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Презентация на тему Diabetes Anterior hypophysis Diabetes insipidus

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DiabetesDefinition ,classification, type 1 and 2, acute and chronic complications , treatment
Diabetes  Anterior hypophysis Diabetes insipidus Dr. Michael Leonid,MDSpecialist in internal medicine and endocrinology11/2017 DiabetesDefinition ,classification, type 1 and 2, acute and chronic complications , treatment Diabetes definitionDiabetes is a heterogeneous, complex metabolic disorder characterized by elevated blood Classification of disorders of glycemia Type 1- beta-cell destruction, usually leading to Criteria for diabetes diagnosis according to ADA 2016*In absence of unequivocal Factors affecting HbA1C Diabetes type 1Usually caused by autoimmune heterogenic destruction of beta-cells.The prevailing immune Diabetes type 1Roughly 5-15% of all cases of diabetes.Two peaks:5-7 year and Risk of Type195% of persons who develop Type1DR-3-DQ2DR4-DR8 Autoantibodies (90% at the diagnosis of type 1)Anti GAD(Glutamic Acid Decarboxilase) 65 Diabetes type290 % of all diabetes in the world9.3% of USA population Pathogenesis of type 2 Genetic defects of insulin secretion2-5% of all cases of diabetes mellitusHeterogeneous High index of suspicion of MODYA family history of diabetes in one Beta- cell: insulin secretion Monogenic defects in insulin secretion MODY 3(HNF1α mutation)Most prevalent MODY:50-70 % of all mutations.Onset before age of MODY 2Mild hyperglycemia started at birth.The glucokinase enzyme catalyzes the rate limiting Diagnostic approach to monogenic diabetes Genetic defects in insulin actionRabson Mendenhall :short stature,protuberant abdomen ,teethand nail abnormalitiesLeprehuanism: Disorder of exocrine pancreasChronic pancreatitis: more than 20 years of disease -80-90% EndocrinopathiesCushing disease and syndrome-glucose intolerance and overt diabetes (30 %).Acromegaly –direct anti- examples))Drug and chemicalsEthanol – chronic pancreatitis-overt diabetes(1% of all diabetes in USA)Glucocorticoids: InfectionsPredisposition to type 1- enteroviruses.Direct beta- cells destruction-mumps ,coxsackieviruses B, adenoviruses .Congenital Uncommon immune form of diabetes High titers of antibodies to insulin receptors Pregnancy in women with normal glucose metabolism   Fasting Gestational diabetes mellitus(GDM)Disbalance between insulin secretion and increased insulin resistance especially in Screening for GDM Algorithm of glucose testing in pregnancyAll women have to be screened for Goals of diabetes treatmentPrevent macrovasular diabetes complication-cardiovascular disease (IHD, diabetic cardiomyopathy, TIA, Aspects of diabetes treatmentGlycemic control Lifestyle intervention include obesity treatment Medical nutritional Glycemic control and diabetic complicationType 1 study:  DCCT –EDIC(Diabetes Control and DCCT  N = 1441 T1DM  Intensive (≥ 3 injections/day or Inclusion criteria for DCCT Primary prevention group : DM type 1: 1-5 Baseline characteristics Goals and modes of therapy conventional group Conventional group therapy goals: to Goals and modes of treatment  intensive treatment group 3 or more Study questions Prevention of diabetic retinopathy in primary prevention group by intensive Reduction in RetinopathyThe Diabetes Control and Complications Trial Research Group. N Engl Solid line = risk of developing microalbuminuriaDashed line = risk of developing Reduction in NeuropathyThe Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986. DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653.Reduction of cardiovascular event Hypoglycemia and other adverse events General and severe hypoglycemia 3 times higher GLYCEMIC CONTROL IN TYPE 2  UKPDS20-year interventional trial from 1977 UKPDS: AimsTo determine whether improved glucose control of Type 2 diabetes will UKPDS patient characteristics5102 newly diagnosed Type 2 diabetic patientsage 25 - 65 Treatment Policies in 3867 patientsConventional Policy n = 1138initially with diet alone	aim UKPDS Study Group. Lancet 1998; 352:837–853. UKPDS: intensive control reduces complications in type 2 diabetes UKPDS Any diabetes related endpoints UKPDS- metformin Main Randomisation 4209Overweight 1704Non overweight 2505Conventional Policy 411Intensive Policy 1293Metformin Metformin in overweight patients in comparison with conventional treatment 32% risk reduction ACCORD trial 10251 patients with diabetes with HbA1c 7.6-8.9 randomly assigned to Treatment group (ACCORD study (glycemic arm Gerstein HC et al. The ACCORD Study Group. N Engl J Med. ACCORD study  glycemic group ADVANCE collaborative group Results of intensive glucose lowering in ADVANCE trialAverage lowering of HbA1c from VA Diabetes Trial (VADT)Similar study design: intensive therapy versus standard therapy.Primary endpoint: Differences in ACCORD/ADVANCE/VADTSkyler JS, Bergenstal R, Bonow RO, et al. Diabetes Care. 2009;32:187-192. Change in HbA1c during the trial Initial resultsNo excess of cardiovascular mortality.No improvement of cardiovascular morbidity.No change in 10 years follow up of VADT cohort: glycemic control Cardiovascular outcomes after 10 years Glycemic targets in diabetes: general consideration (ADA 2016) Individualized treatment  ADA 2016 Glycemic targets for treatment of pregnant women with type 1 and 2 Glycemic targets for treatment of pregnant women with type 1 and 2 Type 1 insulin treatment  Concept of basal - bolusPrescription of short Serum Insulin LevelTimeguidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association Insulin analogues Treatment scheme :Principles of type 2 treatment (1)non –pharmacologic therapyPhysical activity. 1.1Minimum 150 minutes :Principles of type 2 treatment (2)non –pharmacologic therapyDiet and carbohydrates500-750 kcal/d deficit:1200-1500 :Principles of type 2 treatment (3)non –pharmacologic therapyDiet and proteins0.8 g/kg daily Pharmacological treatment of glycemia type 2:drug classificationBiguanidesSecretagoguesDPP4 inhibitorsα- glycosidase inhibitorThiazolidinedioneGLP1 agonistsSGLT2 inhibitorsInsulin BiguanidesMetfomin(Glucomin,Glucophage)Preferred initial pharmacologic agent because of long standing record of efficacy and MetforminHalf-life up to 3 hour.No metabolism ,excreted by kidney as active compound.May Metformin toxicity and side effectsGastrointestinal (20-30%): start with lower dose with or SecretagoguesSulfonylureas: bind to SUR1 site of inward rectified KATP channel on 2-nd generation sulfonylureasAdverse effect : hypoglycemia ,weight gainSecondary failure : sulfonylureas require GlinidesBinding to distinct (from sulfonylurea) SUR 1 site Burst phase-1 insulin secretion DPP-IV: ACTIONCleaves GLP-1Results in decreased signal to the pancreas—limiting insulin response.That in The Role of GLP-1DPP-4 Inhibitors Increase ½ Life of GLP-1 DPP4 inhibitorsJanuviaTrajentaOnglysaGalvusName GLP1  agonists(injectable agents)Breakthrough in DM 2 treatmentGlycemic ,cardiovascular (LEADER study)benefit , α- glucosidase inhibitorsAcarbose (Prandase ) max 100 mg *3/dMay have cardiovascular benefits Thiazolidinediones Gamma- PPAR agonists.Increase of insulin sensitivity in adipose tissue skeletal muscle SGLT2 inhibitors SGLT2 inhibitors medicationsEmpafliglozin (Jardiance)10 mg ,25 mg Dapafliglozin(Forxiga) 10 mgPositive effects Algorithm ADA of glycemic treatment 2016 Comprehensive care of diabetes(ADA 2016) Stop smoking.Treat blood pressure to targets :less Statin treatment and diabetes Patients 40-75 without additional atherosclerotic cardiovascular disease(ACVD) risk Other recommendationAspirin in 75-162 mg for secondary prevention.Primary prevention only for
Слайды презентации

