are
complex and not clearly defined.

Current Classification of DM (ADA,1996 & 2010)



Other specific types of Diabetes.

Gestational Diabetes Mellitus (GDM)

High risk categories (IFG,IGT & abnormal
A1c)

4- Other specific types of diabetes

Genetic defects

Diseases of the exocrine pancreas

Endocrinopathy

Drug or chemical-induced

B-cell
↓
Pro-insulin
↓
Insulin
↓
Insulin + Insulin Receptor
↓
Glucose entry into the cells

A) Genetic defects of the β–cell

Maturity-Onset Diabetes of the Young (MODY),
characterized by :
- Onset at an early age (generally before age 25 y).
- Impaired insulin secretion with minimal or no
defects in insulin action.
- Inherited in an autosomal dominant pattern.


Abnormalities at three(?) genetic loci on different
chromosomes have been identified to date:
- MODY -1: associated with a mutation in the HNF-
4 gene on chromosome 20q
- MODY -2: associated with mutations in the
glucokinase gene on chromosome 7p
- MODY -3:The most common form, associated
with mutations on chromosome 12 (HNF-1)

B) Genetic Defects in Insulin
1 – Defective conversion of pro-insulin to
insulin
- Genetic basis.
- The resultant glucose intolerance is mild.
2 - Production of mutant insulin molecules
- Results in impaired receptor binding.
- Glucose metabolism is only mildly impaired
or even normal

C) Genetic defects in insulin action

The metabolic abnormalities associated with
mutations of the insulin receptor may range
from hyperinsulinemia and modest
hyperglycemia to severe diabetes.

Some individuals with these mutations may
have acanthosis nigricans or cystic ovaries

D) Diseases of the exocrine pancreas

Any process that diffusely injures the pancreas
can cause Diabetes.

Acquired processes include:
* pancreatitis
* trauma
• * infection
* pancreatectomy
* pancreatic carcinoma


With the exception of cancer, damage to the pancreas
must be extensive for diabetes to occur.

Adenocarcinomas involving only a small portion of the
pancreas have been associated with DM. This implies a
mechanism other than simple reduction in β-cell mass.

If extensive , cystic fibrosis and hemochromatosis will
also damage β-cells impairing insulin secretion.

E) Endocrinopathies
Growth hormone, cortisol, glucagon & epinephrine
antagonize insulin action.
Excess amounts of these hormones can cause DM.
This generally occurs in individuals with pre-
existing defects in insulin secretion
Hyperglycemia typically resolves when the hormone
excess is removed.

Endocrinopathies(Cont.)

Examples of endocrinopathies causing diabetes
mellitus include:
- Acromegaly
- Cushing's syndrome
- Glucagonoma
- Pheochromocytoma

F) Drug/chemical-induced Diabetes

Many drugs and chemicals can precipitate
diabetes

These drugs do not cause diabetes by
themselves, but may precipitate the disease in
individuals with insulin resistance.

Certain toxins such as Vacor (a rat poison) can
permanently destroy pancreatic β-cells.

Other drugs can impair insulin action.

Drugs & Chemicals causing DM
- Nicotinic acid - Glucocorticoids
- Thyroid hormones - Diazoxide
- β-adrenergic agonists - Thiazide diuretics
- α- interferon - Dilantin

Gestational Diabetes mellitus
(GDM)

Defined as any degree of glucose intolerance
with onset or first recognition during
pregnancy.

The definition does not exclude the possibility
that unrecognized glucose intolerance may
have antedated the pregnancy.

Six weeks after pregnancy ends, the woman
should be reclassified.


GDM complicates 4% of all pregnancies in the
U.S., resulting in 135,000 cases annually

Clinical recognition of GDM is important because
therapy can reduce GDM-associated perinatal
morbidity and mortality.

Maternal complications related to GDM include
an increased rate of CS and chronic
hypertension.


Many patients diagnosed with GDM will not
develop diabetes later in life

Others will be diagnosed many years
postpartum as having type 1 diabetes, type
2 diabetes, IFG, or IGT.

