Download Treatment with leptin

•Pharmacologic
therapy of
DM
‫‪Management‬‬
‫‪no‬‬
‫‪Treatment‬‬
‫ای بسا تدبیر باید تا زقند‬
‫کرد شیرین کام تلخ درد مند‬
Macrovascular disease & majority of
the morbidity and mortality of DM
• is associated with more stringent guidelines for the
treatment of comorbidities such as
dyslipidemia
hypertension
make the fasting glucose cut points more
and
, it seems likely that the
diagnostic criteria for diabetes will be lowered again to
sensitive.
•
Medical Care for Patients with D M
Glycemic control
• It is clear that
glucose
levels above normal but
below the current thresholds for
diabetes (prediabetes) are
associated with increased
cardiovascular risk.
New Drugs
(Increatins memetic drugs)
Biguanides
•Metformin
• is representative of this class of agents.
• It reduces :
• hepatic glucose production through an
undefined mechanism and
• improves peripheral glucose utilization
slightly.
Metformin
• reduces fasting plasma glucose
• reduces insulin levels,
• improves the lipid profile,
• promotes modest weight loss
Metformin
•The initial starting dose of
500 mg once or twice a day
can be increased to 1000
mg bid.
Metformin
•
may have fewer gastrointestinal
side effects :
•
•
•
•
diarrhea,
anorexia,
nausea,
metallic taste
Metformin
•should be discontinued in
patients who are:
• seriously ill,
• can take nothing orally,
• receiving radiographic contrast
material
Metformin
• should not be used in patients with:
• renal insufficiency [serum creatinine > 1.5
mg/dL in men or > 1.4 mg/dL in women,
• any form of acidosis,
•
CHF,
•
liver disease,
• severe hypoxia.
Insulin Secretagogues
stimulate insulin secretion by
interacting with the ATP-
sensitive potassium
channel on the beta cell .
Insulin Secretagogues
• are most effective in
individuals with type 2 DM
of relatively recent onset
(<5 years).
Sulfonylureas
• reduce both fasting and
postprandial glucose and should
be initiated at low doses and
increased at 1- to 2-week
intervals based on SMBG.
Sulfonylureas
• Most sulfonylureas are metabolized in the liver to
compounds (some of which are active) that are
cleared by the kidney.
• Thus, their use in individuals with significant
hepatic or renal dysfunction is not advisable.
• Weight gain, a common side effect of sulfonylurea
therapy, results from the increased insulin levels
and improvement in glycemic control.
Properties of Insulin Secretagogues
Sulfonylureas
• Gliclazide 80 mg 40 to 320 mg daily in two divided
doses,
• - 30 mg and 60 mg modified release
formulation
• may be given at a dose of 30 to 120 mg once daily
at breakfast.
Sulfonylureas
• Glyburide (Glibenclamide) 5mg
Doses of 1.25, 2.5, and 5 mg,
This drug is a major cause of drug induced hypoglycemia.
The risk is increased against other sulfonylureas.
Cholestatic jaundice is noted.
Glibenclamide may be contraindicated in those with G6PD deficiency,
as it may cause acute haemolysis.
• Recently published data suggest glibenclamide is associated with
•
•
•
•
•
significantly higher annual mortality when combined with
metformin than other insulin-secreting medications, after
correcting for other potentially confounding patient characteristics.
• The safety of this combination has been questioned
Sulfonylureas
• Glimepiride(Amaryl) 1, 2 ,4 mg
• Side effects from taking glimepiride
include gastrointestinal tract (GI) disturbances,
occasional allergic reactions, and rarely blood
production disorders including thrombocytopenia,
leukopenia, and hemolytic anemia. In the initial weeks
of treatment, the risk of hypoglycemia may be
increased. Alcohol consumption and exposure to
sunlight should be restricted because they can worsen
side effects
Thiazolidinediones
 promote a redistribution of fat from central to
peripheral locations.
 Circulating insulin levels decrease with use of the
thiazolidinediones, indicating a reduction in insulin
resistance.

pioglitazone is 15–45 mg/d in
a single daily dose, and for
rosiglitazone the total daily
dose is 2–8 mg/d administered either
once daily or twice daily in divided doses.
Thiazolidinediones
• The FDA has issued an alert that:
• rare patients taking these agents may
experience a worsening of diabetic
macular edema.