Слайд 2 Diabetes
Definition ,classification, type 1 and 2, acute and

DiabetesDefinition ,classification, type 1 and 2, acute and chronic complications , treatment

chronic complications , treatment


Слайд 3 Diabetes definition
Diabetes is a heterogeneous, complex metabolic disorder

Diabetes definitionDiabetes is a heterogeneous, complex metabolic disorder characterized by elevated

characterized by elevated blood glucose concentration secondary to either

resistance to the action of insulin, insufficient insulin secretion, or both.

Слайд 4 Classification of disorders of glycemia
Type 1- beta-cell

Classification of disorders of glycemia Type 1- beta-cell destruction, usually leading

destruction, usually leading to absolute insulin deficiency
1. Autoimmune
2.

Idiopathic
Type 2 – progressive loss of insulin secretion on background of insulin resistance
Other specific types:
Genetic defects of beta-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
Gestational diabetes


Слайд 5 Criteria for diabetes diagnosis according to ADA 2016
*In

Criteria for diabetes diagnosis according to ADA 2016*In absence of

absence of unequivocal hyperglycemia, result to be confirmed by

repeat testing FPG=fasting plasma glucose; OGTT=oral glucose tolerance test; PG=plasma glucose

American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S1-S106.


Слайд 6 Factors affecting HbA1C

Factors affecting HbA1C

Слайд 7 Diabetes type 1
Usually caused by autoimmune heterogenic destruction

Diabetes type 1Usually caused by autoimmune heterogenic destruction of beta-cells.The prevailing

of beta-cells.
The prevailing immune process that destructs beta-cells is

cellular , mostly T-cell mediated.
Pathogenic role of accompanying antibodies is less clear.

Слайд 8 Diabetes type 1
Roughly 5-15% of all cases of

Diabetes type 1Roughly 5-15% of all cases of diabetes.Two peaks:5-7 year

diabetes.
Two peaks:5-7 year and adolescence.
Yearly incidence of 15-25 cases

per 100,000 people younger than 18 years.
Finland (60 cases per 100000 people)and Sardinia has the highest prevalence rates for type 1 DM (approximately 20% of the total number of people with DM), while China and Japan have the lowest prevalence rates, with less than 1% of all people with diabetes.