High risk categories

The terms IGT and IFG refer to a metabolic
stage intermediate between normal glucose
homeostasis and Diabetes.

Recently abnormal HbA1c (5.7-6.4) was
included in this category.


Many individuals with IGT are euglycemic in
their daily lives and may have normal or near
normal glycated hemoglobin levels.

Individuals with IGT often manifest
hyperglycemia only when challenged with the
oral glucose load used in the standardized OGTT.


IFG and IGT are associated with the insulin
resistance syndrome (also known as syndrome X
or the metabolic syndrome), consisting of insulin
resistance, obesity (especially abdominal or
visceral obesity), dyslipidemia and hypertension.

Insulin resistance is directly involved in the
pathogenesis of type 2 Diabetes

IFG and IGT appear as risk factors for this type of
Diabetes.

Clinical features

Polyurea and thirst

Weakness or fatigue

Polyphagia with weight loss

Recurrent blurred vision

Pruritus or vulvovaginitis

Peripheral neuropathy

Nocturnal enuresis

Asymptomatic


Complications at presentation:
- Type 1 DM
(Acute complications): Acute abdomen
Coma
- Type 2 DM
(Chronic complications): Stroke
CAD
P.N.

Diagnosis of Diabetes Mellitus

The diagnostic criteria for diabetes mellitus
have been modified from those previously
recommended by the NDDG or WHO.

The revised criteria include three ways to
diagnose diabetes

The test used for diagnosis must be
confirmed, on a subsequent day, by any one
of the three methods given

Criteria for the Diagnosis Of
Diabetes Mellitus

FPG 126 ≥ mg/dl.
Fasting is defined as no caloric intake for at least 8 h.
OR

Symptoms of hyperglycemia and a casual plasma glucose ≥
200 mg/dl.
Casual is defined as any time of day without regard to time since
last meal.
OR
 2-h plasma glucose ≥ 200 mg/dl during an OGTT.
The test should be performed using a glucose load containing the
equivalent of 75 g glucose dissolved in water.

Fasting Plasma Glucose Values

FPG <100 mg/dl = normal

FPG 100 ≤ 126 mg/dl = IFG

FPG ≥ 126 mg/dl = provisional Diabetes
(the diagnosis must be confirmed ).

Values of OGTT

2-h PG <140 mg/dl = normal glucose tolerance

2-h PG 140 - ≤200 mg/dl = IGT

2-h PG ≥ 200 mg/dl = provisional Diabetes
(the diagnosis must be confirmed).

Note
 HbA1c remains a valuable tool for glycemic
monitoring but is not currently recommended
for the diagnosis

This statement was changed in 2010 ADA
recommendations identifying a cut off point of
HbA1c ≥ 6.5% for diagnosis of diabetes

A1C should be tested in a lab. that is National
Glycohemoglobin Standardization Program
(NGSP) certified

Screening for Diabetes
I. Type 1

Type 1 Diabetes is usually an autoimmune
disease, characterized by the presence of a
variety of autoantibodies.

The presence of such markers before the
development of overt disease can identify
patients at risk.


At this time many reasons preclude the
recommendation to test for the presence of the
immune markers outside of a clinical trials
setting:
- Cut-off values for some of the assays for
immune markers have not been completely
established.
- There is no consensus yet as to what action
should be taken for a positive autoantibody test.

Screening for Diabetes
II. Type 2

50% of patients with type 2 diabetes are undiagnosed.

Retinopathy begins to develop at least 7 years before the
clinical diagnosis of type 2 diabetes.

Patients with undiagnosed type 2 diabetes are at
increased risk for CHD, stroke, and PVD.

In addition, they have a greater likelihood of having
dyslipidemia, hypertension, and obesity.


Early detection, and consequently early
treatment, might well reduce the burden of
type 2 Diabetes and its complications.

To increase the cost-effectiveness, testing
should be considered in high-risk populations.

