Transcript CURRENT CHALLENGES IN DIABETES THERAPY

DR. N.S. NEKI
PROFESSOR OF MEDICINE
GOVT. MEDICAL COLLEGE, AMRITSAR (INDIA)
Diabetes mellitus is a chronic metabolic disorder with adverse
effects on all organs of body
Type 1
Type 2
Age
Type I At any age but usually Type 2 At any age but usually
before 30 years
after 30 years
Body constitution
Mostly lean
Pathogenesis
Autoimmune distruction of beta Insulin resistance
cells
Insulin deficiency
Asolute insulin deficiency
Lifelong
required
90% overweight
exogenous
Relative insulin deficiency
insulin Endogenous insulin levels below
normal or high
More prone to develop DKA
Greater “glucose variability
Less prone to DKA
PREVALENCE OF T1 DM In US
•About 1 million individuals.
•Overall prevalence of diabetes has been
increasing steadily.
•Lifetime prevalence of type1 diabetes
•United states 0.4%
•High incidence in countries such as Finland &
Sweden 1%.
•Lowest incidence in Japan.
•Incidence of type1 DM is increasing.
• An average of 3.4% increase per year
•No difference in trend between boys and girls
•No known explanation for this increasing
incidence
Treatment Goals: Juveniles
Plasma blood glucose and Hb A1c goals by group.
Plasma blood glucose goal range (
mg/dl)
Before meals
Bed
time/overnight
HbA1c
Rational
Toddlers
and 100-180
preschoolers <6 yrs
110-200
<8.5% (>7.5%)
High risk and prone
to hypoglycemia
School age 6-12 yrs
100-180
<8%
Risk
of
hypoglycemia and
relatively low risk of
complication before
puberty
90-150
<7.5%
Risk
hypoglycemia
developmental
psychological
issues.
90-180
Adolescents
and 90-130
young adults 13-19
yrs
of
and
Treatment Goals :
Definition
HbA1c
ADA guidelines
1.
Measures the amount <7%
of glycosylated Hb in
patients blood
2.
Estimates how well
diabetes is managed
over time.
3.
Tested
months
every
Adults
AACE guide lines
<6.5%
3-6
Pre-prandial glucose
Blood glucose level taken 70-130 mg/dl
before a meal
<110 mg/dl
Post-prandial glucose
Blood glucose level taken <180mg/dl
1-2 has after a meal
<140 mg/dl
Blood Pressure
<130/80
<130/80
Major challenge in type 1 DM is the patient is on
insulin therapy for lifelong
I.
1.
-
Barriers in achieving glycemic targets:
Hypoglycemia. Risk of hypoglycemia is a significant barrier in achieving
aggressive blood glucose targets in T1DM. Education of patient to recognize the
signs of hypoglycemia and its treatment.
Parents must be made familiar with the signs and symptom of hypoglycemia and its
treatment.
Positive reinforcement for cooperation with regimen.
Reassure the child that diabetes is no one’s fault.
Making diabetes regimen flexible to allow for participations in school/peer
activities.
Allowing patient to live normal life.
Managing increased insulin requirement during puberty.
Monitoring for signs of depression, eating disorders and risky behaviours.
Select once or twice daily regimen.
-Self monitoring of blood glucose levels
Intensified regimens result in 3-4 times higher incidence of causing hypoglycemia.
2.
Weight gain
3.
Genetic susceptibility
4.
Environmental factors.
5.
Appearance of islet autoantibodies
II.
ISLET CELL TRANSPLANTATION
•Following the introduction of Edmonton transplant protocol in 1999, developed at the university
of Alberta in Canada, major islet transplant centre have developed and refined new procedures.
•There are sufficient data to conclude that there is a high rate of technical success for islet cell
transplantation.
•Recent clinical trials have shown that 50% - 90% of patients are free from insulin after 1 year.
•Side effects (from long term immunosuppression with cyclosporine) include mouth ulcers,
diarrhoea, neutropenia.
But there are limitations
•Need for chronic immunosupression will limit transplantation to only the most brittle patient.
•Organ availability will limit the number of procedures performed.
•Each transplant requires at least 2 pancreas.
III.
TREATMENT ALGORITHM FOR PATIENTS WITH T2 DM ADA/EASD
CONSENSUS
Ideal drug for T2DM (oral or otherwise) should have the following properties.