Слайд 9 Risk of Type1
95% of persons who develop Type1
DR-3-DQ2
DR4-DR8

Risk of Type195% of persons who develop Type1DR-3-DQ2DR4-DR8

Слайд 10 Autoantibodies (90% at the diagnosis of type 1)
Anti

Autoantibodies (90% at the diagnosis of type 1)Anti GAD(Glutamic Acid Decarboxilase)

GAD(Glutamic Acid Decarboxilase) 65 .
Anti ICA (IA-2) 512.
Anti –Insulin.
Anti

Zn T8.
4% of normal persons express one of more of the four auto-antibodies.
Prior probability of disease greatly improved diagnostic value of antibodies .
Two or more auto-antibodies – risk of 90% for type 1 developement for 10 years.


Слайд 12 Diabetes type2
90 % of all diabetes in the

Diabetes type290 % of all diabetes in the world9.3% of USA

world
9.3% of USA population in 2014(29.1 million people),8.1 million

of them was undiagnosed(27.9%)
 11% of total health spending on adults. 
“Epidemic” of diabetes

Слайд 13 Pathogenesis of type 2

Pathogenesis of type 2

Слайд 14 Genetic defects of insulin secretion
2-5% of all

Genetic defects of insulin secretion2-5% of all cases of diabetes

cases of diabetes mellitus
Heterogeneous group of diabetes mellitus including

MODY (maturity-onset diabetes of the young), mitochondrial diabetes and neonatal diabetes
Common pathophysiological pathway in monogenic disorders is impaired insulin secretion of the pancreatic beta cell 

Слайд 15 High index of suspicion of MODY
A family history

High index of suspicion of MODYA family history of diabetes in

of diabetes in one parent and first-degree relatives, age

at diagnosis usually before 25–30 years.
Lack of islet autoantibodies (to differentiate from type 1 diabetes at a young age).
Low or no insulin requirements 2 years after diagnosis.
Absence of obesity (based on body mass index [BMI] values at diagnosis and follow-up examination).


Слайд 16 Beta- cell: insulin secretion

Beta- cell: insulin secretion

Слайд 17 Monogenic defects in insulin secretion

Monogenic defects in insulin secretion

Слайд 18 MODY 3(HNF1α mutation)
Most prevalent MODY:50-70 % of all

MODY 3(HNF1α mutation)Most prevalent MODY:50-70 % of all mutations.Onset before age

mutations.
Onset before age of 30.
Accented postprandial hyperglycemia (increases over

time due to decline of beta cell insulin secretion over time 1-4 % per year).
Same rate of complication as type 1and 2.
Very sensitive to sulfonylurea treatment , insulin in pregnancy.


Слайд 19 MODY 2
Mild hyperglycemia started at birth.
The glucokinase enzyme

MODY 2Mild hyperglycemia started at birth.The glucokinase enzyme catalyzes the rate

catalyzes the rate limiting step of glucose phosphorylation –”glucose

sensor” in the pancreas and liver.
Mild fasting hyperglycemia.
No apparent deterioration of beta-cell function.

.

Слайд 20 Diagnostic approach to monogenic diabetes

Diagnostic approach to monogenic diabetes

Слайд 21 Genetic defects in insulin action
Rabson Mendenhall :short stature,protuberant

Genetic defects in insulin actionRabson Mendenhall :short stature,protuberant abdomen ,teethand nail

abdomen ,teethand nail abnormalities
Leprehuanism: IUGR,fasting hypoglycemia ,death within the

first year of life
Mutation of insulin receptor : severe insulin resistance
Type A insulin resistance: acanthosis nigricans, hyperandrogenism, milder type of resistance than other
Lipoatrophic diabetes : severe insuline resistance , lipoatrophy ,hypertygliceridemia

Слайд 22 Disorder of exocrine pancreas
Chronic pancreatitis: more than 20

Disorder of exocrine pancreasChronic pancreatitis: more than 20 years of disease

years of disease -80-90% risk of DM.
Pancreatectomy, pancreatic cancer,

CF.
These form of diabetes are milder than typical DM type 1 because of glucagon deficiency.
Hemochromatosis.

Слайд 23 Endocrinopathies
Cushing disease and syndrome-glucose intolerance and overt diabetes

EndocrinopathiesCushing disease and syndrome-glucose intolerance and overt diabetes (30 %).Acromegaly –direct

(30 %).
Acromegaly –direct anti- insulin effect - from IGT

to overt diabetes.
Pheochromocytoma
Hyperaldosteronism.
Somastatinoma and glucagonoma.

Слайд 24 examples))Drug and chemicals
Ethanol – chronic pancreatitis-overt diabetes(1% of

examples))Drug and chemicalsEthanol – chronic pancreatitis-overt diabetes(1% of all diabetes in

all diabetes in USA)
Glucocorticoids: inhibition of insulin secretion and

insulin resistance.
Cytotoxic medication(e.g. cyclosporine)-inhibition of insulin release from beta-cell.
Protease inhibitors-insulin resistance.
Interferon- β- antibodies to beta cells.
Pentamidin – beta -cell destruction.
Vacor –rodentacid- beta- cell destruction.