Screening For Type 2 Diabetes

All adults ≥ 45y, if normal repeat in 3 years

Screening at younger age if:
- Obese ( BMI ≥ 27 )
- First degree relative with diabetes
- High risk ethnic group e.g. African Americans.
- Delivering a baby ≥ 9 Ib or H/O GDM
- Hypertension ≥ 140/90
- Previous diagnosis of IGT or IFG
- Associated dyslipidemia

Testing for Gestational Diabetes
Mellitus (GDM)

Previous recommendations have been that screening for
GDM be performed in all pregnancies.

There are certain factors that place women at lower risk
for the development of glucose intolerance during
pregnancy

It is not cost-effective to screen low risk patients.

Low Risk for GDM
Women with all of the following:
- Women ≤ 25 years of age
- Normal body weight
- No family history (i.e., first-degree relative) of
diabetes
- Not members of a high risk ethnic/racial group
(e.g., Hispanic-American, Native American,
Asian-American, African-American, Pacific
Islander).

High Risk Criteria for GDM

Severe obesity

Prior history of GDM or delivery of large-
for-gestational-age infant

Presence of glycosuria

Diagnosis of PCOS

Strong family history of type 2 diabetes

diagnosis of gestational diabetes
mellitus
Pre-conception risk assessment
↓ ↓
Low risk High risk
↓ ↓
Testing at 24-28 w Screen at 1st
antenatal
visit
↑ ↓
←←←←←←←←←←← Normal

Approaches for GDM Screening

Two-step approach:

Initial screening of plasma or serum glucose 1 h after a
50-g glucose load

Perform a diagnostic 100-g OGTT on a separate day in
women who exceed 140 mg/dl on 50-g screening.

One-step approach :
Perform a diagnostic 100-g OGTT in all women to be
tested at 24–28 weeks.

Criteria for Diagnosis of GDM

P Glucose 50-g screening 100-g diagnostic test
Fasting - 105 mg/dl
1-h 140 mg/dl 190 mg/dl
2-h - 165 mg/dl
3-h - 145 mg/dl
The diagnosis of GDM is made if any two out of four threshold
values are met or exceeded.


One step test:

75- gm OGTT

Diagnosis is made with any one of:
- Fasting ≥ 92 mg/dL
- 1 hour ≥ 180 mg/dL
- 2 hours ≥ 153 mg/dL

Prevalence of Diabetes Mellitus

It is estimated that approximately 285
million people worldwide, or 6.6%, in
the age group 20-79 are having diabetes
in 2010.

Some 70% of this number are living in
low- and middle-income countries.

IDF Regions and global projections for the number of
people with diabetes (20-79 years), 2010-2030

Prevalence (%) estimates of diabetes (20-79 years), 2010

Prevalence (%) estimates of diabetes (20-79 years),
2030

Prevalence (%) estimates of impaired glucose tolerance (20-79 years), 2010

New cases of type 1 diabetes in children, 0-14 years (cases
per 100,000 aged 0-14 years per year), 2010


The number of diabetics is expected to
increase by >50% in the next 20 years if
preventive programmes are not put in place.

By 2030, some 438 million people, or 7.8%
of the adult population, are projected to
have diabetes.

The largest increases will take place in the
regions dominated by developing economies

Top 10 Countries for 2000&2030

GENES Obesity, ↓β-cell, insulin resistance
+
Environmental factors Sedentary life, Abundant food
↓
Insulin resistance Hyperinsulinemia, β-cell compensation
↓
β-cell decompensation Impaired Glucose Tolerance(IGT)
↓
Decline in β-cell mass Hyperglycemia, glucotoxicity
↓
Type 2 diabetes mellitus


INTRODUCTION

DEFINITION

CLASSIFICATION

Clinical Findings

DIAGNOSIS

PREVALENCE

PATHOGENESIS

TREATMENTTREATMENT

ACUTE COMPLICATIONS

CHRONIC COMPLICATIONS

PREVENTION/DELAY OF TYPE 1
DIABETES

No standardized prevention program is
available for type 1 diabetes mellitus

DIABETES

Patients with IGT or IFG should be advised to
loose 5–10% of body weight, as well as to
increase physical activity to at least 150
min/week of moderateactivity.

Intensive lifestyle modification program has
been shown to significantly decreasethe rate of
onset of diabetes (58% reduction after 3 years)

DIABETES(Cont.)