It should reduce blood sugar levels by facilitating insulin secretion from the failing beta
cells.
It should facilitate insulin action by reducing insulin resistance.
It should suppress uncontrolled hepatic glucose output.
Avoid hypoglycemia, which is a consequence of fight glycemic control.
It should be weight neutral or facilitate weight loss.
It should preserve beta cell and if possible generate beta cells.
Well-Validated core therapies
Life
style+metformin+basal
insulin
At diagnosis life
style +metformin
Life style +metformin+
instensive insulin
`
Life style +
sulfonylurea
Step 1
Step2
metformin
+
Step3
Less well-validated therapies
Life
style+metformin
+pioglitazone
At Diagnosis
life style
+
metformin
Life Style + Metformin +
GLP 1 Agonist
 No hypoglycemia
 Weight loss

Step1
Life
style+metformin
+
pioglitazone+sulf
onylurea
Life
style+metformin
+ Basal insulin
Nausea/vomiting
Step2
Step3
Life style
+metform
in+
intensive
insulin
Life style management LSM
•People with T2DM often have life styles (eating and physical
activity) which lead to disease.
•Evidence supports the effectiveness of nutrition therapy and
exercise in the prevention and management of T2DM
•Studies of medical nutrition therapy reported HbA1c decrease
by 0.25-2.9. Intervention included reduced CHO intake and
healthy food choices.
•Metaanylisis of exercise reported an HbA1c reduction of 066%, independent of changes in body weight, in T2DM as well
as improvement in insulin sensitivity.
•As the gain from LSM, in term of glucose control is more and
less expensive than any individual therapy, so LSM is greatly
promoted.
•But sometimes LSM is difficult to maintain.
Therapeutic Agents for T2DM
Drug class
1.
Sulfonylureas
Mechanism of action
Stimulate cell in pancreas to release more insulin
2.
Meglitindes
Stimulate cell in pancreas to release more insulin
3.
Biguanides
4.
Thiazolidinediones
Decrease the amount of glucose production by
liver.
Make muscle tissue more sensitive to insulin, so
glucose can be absorbed
↑ insulin sensitivity by increasing the efficiency of
glucose transporters
Prevent breakdown of GLP-1, which reduces blood
glucose levels in the body
Lower blood glucose levels by blocking breakdown
of starches and sugars in the intestine
5.
DPP-4 inhibitors (dipeptidyl peptidase4)
6.
Glycosidase inhibitors
7.
GLP-receptor agonists (glucagen like peptide) Increase glucose dependent insulin secretion from
the pancreas.
 Slow gastric emptying
 Reduce post prandial glucagen secretion
 Reduce food intake
Insulin
Compensates for inadequate endogenous insulin
production
Exenatide (Exendin-4) is a GLP-1 recptor agonist.
• Synthetic version of salivary protein found in the gila monster.
• About 50% identity with human GLP-1
• Binds to known GLP-1 receptors on cells in vitro.
• Resistant to DPP-4 inactivation.
• Exenatide remains in the circulation longer than GLP-1
• Reduce fasting hypoglycemia in T2DM.
• Reduces post prandial hyperglycemia in T2DM
• Reduces the beta cell workload and post prandial glucagon secretion in
T2DM.
• Exenatide infusion actutely restores first phase insulin response in
T2DM.
• Reduces body weight and food intake.
Side effect of exenatide: usually well tolerated. It causes antibody
production, nausea (34%), vomiting (24%).
But it is given subcutaneously twice daily as compared to Liraglutide
(given once daily). Fasting glucose reduction is more with liraglutide
than exenatide.
DPP-4 Inhibitor
Sitagliptin – used as monotherapy.
1.
2.
3.
4.
It improves insulin secretion after OGTT.
Prevents degradation of active GLP-1.
Decreases glucagon level after OGTT.
Reduces fasting, postprandial hyperglycemia
Vildagliptin is weight neutral reduces HbA1c.
Side effects
• As add on therapy with glimepride, metformin, insulin, it causes
hypoglycemia.
• As add an therapy with sitagleptin, pioglitazone, metformin,
glimepride/metformin – sitagliphtin it causes URC, Headache.
• A DPP-4 inhibitor (vildagliptin) does not have affect on gastric
emptying.
• Videgliptin as monotherapy can cause commonly dizziness.