Слайд 25 Infections
Predisposition to type 1- enteroviruses.
Direct beta- cells destruction-mumps

InfectionsPredisposition to type 1- enteroviruses.Direct beta- cells destruction-mumps ,coxsackieviruses B, adenoviruses

,coxsackieviruses B, adenoviruses .
Congenital rubella ? .
Abscess and phlegmone

of pancreas.

Слайд 26 Uncommon immune form of diabetes
High titers of

Uncommon immune form of diabetes High titers of antibodies to insulin

antibodies to insulin receptors - severe hyperglycemia,acanthosis nigricans
Hirata

syndrome – unusual high titers of auto-insulin antibodies- associated with hypoglycemia.
Type 1 as a part of different autoimmune syndrome(APS-1,IPEX) or “ mixed type” diabetes in POEMS myeloma.

Слайд 27 Pregnancy in women with normal glucose metabolism
Fasting levels

Pregnancy in women with normal glucose metabolism  Fasting levels

of blood glucose that are lower than in the

non-pregnant state due to insulin-
independent glucose uptake by the placenta.
Postprandial hyperglycemia and carbohydrate intolerance as a result of diabetogenic placental hormones.(hPL).

Слайд 28 Gestational diabetes mellitus(GDM)
Disbalance between insulin secretion and increased

Gestational diabetes mellitus(GDM)Disbalance between insulin secretion and increased insulin resistance especially

insulin resistance especially in the third trimester.
Any degree

of glycose intolerance that was recognized during pregnancy.
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) multinational cohort study a 25,000 pregnant women, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks.

Слайд 29 Screening for GDM





Screening for GDM

Слайд 30 Algorithm of glucose testing in pregnancy
All women have

Algorithm of glucose testing in pregnancyAll women have to be screened

to be screened for diabetes as essential part of

pregnancy planning and be counseled about importance of strict glycemic control in pregnancy.
All women must be tested for diabetes in the first pregnancy visit (as early as possible in the first trimester).
6-12 week after delivery all women with GDM have to undergo OGTT with 75 gram glucose load in order to rule out or rule in persistent diabetes or prediabetes(IGT).
Treatment of woman with previous GDM and IGT with lifestyle intervention and metformin can delay or prevent diabetes in the future(30-40% for 10 years comparing with placebo , for 3 years NNT is 5-6 for 1 case ) .



Слайд 31 Goals of diabetes treatment
Prevent macrovasular diabetes complication-cardiovascular disease

Goals of diabetes treatmentPrevent macrovasular diabetes complication-cardiovascular disease (IHD, diabetic cardiomyopathy,

(IHD, diabetic cardiomyopathy, TIA, fatal and non- fatal CVA).
Prevent

microvascular diabetes complication:
Retinopathy
Neuropathy
Nephropathy- diabetic kidney disease
Alleviate hyperglycemic symptoms.
Prevent/treat diabetic ketoacidosis(DKA) and non-ketotic hyperosmolar state (coma).


Слайд 32 Aspects of diabetes treatment
Glycemic control
Lifestyle intervention include

Aspects of diabetes treatmentGlycemic control Lifestyle intervention include obesity treatment Medical

obesity treatment
Medical nutritional therapy
Control of high blood

pressure
Control of dyslipidemia
Anti-agreggant therapy

Слайд 33 Glycemic control and diabetic complication
Type 1 study:

Glycemic control and diabetic complicationType 1 study: DCCT –EDIC(Diabetes Control and

DCCT –EDIC(Diabetes Control and Complication Trial-
Epidemiology

of Diabetes Control and Complications)
Principal type 2 studies:
UKPDS(The UK Prospective Diabetes Study).
ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation ).
ACCORD (Action to Control Cardiovascular Risk in Diabetes).
VADT(Veteran Affairs Diabetes Trial).
Be careful of new “wonder” drugs for diabetes and “smashing hit” studies!!!

Слайд 34
DCCT N = 1441 T1DM Intensive (≥ 3 injections/day or CSII)

DCCT N = 1441 T1DM Intensive (≥ 3 injections/day or CSII)

vs. \ Conventional (1-2 injections per day)


Слайд 35 Inclusion criteria for DCCT
Primary prevention group :

Inclusion criteria for DCCT Primary prevention group : DM type 1:

DM type 1: 1-5 years, no retinopathy or severe

diabetic complication, no hypertension or hypercholesteremia, no severe medical condition: urinary microalbumin less than 40 mg for 24 hour .
Primary intervention group: the same duration of diabetes, very mild –to moderate non-prolipherative retinopathy, albumin secretion less than 400 mg for 24 hours, no severe diabetic complication ,no hypertension or hypercholesteremia, no severe medical condition.