The use of pharmacologic agents as metformin, has been
shown to decreaseincident diabetes to various degrees

Metformin use is restricted to those with IFG & IGT

Monitoring for the developmentof diabetes in those with
pre-diabetesshould be performed every year.

Treatment Rules

Maintaining glycemic levels as close to the non
diabetic range as possible

Except in rare circumstances, hospitalization is
not required.

Therapies should be directed at other associated
comorbidities.

The choice of glycemic goals and the medications
used to achieve it must be individualized

Benefits of tight glycemic control

Principles in selecting anti-hyperglycemic
drugs

Effectiveness in lowering glucose

Extraglycemic effects that may reduce long-
term complications

Safety profiles

Tolerability

Ease of use

Expense.

Management Goals in Patients with DM

Components of Diabetes
Management
- Comprehensive evaluation
- Physical examination
- Lab. Investigations
- Life style modifications
- Drug therapy

I.comprehensive diabetes evaluation

Medical history:
- Age and characteristics of onset of diabetes (e.g.,
DKA, asymptomatic laboratory finding)
- Eating patterns, nutritional status, and weight
history
- Diabetes education history
- Current treatment of diabetes, including
medications, meal plan, physical activity patterns,
and results of glucose monitoring

Comprehensive Diabetes Evaluation (Cont.)

Review of previous treatment and response to
therapy (A1C records)

DKA frequency, severity, and cause

Hypoglycemic episodes

History of diabetes-related complications:

Microvascular: retinopathy, nephropathy, neuropathy

Macrovascular: CHD, cerebrovascular disease, PAD

II.Physical examination

Height, weight, BMI & WC

Blood pressure , including orthostatic measurements

Fundoscopic examination

Thyroid palpation

Skin examination (for acanthosis nigricans, stria..etc)


Comprehensive foot examination:

Inspection

Palpation of dorsalis pedis and posterior tibial
pulses

Presence/absence of patellar and Achilles reflexes

Determination of proprioception, vibration, and
monofilament sensation

III.Laboratory evaluation

A1C, if results not available within past 2–3 months

Fasting lipid profile, including total, LDL, and HDL
cholesterol and triglycerides

Test for urine albumin excretion with spot urine
albumin-to-creatinine ratio

Thyroid-stimulating hormone in type 1 diabetes,
dyslipidemia or women over age 50

IV.Referrals

Annual dilated eye exam

Family planning for women of reproductive age

Registered dietician for MNT

Diabetes self-management education

Dental examination

Psychiatrist consultation, if needed

V. Drug Therapy

Therapy for type 1 diabetes: INSULIN
1) use of multiple dose insulininjections (3–4
injections per day of basal and prandialinsulin)
or CSII therapy
2) Matching of prandial insulin tocarbohydrate
intake, premeal blood glucose, and anticipated
activity
3) For many patients (especially if hypoglycemia
is a problem), use of insulin analogs.

Therapy for type 2 diabetes

Life style interventions

Hypoglycemic medications

Treatment of associated conditions

Treatment of complications

Stepwise approach in patients with type 2 DM

Life Style Interventions

A lifestyle intervention program to promote
weight loss and increase activity levels
should, with rare exceptions, be included as
part of any diabetes management.

Weight. loss of as little as 4 kg will often
ameliorate hyperglycemia

The long-term success is limited and the
large majority of patients will require the
addition of medications with time.

Medical Nutrition Therapy (MNT)

Weight loss is recommended for all overweight or obese
individualswho have or are at risk for diabetes.

Low-carbohydrate ,low-fat and calorie-restricteddietsmay
be effective in the short term (up to 1 year).

Physical activityand behaviour modification are important
componentsof weightloss programs and are most helpful
in maintenanceof weightloss.


Dietary fat intake in diabetes management

Saturated fat intake should be <7% of total calories.

Carbohydrate intake in diabetes management

carbohydrate intake, should constitute 55% of total
calories.