But headache, constipation, arthralgia, hypoglycemia, URC are rare
• Sitagliptin causes nausea in 12% and vomiting in 3%, usually well
tolerated
Adverse events: DPP-4 inhibitors vildegliptin as add in therapy
Adverse events
Vildagliptin+met Vildagliptin _ Vildagliptin
formin
sulphonylurea TZD
Tremor
Common
Common
Headache
Common
Common
Dizziness
Common
Common
Fatigue
Uncommon
Nausea
Common
Hypoglycemia
Common
Common
Nasophrengitis
Very rare
Constipation
Uncommon
Asthemia
Common
Uncommon
Uncommon
Uncommon
Weight gain
Common
Oedema peripheral
Common
+
Psychological issues are involved in therapy
•Adults with depression have 37% increased risk of T2DM.
•Depression and distress missed by physicians in 30 - 70% of cases.
•Severity of symptoms and cognitive symptoms are underestimated.
•Increased costs.
•Anxiety disorders are prevalent in diabetics than the community at large.
•Always have fear of hypoglycemia
a) Diabetes specific fear.
b) Intense worrying about/fear of (being at risk for) low blood glucose level
usually
accompanied by excessive self monitoring of blood glucose and
corrective behaviours.
c) Continuous from mild to extreme (phobia)
d) Higher risk in cases of hypoglycemia unawareness.
e) Often comorbid anxiety and psychiatric disorders are present.
f) Avoidance behaviours – active and passive with subsequent poor diabetes
control.
g) Also present in parents and spouses of patients
-Can be higher in parents with patients.
-Affected by recent severe hypoglycemia episodes.
Why does hypoglycemia cause anxiety
•Unpleasant symptom/disruptive
•Loss of control.
•Cause accident, harm others.
•Brain damage, death.
•Social embarrassment.
•Negative effect on relationships, burden to others.
•Negative effect on work performance, carrier
Fear of hypoglycemia risk factors and assessment
Risk factors for hypoglycemia
•Impaired hypoglycemia awareness i.e. reduced bodily signs such as
shaking and sweating or not reacting to low blood glucose readings.
•High trait anxiety/phobia.
•Having witnessed one or more episodes of severe hypoglycemia in other
patient, partner or child.
Assessment
•Observation
•Increasing HbA1c levels (following one or more hypoglycemic
episodes).
•Report from patients and or significant others.
•Questionnaire Problem Areas in diabetes scale and Hypoglycemia Fear
Survey.
Patient adherence – general findings
•Adherence to life style recommendation is usually poor.
•Medication adherence drops with longer duration of treatment.
•Adherence is highest in HIV, arthritis and cancer.
•Adherence is lowest in diabetes, pulmonary disease and sleep disorder.
•Oral hypoglycemic agent adherence rates are 36-93%
•Higher adherence with once daily v/s multiple tablets.
•Suboptimal adherence in polypharmacy may be related to one
medication instead of whole regimen.
•Insulin adherence is 63-71%.
Lifelong management stressors in diabetes
•Continuing need to self manage: always and everywhere.
•Self-care tasks are unpleasant.
•Future goals (secondary prevention), but immediate frustrations.
•Blood glucose fluctuation disrupt psychobehavioral functioning (fear of
hypoglycemia).
•Good behavior” does not always pay of (effort-reward imbalance).
•Minimal good news in diabetes: progressive disease and serious risk of developing
complications.
•Social reactions (lack of understanding, discrimination, over/underinvolvement.
Self Management Education: More than proving information.
•Promotes understanding of diabetes and health risks.
•Promotes intrinsic motivation to self manage/ engage in diabetes.
•Promotes behavioural strategies.
•Positively impacts metabolic outcomes.
•Psychological support options for self management education.
•Support groups.
•Stress Management training.
•Coping skills training.
•Psychotherapy/cognitive behavioural therapy. It will have significant effect on HbA1c
control in T2DM and T1 DM patients.
VII Glycosylated Hb
:
Extensive evidence support the benefits of treating to HbA1c goal both in terms of health and
economic outcomes.
•In UKPDS & DCCT trial, the risk of patient with T2DM developing vascular complications is
strongly correlated with HbA1c levels and the duration of poor glycemic control .Good glycemic
control significantly reduces the risk of complication.
HbA1c – how low do we go?
It is an important challenge.