Слайд 36 Baseline characteristics





Baseline characteristics

Слайд 37 Goals and modes of therapy conventional group
Conventional group therapy

Goals and modes of therapy conventional group Conventional group therapy goals:

goals: to prevent symptoms attributable to glycemia or glycosuria,

absence of ketones in urine, maintenance of normal growth development ,” ideal “ body weight ,freedom from severe and frequent hypoglycemia.
Treatment of conventional group :one or two insulin injection including mixed intermediate and rapid acting insulin, self -monitoring of blood and urine glucose, education about diet and exercise, no usual daily adjustment of insulin dose .

Слайд 38 Goals and modes of treatment intensive treatment group

Goals and modes of treatment intensive treatment group 3 or more


3 or more insulin injection or pump therapy.
Self monitoring

of blood glucose at least 4 times a day.
Dose or method adjustment to treatment goals :
fasting glucose 70-120 mg/dl
postprandial of less than 180 mg/dl
Weekly 3a.m. more than 65 mg/dl
HbA1- 6 % and less
Women who were planning a pregnancy or became pregnant receive intensive therapy until the time of delivery .

Слайд 39 Study questions
Prevention of diabetic retinopathy in primary

Study questions Prevention of diabetic retinopathy in primary prevention group by

prevention group by intensive treatment versus conventional group .
Influence

on progression of diabetic retinopathy in secondary intervention groupintensive treatment versus conventional group .
Renal, neurologic, neuropsychological cardiovascular outcomes in two groups.
Adverse effect of two modes of treatment.

Слайд 40 Reduction in Retinopathy
The Diabetes Control and Complications Trial

Reduction in RetinopathyThe Diabetes Control and Complications Trial Research Group. N

Research Group. N Engl J Med 1993;329:977-986.
Primary Prevention
Secondary

Intervention

76% RRR
(95% CI 62-85%)

54% RRR
(95% CI 39-66%)

RRR = relative risk reduction CI = confidence interval


Слайд 41 Solid line = risk of developing microalbuminuria
Dashed line

Solid line = risk of developing microalbuminuriaDashed line = risk of

= risk of developing macroalbuminuria
DCCT: Reduction in Albuminuria
The Diabetes

Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

34% RRR (p<0.04)

43% RRR
(p=0.001)

56% RRR
(p=0.01)

Primary Prevention

Secondary Intervention

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association

RRR = relative risk reduction
CI = confidence interval


Слайд 42
Reduction in Neuropathy
The Diabetes Control and Complications Trial

Reduction in NeuropathyThe Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

Research Group. N Engl J Med 1993;329:977-986.


Слайд 43 DCCT/EDIC Study Research Group. N Engl J Med

DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653.Reduction of cardiovascular

2005;353:2643–2653.
Reduction of cardiovascular event in DCCT –EDIC
57% risk

reduction (P=0.02; 95% CI: 12–79%)

MI, stroke or CV death

Conventional treatment

Intensive treatment


Years since entry

0.12
0.10
0.08
0.06
0.04
0.02
0.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21


Слайд 44 Hypoglycemia and other adverse events
General and

Hypoglycemia and other adverse events General and severe hypoglycemia 3 times

severe hypoglycemia 3 times higher in intensively treatment group

including coma and seizures.
Weight gain 4.6 kg more in intensively treated group.
No death , no more cardiovascular events during hypoglycemia.
No decline of quality of life, no difference in neuropsychological functioning.
May be more MVA in cases of severe hypoglycemia.

Слайд 45 GLYCEMIC CONTROL IN TYPE 2 UKPDS
20-year interventional

GLYCEMIC CONTROL IN TYPE 2 UKPDS20-year interventional trial from 1977

trial from 1977 to 1997.
5,102 patients with newly-diagnosed type

2 diabetes recruited between 1977 and 1991.
Median follow-up 10.0 years, range 6 to 20 years.

Слайд 46 UKPDS: Aims
To determine whether improved glucose control of

UKPDS: AimsTo determine whether improved glucose control of Type 2 diabetes

Type 2 diabetes will prevent clinical complications

Does therapy

with
sulphonylurea - first or second generation
insulin
metformin
has any specific advantage or disadvantage

Слайд 47 UKPDS patient characteristics
5102 newly diagnosed Type 2 diabetic

UKPDS patient characteristics5102 newly diagnosed Type 2 diabetic patientsage 25 -

patients

age 25 - 65 y mean 53 y
gender

male : female 59 : 41%
ethnic group Caucasian 82% Asian 10%
BMI mean 28 kg/m2
FPG median 11.5 mmol/L (207 mg/dl)
HbA1c median 9.1 %
hypertensive 39%

Слайд 48 Treatment Policies in 3867 patients

Conventional Policy n =

Treatment Policies in 3867 patientsConventional Policy n = 1138initially with diet

1138
initially with diet alone
aim for near normal weight, best

fasting plasma glucose < 15 mmol/l (270 mg/dl ), asymptomatic
when marked hyperglycaemia develops allocate to non-intensive pharmacological therapy

Intensive Policy with sulphonylurea or insulin n = 2729
aim for fasting plasma glucose < 6 mmol/L(108 mg/dl), asymptomatic
when marked hyperglycaemia develops on sulphonylurea add metformin, move to insulin therapy on insulin, transfer to complex regimens