The use of the glycemic indexand glycemic load may
providea modest additional benefit forglycemic control
over that observedwhen total carbohydrateis
considered alone. (B)

Other nutrition recommendations

Non nutritive sweeteners are safe

Routine supplementationwith antioxidants, such as
vitaminsE and C and carotene, isnot advised because of
lack of evidenceof efficacy and concernrelated to long-
term safety.

Chromium supplementationin people with diabetesor
obesity has not shown benefit and are not recommended.


total caloric intake must be appropriate to
weight managementgoal.

Average daily caloric requirements are 25
Kcal/Kg/day

Individualization of the macronutrient
compositionwill depend on the metabolic status
of the patient (e.g., lipidprofile, renal function).

Physical activity Recommendations

People with diabetes should be advised to
perform at least 150min/week of moderate-
intensity (50–70%of maximum heart rate).

Regular exercise has been shown to improve
blood glucose control andreduce cardiovascular
risk even with no significant change in BMI .

Resistance exercise improves insulin sensitivity to
about thesame extent as aerobic exercise.

Evaluation before recommending an exercise program

Assess patients withmultiple cardiovascular
risk factors for coronary artery disease.

High-risk patientsshould start with short
periods of low-intensityexercise.

The patient's age and previous physical
activity level shouldbe considered

Assess patients for conditions that might
contraindicatecertain types of exercise

Precautions

vigorous activity should be avoidedin the
presence of ketosis.

For individualson insulin secretagogues and/or
insulin, added carbohydrate should be ingested if
pre-exercise glucose levels are <100 mg/dl

In the presence of proliferative retinopathy,
vigorous aerobic or resistance exercisemay be
contraindicated because of the risk of triggering
vitreoushemorrhage or retinal detachment

Immunization
Recommendations

Annual influenza vaccine to all diabetics.

At least one lifetime pneumococcalvaccine
for adultswith diabetes.

Repeat vaccination may be required in
certain conditions.

Antiplatelet agents

Use aspirin therapy (75–162 mg/day) as a secondary
preventionin those with diabetes with a history of CVD. (A)

Aspirin therapyis not recommended in people under 30 and is
contraindicatedin patients underthe age of 21 years because of
the associatedrisk of Reye'ssyndrome. (E)

Combination with other antiplateletagents such asclopidrogel
should beused in patientswith severe and progressive CVD. (C)

Otherantiplatelet agents may be a reasonable alternative for
high-riskpatients with recent gastrointestinalbleeding . (E)

Smoking cessation

Advise all patients not to smoke. (A)

Cigarette smoking contributes to one of every
five deaths inthe U.S. and is the most important
modifiable cause of prematuredeath

Risk of CVD and premature death is heightened
among diabetic smokers.

Smoking is alsorelated to the premature
development of microvascular complications

Smoking may have a role in the development of
type 2diabetes ???.

Hypoglycemic Medications

When levels of glycemia are high (e.g., A1C 8.5%),
classes with greater effectiveness, or earlier
initiation of combination therapy, are recommended

When glycemic levels are closer to the target levels
(e.g., A1C7.5%), medications with lesser potential
may be considered.

Patients with recent-onset diabetes often respond
adequately to less intensive interventions


Rapid addition of medications, and transition to
new regimens, when glycemic goals are not met.

Early addition of insulin therapy in patients
who do not meet target goals

In severely uncontrolled diabetes: FBS > 250
mg/dl, RBS >300 mg/dl, A1C >10%, ketonuria
and symptomatic diabetes with weight loss,
insulin therapy with lifestyle intervention is the
treatment of choice.


Diabetes medications include:
- Metformin
- Insulin secretagogues: SU & Glinides
- α- glucosidase inhibitors
- Thiazolidinediones
- Exenatides(GLP-1 agonists)
- DPP-4 inhibitors
- Insulin
- SGLT inhibitors

I.Metformin.

In most of the world, metformin is the only
biguanide available.

Its major effect is to decrease hepatic glucose
output and lower fasting glycemia.

Typically, metformin monotherapy will
lower A1C levels by 1.5%

It is generally well tolerated, with mainly
gastrointestinal side effects.


Metformin monotherapy is not usually
accompanied by hypoglycemia.

Metformin interferes with vitamin B12
absorption but is very rarely associated with
anemia .