Regarding this ACCORD (Action to Control Cardiovascular Risk in diabetes) trial and
Advance trials were conducted in USA and Canada.
ACCORD Trial
•10251 T2DM patients from USA and Canada enrolled.
•Subjects randomized to intensive glucose control with a target of HbA1c<6% of and
standard glucose control with a target of HbA1c 7-7.9%.
•All subjects provided with diabetes education glucose monitoring equipment and
diabetes medication.
•Doses of medication increased every month if HbA1c levels exceed 6% or if more than
50% of the pre-post meal blood glucose values were >100mg or >140 mg/dl
respectively.
•After a median 3.2 year followup, a 1.1% difference in mean HbA1c was observed
between groups.
•After a median 3.2 year followup, a 1.1% difference in mean HbA1c was observed between
groups.
•This trial was stopped prematurely because subjects from intensified glucose lowering arm
(n=5128) had 22% of higher relative risk for death compared with patients assigned to the
standard glucose control arm.
ADVANCE Study:
•11140 T2DM patients with high cardiovascular risk factors Europe, Asia and North
America included.
•Subjects randomized to intensive glucose control with a target of HbA1c <6.5%.
•All subjects provided with diabetes medication gliclazide MR.
•After a 5 year followup, a 0.67% difference in mean HbA1c was obtained between
groups (6.5% versus 7.3%; p<0.001) with no change in body weight.
•The trial showed significant reduction in overall risk of serious diabetes complications
by 10%, with 21% reduction in kidney disease and 30% reduction in the development
of proteinurea.
•This trial achieved a positive trend towards reduction in the risk of cardiovascular
death (12%), although this did not achieve statistical significance.
Difference between two trials
•HbA1c goal for intensive group was <6% in ACCORD Trial and <6.5% in ADVANCE
study.
•Glycaemic control was achieved more rapidly in ACCORD as compared with
ADVANCE study.
•Use of insulin was significantly higher in ACCORD – 77% and 55% in the intensive
and standard arms respectively as compared to 41% and 24% of intensive and standard
arms of ADVANCE.
•Rosiglitazone was used in 92% and 58% in the intensive and standard arms
respectively of the ACCORD Trial as compared with 17% and 11% of the comparable
arms of ADVANCE.
•Gliclazide MR prescribed in all patients in ADVANCE trial while no patients in
Accord Trial received it.
•Use of Aspirin and Statin was more in ACCORD than ADVNACE study.
•Hypoglycemia requiring assistance reported was more in ACCORD trial as compared
to ADVACE trial.
•Weight gain reported more in ACCORD trial (3.5kg) while no weight gain in
ADVANCE trial.
*ADA & EASD have set targets for glycemic control of HbA1c <7% while
AACE and ACE <6.5%.
VIII.
Replacing amylin with pramlintide as an adjunctive therapy to insulin
reveals potencyequal to that of human amylin, subcutaneous injection of
premlintide before meals in addition to insulin therapy significantly
reduced post prandial glucose excursion and lowered HbA1c levels in
patients with type 1 and type 2 diabetes mellitus. There was significant
reduction in body weight, no severe hypoglycemia without increases in
total daily insulin use.
Amylin is second beta cell hormone, consecreted with insulin in
response to meals and is deficient in T1DM and insulin requiring T2DM,
Pramlintide is soluble nonaggregating synthetic peptide analog of human
amylin.
SUMMARY
Current Challenges in diabetes management include:
•Optimizing the use of currently available therapies to ensure adequate
glycemic, blood pressure and lipid control and to reduce complicates.
•Educating patients on diabetes self management
•Improving patients adherence to life style and pharmacological
interventions.
•Reducing barriers to the early use of insulin.
•Improving the delivery of health care to people with chronic
complications.
•The ultimate aim of diabetes therapy is to prevent diabetes
complications macrovascular and such as nephropaty, retropathy and
microvascular in order to improve quality of life and life expectancy.
•Order people are more prone to develop severe hypoglycemia as well as
renal impairment and elderly people also take multiple pharmacological
treatments, so it is difficult for them to adhere to all of their prescribed
medications.
REFERENCES:
1.
2.
3.
4.
American Association of Clinical
Endocrinologists Endo Prac 2007: 20th Edition
805-847.
Nothan D et al Diabetes care 2006; 29: 1963-72.
ADA diabetes care 2009; 513-561.
JAMA 2001, 280: 1218-27.