Слайд 49 UKPDS Study Group. Lancet 1998; 352:837–853.
UKPDS: intensive

UKPDS Study Group. Lancet 1998; 352:837–853. UKPDS: intensive control reduces complications in type 2 diabetes

control reduces complications in type 2 diabetes


Слайд 50 UKPDS Any diabetes related endpoints

UKPDS Any diabetes related endpoints

Слайд 51 UKPDS- metformin
Main Randomisation 4209
Overweight 1704
Non overweight 2505
Conventional Policy 411
Intensive Policy 1293
Metformin 342
Insulin or

UKPDS- metformin Main Randomisation 4209Overweight 1704Non overweight 2505Conventional Policy 411Intensive Policy

Sulphonylurea 951
overweight (>120% Ideal Body Weight) UKPDS patients could be

randomised to an intensive glucose control policy with metformin

Слайд 52 Metformin in overweight patients in comparison with conventional treatment

Metformin in overweight patients in comparison with conventional treatment 32% risk


32% risk reduction in any diabetes-related endpoints, p=0.0023
42% risk

reduction in diabetes-related deaths, p=0.017
36% risk reduction in all cause mortality, p=0.011
39% risk reduction in myocardial infarction,p=0.01

Слайд 53 ACCORD trial
10251 patients with diabetes with HbA1c

ACCORD trial 10251 patients with diabetes with HbA1c 7.6-8.9 randomly assigned

7.6-8.9 randomly assigned to intensive therapy in order to

achieve HbA1c below 6% versus standard therapy (HbA1c 7-7.5%).
 4733 patients were randomly assigned to lower their blood pressure by receiving either intensive therapy (systolic blood-pressure target, <120 mm Hg) or standard therapy (systolic blood-pressure target, <140 mm Hg).
5518 patients were randomly assigned to receive either fenofibrate or placebo while maintaining good control of low-density lipoprotein cholesterol with simvastatin.
Mean age 62 years ,10 years of diagnosed diabetes, with 35% CVD in baseline.


Слайд 54 Treatment group

Treatment group

Слайд 55 (ACCORD study (glycemic arm

(ACCORD study (glycemic arm

Слайд 56
Gerstein HC et al. The ACCORD Study Group.

Gerstein HC et al. The ACCORD Study Group. N Engl J

N Engl J Med. 2008;358:2545–2559.
Results of the Randomized Comparison

of an Intensive Versus a Standard Glycemic Strategy

Unadjusted HR for P-value
Intensive vs. Standard (95% CI)

All-cause mortality 1.22 (1.01-1.46) 0.04

Primary endpoint:
CV death, MI, stroke 0.90 (0.78-1.04) 0.16

CV death 1.35 (1.04-1.76) 0.02
Non-fatal MI 0.76 (0.62-0.92) 0.004
Non-fatal stroke 1.06 (0.75-1.50) 0.74




Слайд 57 ACCORD study glycemic group

ACCORD study glycemic group

Слайд 58 ADVANCE collaborative group








ADVANCE collaborative group

Слайд 59 Results of intensive glucose lowering in ADVANCE trial
Average

Results of intensive glucose lowering in ADVANCE trialAverage lowering of HbA1c

lowering of HbA1c from 7.2 to 6.5%
Similar base line

characteristic of patients. (average age :66 years, diabetes duration of 8 years in average , prevalence of CVD 32%)




Слайд 60 VA Diabetes Trial (VADT)
Similar study design: intensive therapy

VA Diabetes Trial (VADT)Similar study design: intensive therapy versus standard therapy.Primary

versus standard therapy.
Primary endpoint: first CVD event after randomization.
Subjects

with longer durations of diabetes, more CVD, higher baseline A1C.

Duckworth W, Abraira C, Moritz T, et al. N Engl J Med. 2009;360:129-139.


Слайд 61
Differences in ACCORD/ADVANCE/VADT
Skyler JS, Bergenstal R, Bonow

Differences in ACCORD/ADVANCE/VADTSkyler JS, Bergenstal R, Bonow RO, et al. Diabetes Care. 2009;32:187-192.

RO, et al. Diabetes Care. 2009;32:187-192.


Слайд 62 Change in HbA1c during the trial

Change in HbA1c during the trial

Слайд 63 Initial results
No excess of cardiovascular mortality.
No improvement of

Initial resultsNo excess of cardiovascular mortality.No improvement of cardiovascular morbidity.No change

cardiovascular morbidity.
No change in incidence of neuropathy or no

change in rate of progression of neuropathy.
But …improvement in progression from normal kidney function to microalbuminuria and from microalbuminuria to macroalbuminuria was significant favoring intensive arm .

Слайд 64 10 years follow up of VADT cohort: glycemic

10 years follow up of VADT cohort: glycemic control

control


Слайд 65 Cardiovascular outcomes after 10 years

Cardiovascular outcomes after 10 years

Слайд 66 Glycemic targets in diabetes: general consideration (ADA 2016)


Glycemic targets in diabetes: general consideration (ADA 2016)

Слайд 67 Individualized treatment ADA 2016

Individualized treatment ADA 2016

Слайд 68 Glycemic targets for treatment of pregnant women with

Glycemic targets for treatment of pregnant women with type 1 and 2

type 1 and 2


Слайд 69
Glycemic targets for treatment of pregnant women with

Glycemic targets for treatment of pregnant women with type 1 and

type 1 and 2 diabetes
Glycemic targets for women with

GDM

Optimal Hba1C :6-6,5% (avoid maternal hypoglycemia!)