• An increased risk of fractures has
been noted in women taking
these agents.
alfa- Glucosidase Inhibitors
• Acarbose
• Miglitol
• reduce postprandial hyperglycemia by
delaying glucose absorption; they do not
affect glucose utilization or insulin secretion
Increatins memetic drugs
Increatins memetic drugs
• Liraglutide
• is a once-daily GLP-1 derivative for the treatment of type 2
diabetes.
• It reduces meal-related hyperglycemia (for 24
hours after administration) stimulate insulin secretion
• it shows negligible risk of hypoglycemia.
• It has the potential for inhibiting apoptosis
• stimulating regeneration of beta cells .
• It decreases appetite and maintains body weight,
• It lowers blood triglyceride levels.
nce-weekly exenatide
• okayed by FDA for type 2 diabetes
• lowered hemoglobin A1c by 1.6 percentage
points from baseline.
• The most common adverse effects that emerged
in clinical trials were nausea (which usually
decreased over time), hypoglycemia, vomiting,
diarrhea, feeling jittery, dizziness, headache,
dyspepsia, constipation, and asthenia.
Sitagliptin
• Tab Januvia® 25 50 100 mg
• dipeptidyl peptidase-4 (DPP-4) inhibitor class.
• oral antidiabetic drug
less hypoglycemia,
• less weight gain
•
• often recommended to be combined with
other agents such as metformin
Insulin Preparations
• Banting and Best
First Human Patient
On Jan. 11, 1922, 14-year-old Leonard
Thompson was the first human
patient to receive insulin made by
Banting and Best.
NPH insulin
• - Neutral Protamine Hagedorn
•
- insulin treated with protamine and zinc
protamine is a basic protein that readily
complexes with insulin
zinc to yield particles that slowly dissolve in body
fluids
• onset of 1-2 hrs, peak of 6-12 hrs, duration of 1824 hrs
Insulin Preparations
Regular insulin
NPH insulin
Blood
Glucose
Protamine
zinc insulin
Hours
Lente Insulins
• suspensions of insulin in
•
•
acetate buffer at neutral pH
- physical state and crystal size influences the rate of
absorption from the site of injection
Semilente insulin
Blood
Glucose
Lente
insulin
Ultralente insulin
Hours
• Rapidly acting analogue:
Aspart (NovoRapid)
Lispro(Humalog)
Glulisine(Apidra)
• Long-acting insulin analogue :
Glargine(lantus)
Detemir(Levemir)
Short acting &Rapid acting insulin
• Short acting (regular) insulin is
given30–45 min prior to a meal.
• Rapid acting insulin analoguesshould
be injected just before (<20 min) or just
after a meal.
Aspart& Lispro
• available as a rapidly acting alternative to
Regular insulin and
• as an Biphasic insulins (rapidly acting+
intermediate-acting complex with
protamine).
Biphasic insulins (mixed insulins)
oproviding for both immediate and
prolonged action.
ocombination insulin formulations do not
allow independent adjustment of shortacting and long-acting activity.
oSeveral insulin formulations are
available as insulin "pens," which may
be more convenient for some patients.
Insulin glargine( Lantus)
• given once daily
• It consists of microcrystals that slowly release insulin, giving a long
duration of action of 18 to 26 hours,
•
peakless
• Pharmacokinetically, it resembles basal insulin secretion
of non-diabetic pancreatic beta cells.
• Sometimes, in type 2 diabetes and in combination with a short
acting sulfonylurea (drugs which stimulate the pancreas to make
more insulin), it can offer moderate control of serum glucose
levels.
• In type 1 diabetes, depleted type 2 (in some cases) insulin
glargine needs the support of fast acting insulin taken with
food to reduce the effect of prandially derived glucose.
Insulin regimens
Multiple injection regimens,
• 1)Combination of Rapid-Acting Insulin Given
with Meals and Long-Acting Insulin at Bedtime
(Basal plus approach )
• 2)Combination of Rapid-Acting and
Intermediate-Acting Insulin with Breakfast and
Dinner Intermediate-Acting Insulin at Bedtime.
(basal-bolus approach )
a continuous subcutaneous infusion of
insulin (CSII) via an insulin pump
Basal plus approach
• Addition of basal insulin (glargine, detemir, or NPH/neutral
protamine lispro insulin) to previous treatment is accepted as the
simplest way to start insulin therapy in those
patients. But even when basal insulin is adequately titrated, some
patients will also need prandial insulin to
achieve or maintain individual glycemic targets over time.