The major nonglycemic effect of metformin is
either weight stability or modest weight loss.

A beneficial effect of metformin therapy on CVD
outcomes needs to be confirmed.


Renal dysfunction is considered a contraindication to
metformin use because it may increase the risk of lactic
acidosis, an extremely rare (< 1/ 100,000 ) but
potentially fatal complication .

However, recent studies have suggested that metformin
is safe unless the estimated glomerular filtration rate
falls to 30 ml/min.

Other organ failure is a relative contraindication

TITRATION OF METFORMIN
1. Begin with low-dose metformin (500 mg)
taken once or twice per day with meals
(breakfast and/or dinner) or 850 mg q.d.
2. After 5–7 days, if gastrointestinal side effects
have not occurred, advance dose to 850, or two
500 mg tablets, twice per day
3. If gastrointestinal side effects appear as doses
advanced, decrease to previous lower dose and
try to advance the dose at a later time.

4. The maximum effective dose can be up
2,500 mg/day.
5. Gastrointestinal side effects may limit the
dose that can be used.
6. A longer-acting formulation is available in
some countries and can be given once

II.Sulfonylureas

Sulfonylureas lower glycemia by enhancing
insulin secretion.

In terms of efficacy, they appear to be similar
to metformin, lowering A1C levels by 1.5 %

The major side effect is hypoglycemia, which
can be prolonged and life threatening, but
severe episodes are infrequent.

Severe episodes are relatively more frequent in
the elderly.


Chlorpropamide and glibenclamide (known as
glyburide in the U.S. and Canada), are
associated with a substantially greater risk of
hypoglycemia than other second-generation
sulfonylureas (gliclazide, glimepiride, glipizide,
and their extended formulations), which are
preferable .


Weight gain of 2 kg is common following the
initiation of sulfonylurea therapy.

Although the onset of the glucose lowering
effect of sulfonylurea monotherapy is
relatively rapid, maintenance of glycemic
targets over time is not as good as
monotherapy with a TZD or metformin


Sulfonylurea therapy was implicated as a
potential cause of CVD mortality in the↑
University Group Diabetes Program (UGDP)
study.

Similar results were not substantiated by the
UKPDS or ADVANCE study.

The glycemic benefits of sulfonylureas are
nearly fully realized at half-maximal doses, and
higher doses should generally be avoided.


Glibeneclamide (Glyburide)

Glipizide

Gliclazide

Gliclazide MR

Glimepride

III.Glinides

Like sulfonylureas, glinides stimulate insulin
secretion.

They bind to a different site within the SU
receptor.

They have a shorter half-life than the SUs.

Of the two glinides currently available,
repaglinide is almost as effective as metformin
or the SU, decreasing A1C levels by 1.5 %

Nateglinide is less effective than repaglinide


The risk of weight gain is similar to that for
the sulfonylureas

Hypoglycemia may be less frequent than
with some sulfonylureas

Summary

Drug/Class: SUs/non-SU secretagogues

Mode of Action : Stimulate insulin secretion
via Na/K channel activation

Side Effects: Hypoglycemia, weight gain

IV. α -Glucosidase inhibitors.

α-Glucosidase inhibitors reduce the rate of
digestion of polysaccharides in the
proximal small intestine, primarily lowering
postprandial glucose levels.

They are less effective in lowering glycemia
than metformin or the sulfonylureas,
reducing A1C levels by 0.5– 0.8 %


Since carbohydrate is absorbed more
distally, malabsorption and weight loss do
not occur.

Increased delivery of carbohydrate to the
colon commonly results in increased gas
production and gastrointestinal symptoms.

In clinical trials, 25–45% of participants
have discontinued α–glucosidase inhibitors
as a result of this side effect

Summary

Drug/Class: Acarbose

Mode of Action : Alpha-glucosidase inhibitor

Side Effects: GI disturbance

Limitations/Contraindications: Poorly
tolerated, limited efficacy

V. Thiazolidinediones

Thiazolidinediones (TZDs or glitazones) are
peroxisome proliferator–activated receptor
modulators (PPAR-γ)

They increase the sensitivity of muscle, fat,
and liver to endogenous and exogenous
insulin (“insulin sensitizers”)


The data regarding the blood glucose–
lowering effectiveness of TZDs when used
as monotherapy have demonstrated a 0.5–
1.4% decrease in A1C.