Слайд 70 Type 1 insulin treatment Concept of basal -

Type 1 insulin treatment Concept of basal - bolusPrescription of short

bolus
Prescription of short and long acting insulins imitating physiologic

insulin secretion.
It is the modern method to treat type1 and advanced type 2 diabetes .
Basal insulin injected once to time daily in order to control hepatic glucose output.
Premeal insulin is added in order to prevent postprandial glycemia.

Слайд 71





Serum Insulin Level
Time



guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright

Serum Insulin LevelTimeguidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

© 2013 Canadian Diabetes Association


Слайд 72 Insulin analogues

Insulin analogues

Слайд 73 Treatment scheme

Treatment scheme

Слайд 74 :Principles of type 2 treatment (1)non –pharmacologic therapy
Physical activity.

:Principles of type 2 treatment (1)non –pharmacologic therapyPhysical activity. 1.1Minimum 150


1.1Minimum 150 minutes weekly moderate intensity physical activity (50-70%

of maximal heart rate ) at least 3 days weekly .
1.2 Reduce sedentary time to 90 min.
1.3Minimum two session in week of resistance exercise : set of 5 exercise involving large muscle group.


Слайд 75 :Principles of type 2 treatment (2)non –pharmacologic therapy
Diet and

:Principles of type 2 treatment (2)non –pharmacologic therapyDiet and carbohydrates500-750 kcal/d

carbohydrates
500-750 kcal/d deficit:1200-1500 kcal /d for women,1500-1800 kcal/d for

men:5% weight loss, ideally 7%
No ideal amount !!(but keep in with total advised caloric intake!).
Replace refined carbohydrate and added sugars with whole grains, legumes, vegetables, and fruits.
Keep in mind carb counting in IDDM.



Слайд 76 :Principles of type 2 treatment (3)non –pharmacologic therapy
Diet and

:Principles of type 2 treatment (3)non –pharmacologic therapyDiet and proteins0.8 g/kg

proteins
0.8 g/kg daily allowance.
Enhance insulin response to carbohydrates.
Don’t use

protein- rich carbohydrate sources to revent hypoglycemia .
Diet and fat
Rich in monounsaturated fat (Mediterranean style diet ).
25-30 % caloric intake.
Sodium in diet:
Restrict to 2300 mg .
Restrict alcohol consumption to one drink a day for adult woman and two drink a day to adult man .


Слайд 77 Pharmacological treatment of glycemia type 2:drug classification
Biguanides
Secretagogues
DPP4 inhibitors
α-

Pharmacological treatment of glycemia type 2:drug classificationBiguanidesSecretagoguesDPP4 inhibitorsα- glycosidase inhibitorThiazolidinedioneGLP1 agonistsSGLT2 inhibitorsInsulin

glycosidase inhibitor
Thiazolidinedione
GLP1 agonists
SGLT2 inhibitors
Insulin


Слайд 78 Biguanides
Metfomin(Glucomin,Glucophage)
Preferred initial pharmacologic agent because of long standing

BiguanidesMetfomin(Glucomin,Glucophage)Preferred initial pharmacologic agent because of long standing record of efficacy

record of efficacy and safety and lowering CV outcomes(UKPDS).
Mechanism:


Decreased hepatic gluconeogenesis by activation of AMP kinase.
Other : lowering peripheral insulin resistance.



Слайд 79 Metformin
Half-life up to 3 hour.
No metabolism ,excreted by

MetforminHalf-life up to 3 hour.No metabolism ,excreted by kidney as active

kidney as active compound.
May be safely continued down to

glomerular filtrationrate (GFR) of 45 mL/min/1.73m2 or even 30 mL/min/1.73 m2 with reduced dosage.
Maximal dosage 2550 mg (usually 2-3 times daily.

Слайд 80 Metformin toxicity and side effects
Gastrointestinal (20-30%): start with

Metformin toxicity and side effectsGastrointestinal (20-30%): start with lower dose with

lower dose with or after meals, make rotation with

various formulation
B12 deficiency.
Lactic acidosis :( very uncommon ) don’t use in advanced CKD, advanced liver disease, shock, severe infection ,alcoholism.

Слайд 81 Secretagogues
Sulfonylureas: bind to SUR1 site of inward rectified

SecretagoguesSulfonylureas: bind to SUR1 site of inward rectified KATP channel on

KATP channel on beta-cells :
2 generation
First generation: now

abandoned because of cases of prolong hypoglycemia ,hyponatremia (chlorpropamide),transient leucopenia and thrombocytopenia (less than 1%) and multiple drug interaction.
Second generation: more safe.

Слайд 82 2-nd generation sulfonylureas
Adverse effect : hypoglycemia ,weight gain

Secondary

2-nd generation sulfonylureasAdverse effect : hypoglycemia ,weight gainSecondary failure : sulfonylureas

failure : sulfonylureas require functional beta -cells ,they lose

efficacy with diabetes progression because of beta -cell failure.