• In reducing hyperglycemia, this modality still
remains the most effective option, even in
people with type 2 diabetes.
•
.
Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S75-83. doi: 10.1089/dia.2011.0001
Basal-bolus approach
• Starting with premixed insulin is an
effective option, but it is frequently
associated with increased
hypoglycemia risk, fixed meal
schedules, and weight gain.
• Diabetes Technol Ther. 2011 Jun;13 Suppl 1:S7583. doi: 10.1089/dia.2011.0001
Continuous subcutaneous insulin
infusion) (CSII)
(external pump )
Open-loop systems comprise an infusion pump with
the infusion rate programmed or controlled
manually according to manual blood-glucose
monitoring.
 Closed-loop systems (the 'artificial pancreas')
consist of an insulin pump, a glucose sensor, and a
computer for analysis of blood-glucose data.
Stability and storage
Preparations of Insulin
• should not be subjected to storage conditions that
lead to freezing.
• preparations in a refrigerator at 2 degrees to 8
degrees.
• protected from excessive heat ,light, and sunlight.
• most insulin preparations consider that storage by
the patient at a temperature of up to 25 degrees
would be acceptable for up to one month.
Glycemic management of type 2 diabetes
Strategy
• 1)Reduce hypoglycemia
• 2)minimize weight gain
• 3)Minimal Insulin Resistance
• 4)Minimal Effort
• 5)Postprandial Targeting Strateg
1)Reduce hypoglycemia.
AGIs and glitazones
• The
have
been reported in small studies to reduce
reactive hypoglycemia.
Theoretically, exenatide and
metformin should not be
associated with hypoglycemia.
2) strategy to minimize weight gain
would emphasize
• Diet and exercise and would
almost certainly employ
metformin as initial therapy.
• Exenatide is associated with substantial
weight loss in most patients with longterm use .
3)Minimal Insulin Resistance Strategy
• The possible atherogenic effects of insulin
have been widely touted in the lay press and
by marketing programs within the
pharmaceutical industry.
The relationship between circulating insulin
levels and cardiovascular risk in nondiabetic
populations is incontrovertible but probably
related to the presence of insulin
resistance rather than the insulin
concentrations per se.
3)Minimal Insulin Resistance Strategy
• There are no clinical data to suggest that
exogenous insulin is associated with adverse
side effects or long-term complications
• beyond its hypoglycemic
associated weight
gain
effects and the
3)Minimal Insulin Resistance Strategy
• The thiazolidinediones have the greatest efficacy in reducing
insulin resistance,
• metformin is second,
•
and AGIs are third.
•
Exenatide has been demonstrated in animal models to produce
modest improvement in insulin sensitivity and would be assumed to
reduce insulin resistance in parallel with weight;
• however, exenatide does increase postprandial insulin levels
.
• Nateglinide is associated with more specific stimulation
of insulin levels after meals than the other insulin
secretagogues, which all increase peripheral insulin levels less than
injected insulin.
4)Minimal Effort Strategy
• Taking a once-a-day
• sulfonylurea or thiazolidinedione
requires the least effort by the patient.
• At least one combination tablet taking
advantage of this concept is available:
• rosiglitazone 4 mg in combination with
either 1 or 2 mg of glimepiride.
4)Minimal Effort Strategy
• Taking
bedtime insulin is
actually relatively well accepted by
patients to whom this consideration
is important.
• Developing strategies to improve adherence
and increase motivation is certainly a longterm goal in this population
5)Postprandial Targeting Strategy
• On the basis of epidemiologic studies, it has been
suggested that :
• PPG is more highly correlated with
cardiovascular disease risk than fasting
glucose levels.
• Furthermore, there are no outcome studies
that have demonstrated the superiority of
these approaches in patients with T2DM
5)Postprandial Targeting Strategy
• Nonpharmacologic techniques that can
improve postprandial control include :
• lowering the carbohydrate content
of meals,
• adding fiber,
• substituting monounsaturated fats for
carbohydrates,
• and encouraging physical activity after meals
5)Postprandial Targeting Strategy
• The pharmacologic approach
includes :
• AGIs,
• exenatide, Liraglutide
• rapid-acting insulin analogues.
• Nateglinide and repaglinide