The TZDs appear to have a more durable
effect on glycemic control, particularly
compared with sulfonylureas .

A favourable effect (Pioglitazone) or
neutral effect (Rosiglitazone) on lipid
profile.

TZD’s Adverse effects
- - Weight gain
- - Fluid retention, with edema
- Increased risk for congestive heart failure.
- Increased adiposity, mainly subcutaneous, with
some reduction in visceral fat.
- Fracture risk specially in old women
- Relatively increased risk for M.I. with
rosiglitazone.

Summary

Drug/Class : Thiazolidinediones

Mode of Action :PPAR-gamma activation

Side Effects : Weight gain, fluid retention,
fractures

Limitations/Contraindications:
Contraindicated in heart failure;
rosiglitazone not recommended in IHD

VI. Insulin

Insulin is the oldest of the currently available
medications (1922).

It is also the most effective at lowering glycemia.

Insulin, used in adequate doses, can decrease any
level of elevated A1C to the therapeutic goal.

Unlike the other blood glucose–lowering
medications, there is no maximum dose of insulin.

Pharmacokinetics of Basal and Prandial Insulins


Relatively large doses of insulin (1 unit/kg),
compared with those required to treat type 1
diabetes, may be necessary to overcome the
insulin resistance of type 2 diabetes and lower
A1C to the target level.

Although initial therapy is aimed at increasing
basal insulin supply, usually with intermediate
or long-acting insulin, patients may also require
prandial therapy with short- acting insulin.


The recently developed insulin analogues have
not been shown to lower A1C levels more
effectively than the older human formulations.

Insulin therapy has beneficial effects on
triglycerides and HDL cholesterol levels,
especially in patients with poor glycemic
control

Insulin is associated with weight gain of 2–4 kg.


Insulin therapy is associated with
hypoglycemia, albeit much less frequently
in type 2 (1-3 per 100 patient-years) than in
type 1 diabetes (61 per 100 patient-years).

Insulin analogues with longer, nonpeaking
profiles, and analogues with very short
durations of action reduce the risk of
hypoglycemia compared with NPH &
regular insulin respectively.

Summary

Drug/Class :Insulin

Mode of Action : Direct activation of insulin
receptor

Side Effects : Hypoglycemia, weight gain

Limitations/Contraindications: Injectable

VII. Glucagon-like peptide-1 agonists
(exenatide)

Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
OGTT and Matched IV Infusion
Glucose(mg/dL)
0
50
100
150
200
-30 0 30 60 90 120 150 180 210
Time (min)
Insulin(pmol/L)
0
100
200
300
400
-30 0 30 60 90 120 150 180 210
Time (min)
Proof of a Gastrointestinal ‘Incretin Effect’: Different Responses to
Oral vs. IV Glucose
Oral IV


Glucagon-Like Peptide-1 (GLP-1)

Glucose-dependent Insulinotropic Peptide
(GIP)
Incretins (Intestinal secretion of insulin)

VII. Glucagon-like peptide-1 agonists
(exenatide)

Glucagon-like peptide-1 (GLP-1), a naturally
occurring peptide produced by the L-cells of
the small intestine

GLP-1 potentiates glucose-stimulated
insulin secretion.

Inhibition of DPP-4 Increases
Active GLP-1
GLP-1
inactive
(>80% of pool)
Active
GLP-1
Meal
DPP-4
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
Adapted from Rothenberg P, et al. Diabetes. 2000; 49(suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126-1131.


Exendin-4 has homology with the human
GLP-1 sequence but has a longer circulating
half-life.

It binds avidly to the GLP-1 receptor on the
pancreatic β-cell and augments glucose-
mediated insulin secretion


Synthetic exendin-4 (exenatide) was approved
for use in the U.S. in 2005 and is administered
twice per day by subcutaneous injection.