Слайд 83 Glinides
Binding to distinct (from sulfonylurea) SUR 1 site

GlinidesBinding to distinct (from sulfonylurea) SUR 1 site Burst phase-1 insulin


Burst phase-1 insulin secretion
In vitro- glucose dependent but

in vivo not
Medications:
Repaglinide(Novonorm)
Nateglinide
Pharmacokinetics:
Rapid onset of action
Plasma half -life less than 1 hour
Intensive hepatic metabulism
Use for coverage postprandial glucose rise
Suitable for CKD
Repaglinide 3 times daily 15 minutes before meal: 0,5 mg to 4 mg 3 to 4 times daily
Adverse effect : hypoglycemia ,weight gain


Слайд 84 DPP-IV: ACTION
Cleaves GLP-1

Results in decreased signal to the

DPP-IV: ACTIONCleaves GLP-1Results in decreased signal to the pancreas—limiting insulin response.That

pancreas—limiting insulin response.

That in turn decreases the signal to

the liver resulting in increased hepatic glucose production.

HYPERGLYCEMIA


X



Слайд 85 The Role of GLP-1
DPP-4 Inhibitors Increase ½ Life

The Role of GLP-1DPP-4 Inhibitors Increase ½ Life of GLP-1

of GLP-1


Слайд 86 DPP4 inhibitors
Januvia
Trajenta
Onglysa
Galvus
Name

DPP4 inhibitorsJanuviaTrajentaOnglysaGalvusName

Class Half-life Dose (mg) Use

Very few side effects: mostly gastrointestinal
Neutral weight effect


Слайд 87 GLP1 agonists(injectable agents)
Breakthrough in DM 2 treatment
Glycemic

GLP1 agonists(injectable agents)Breakthrough in DM 2 treatmentGlycemic ,cardiovascular (LEADER study)benefit ,

,cardiovascular (LEADER study)benefit , significant weight loss .
Side

effects :Gastrointestinal side effects , weakness , mild tachycardia ,local injection reaction .
Exenatide (Byetta) 5-10 mg twice daily SC
Exenatide SR (Bydureon) 2mg once weekly SC
Liraglutide (Victoza)0.6 -1.8 mg once daily
Dulaglutide (Trulicity) 0,75 mg- 1.5 mg once weekly


Слайд 88 α- glucosidase inhibitors
Acarbose (Prandase ) max 100 mg

α- glucosidase inhibitorsAcarbose (Prandase ) max 100 mg *3/dMay have cardiovascular

*3/d
May have cardiovascular benefits (STOP – NIDDM trial)
Prohibited in

advanced CKD

Слайд 89 Thiazolidinediones
Gamma- PPAR agonists.
Increase of insulin sensitivity in adipose

Thiazolidinediones Gamma- PPAR agonists.Increase of insulin sensitivity in adipose tissue skeletal

tissue skeletal muscle and liver.
Warning about potential increase of

acute MI (ACCORD)
Side effects : weight gain because of fluid retention, worsening of heart failure ,anemia, increased risk of fracture.
Medication :
Rosiglitazone (Avandia)4,8 ,16 mg once daily.
Pioglitazone(Actos)15- 45 mg once daily.

Слайд 90 SGLT2 inhibitors

SGLT2 inhibitors

Слайд 91 SGLT2 inhibitors medications
Empafliglozin (Jardiance)10 mg ,25 mg

SGLT2 inhibitors medicationsEmpafliglozin (Jardiance)10 mg ,25 mg Dapafliglozin(Forxiga) 10 mgPositive


Dapafliglozin(Forxiga) 10 mg
Positive effects :glucose lowering without hypoglycemia ,lowering

of blood pressure and weight ,may be cardiovacular benefit(EMPA-REG),lowering proteinuria.
Side effects : renal failure,polyuria,UTI and candidiasis and very ominous complication: normoglycemic DKA

Слайд 92 Algorithm ADA of glycemic treatment 2016

Algorithm ADA of glycemic treatment 2016

Слайд 93 Comprehensive care of diabetes(ADA 2016)
Stop smoking.
Treat blood

Comprehensive care of diabetes(ADA 2016) Stop smoking.Treat blood pressure to targets

pressure to targets :less than140/90 mmHg: ADVANCE – BP

, HOT study and ever ACCORD-secondary outcomes(stroke and proteinuria);
Younger population, population with cardiovascular disease or risk factor, albuminuria, target may be less than 130/80mmHg.
Unique role of ACE and ARB in treatment of diabetic population especially with albuminuria (more benefit in more than 300 mg /mg creatinine).


Слайд 94 Statin treatment and diabetes
Patients 40-75 without additional

Statin treatment and diabetes Patients 40-75 without additional atherosclerotic cardiovascular disease(ACVD)

atherosclerotic cardiovascular disease(ACVD) risk factor- moderate intensity statin+ life

style modification.
Diabetes + ACVD= high potency statin
Younger than 40 and older than 75 patient with additional ACVD factor = consider moderate to high potency statin.

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