Although there are less published data on this
new compound than the other blood glucose–
lowering medications, exendin-4 appears to
lower A1C levels by 0.5–1%, mainly by
lowering postprandial blood glucose levels


Exenatide is associated with weight loss of
2–3 kg over 6 months.

Recent reports have suggested a risk for
pancreatitis associated with use of GLP
agonists; however, the number of cases is
very small and causal relationship is not
clear at this time.

Several other GLP-1 agonists and
formulations are under development.

Summary

Drug/Class : Exenatide

Mode of Action : GLP-1 mimetic, simulates
insulin secretion,stimulate satiety
centre,slows gastric emptying

Side Effects : Nausea, vomiting
?pancreatitis

Limitations/Contraindications: Injectable

IX. Dipeptidyl peptidase-4 inhibitors

GLP-1 and glucose-dependent
insulinotropic peptide (GIP), are rapidly
degraded by dipeptidyl peptidase four
(DPP-4).

DPP-4 inhibitors enhance the effects of GLP-
1 and GIP, increasing glucose-mediated
insulin secretion and suppressing glucagon
secretion.


The first oral DPP-4 inhibitor, sitagliptin, was
approved by FDA in October 2006.

Another DPP-4 inhibitor, vildagliptin, was
approved in Europe in February 2008.

A third DPP-4 inhibitor, saxagliptin was
approved 2010

DPP-4 inhibitors lower A1C levels by 0.6–0.9
%


DPP-4 inhibitors are weight neutral and
relatively well tolerated.

As monotherapy they do not cause hypoglycemia.

A fixed-dose combination pill with metformin is
available.

The potential for this class of compounds to
interfere with immune function is of concern.

Summary

Drug/Class : DPP-IV inhibitors

Mode of Action :Enhancement of incretins,
by inhibiting breakdown of GLP-1 and GIP

Side Effects : Hypoglycaemia in combination
with SU, Skin rashes

 The kidney filters 160 g. glucose daily
 90% reabsorbed by sodium-glucose
cotransporter 2 (SGLT2) and 10% by
SGLT1 in renal tubules.
 Interestingly, in diabetes the maximal
renal tubular reabsorptive capacity is
increased.
Sodium-glucose cotransporter 2
inhibitors


Inhibition of the reabsorption of glucose at
the level of the kidney is a completely new
approach

Avoids the concerning aspects of beta-cell
function and its insulin release.

Besides the efficacy data, this treatment
possibility may additionally offer benefits in
terms of modest weight loss as well as
beneficial changes in blood pressure.
SGLT2 Inhibitors


List et al. studied 389 treatment-naïve type 2
diabetic patients with baseline A1C (7.7–8% ) for
12 weeks.

Patients were given:
- 2.5–50 daily mg of SGLT2 inhibitor dapagliflozin
- 1,500 mg metformin daily
- or placebo


They found dose related 52– 85 g/day
glycosuria with dapagliflozin.

There was no change in serum sodium,
potassium, or creatinine or in serum or
urinary calcium.

Magnesium increased 0.1– 0.2 mEq/l, urate
decreased 1 mg/dl, and serum phosphate
increased 0.2 mg/dl at the highest doses.


HbA1c decreased by:
- 0.7–0.9% with dapagliflozin
- 0.7% with metformin
- 0.2% with placebo

Weight losses in the 3 groups were:
- 2.7–3.4% with dapagliflozin
- 1.7 % with metformin
- 1.2% with placebo


Adverse events with dapagliflozin included:
- urinary tract infection
- nausea
- dizziness
- headache
- fatigue
- back pain
- nasopharyngitis.


Although dapagliflozin* and canagliflozin*
are still under clinical investigation, their
efficacy and safety can be confirmed.

Long-term observation and follow-up are
mandatory to conclude that this new
strategy with a novel mechanism of action is
safe in the long run.

Diabetes revised march 2013

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Diabetes revised march 2013

Similar to Diabetes revised march 2013 (20)

More from Muhammad Eimaduddin

More from Muhammad Eimaduddin (20)

Recently uploaded

Recently uploaded (20)

Diabetes revised march 2013

Editor's Notes