Ueda2016 symposium -managing t2 dm with no compromise - khaled el hadidy

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  • Managing T2DM with no compromise

    BYDR. Khaled El Sayed El Hadidy. MD

    Professor of Internal Medicine.Head of Internal Medicine Department.

    Head of Diabetes and Endocrinology Unit.Beni - Suef University.UEDA ( IDF member )

  • Multiple Pathophysiological Failures Contribute to Hyperglycaemia: The Ominous Octet

    Islet -cell

    Increased

    lipolysis

    Increased

    glucose

    reabsorption

    Increased glucagon

    secretion

    Increased

    hepatic glucose

    production

    Neurotransmitter dysfunction

    Decreased

    glucose uptake

    Islet -cell

    Decreased incretin effectImpaired insulin

    secretion

    Hyper-

    Adapted from DeFronzo RA. Diabetes 2009;58:773795. Wolters Kluwer Health

    Hyper-

    glycemia

    2

  • HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.

    Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386393;

    Kahn SE, et al. N Engl J Med. 2006; 355: 24272443;

    Wright AD, et al. J Diabetes Complications. 2006; 20: 395401.

    Decreasing HbA1c is associated with increased risks

    of hypoglycaemia and weight gain

    Weight gain

    and

    hypoglycaemia

    Body w

    eig

    ht

    HbA1c

    Pla

    sma

    glu

    cose

  • Consequences of hypoglycaemia

    Hypoglycaemia

    Cardiovascular

    complications3

    Weight gain

    by defensive eating5

    Coma3

    Increased risk

    of car accident6

    Hospitalisation

    costs4

    Loss of

    consciousness3

    Increased risk

    of seizures3

    Death2,3

    Increased risk

    of dementia1

    1Whitmer RA, et al. JAMA. 2009; 301: 15651572; 2Bonds DE, et al. Br Med J. 2010; 340: b4909;

    3Barnett AH. Curr Med Res Opin. 2010; 26: 13331342; 4Jnsson L, et al. Value Health. 2006; 9: 193198;

    5Foley JE, Jordan J. Vasc Health Risk Manag. 2010; 6: 541548; 6Begg IS, et al. Can J Diabetes. 2003; 27: 128140; 7McEwan P, et al. Diabetes Obes Metab. 2010; 12: 431436.

    .

    Reduced

    quality of life7

  • Mechanisms ( Hypoglycemia -------------- CVS )

  • CVD=cardiovascular disease; DM=diabetes mellitus; HDL-C=high-density lipoprotein cholesterol; HTN=hypertension;

    IGT=impaired glucose tolerance; IR=insulin resistance; LDL-C=low-density lipoprotein cholesterol; TG=triglyceride.

    Eckel RH, Grundy SM, Zimmet PZ.

    The metabolic syndrome. Lancet. 2005; 365: 1415 428.

    Weight Gain and Co-morbidities

    Weight gain

    Hyperinsulinaemia and IR

    Dyslipidemia

    TG

    small dense LDL-C

    Apo-B

    HDL-C

    HTNProthrombotic state

    PAI-1 , Factor VII

    Fibrinogen

    IGT and DM

    Proinflammatory state

    CVD

  • L L L

    GLP-1 GLP-1 GLP-1

    InsulinGlucagon

    Slowed gastric

    emptying

    Early

    Satiety

    Inactive

    GLP-1

    DPP-4

    enzyme

    (DPP-4

    inhibitor)

    GLP-1

  • Guidelines recommend the combinationADA

    /EASD

    & AACE

    24 hours glycemic control with once daily dose

    Ideal Criteria of OAD* in treatment of T2DM Patientsin order to get High Glycemic Control with Confidence (1/2) :

    Why Saxagliptin / Metformin XR

    can be an Ideal FDC# in management of T2DM patients ?

    Diabetes Care, Diabetologia. 19 April 2012 Garber AJ, et al. Endocr Pract 2013;19(2):327-336.Jadzinsky et al Diabetes, Obesity & metabolism (2009)

    Fonseca V, Zhu T, Kayaker C, et al. Diabetes, Obesity and Metabolism 2012; 14 (4): 365371.Full Prescribing Information

    * OAD: Oral Antidiabetic

    # FDC: Fixed dose combination

    **HbA1c: Haemoglobin A1c

    ##: Fasting plasma glucose

    ***: Postprandial plasma glucose

    Well studied in diabetes type 2 patients with established cardiovascular disease & high cardiovascular risk patients.

    4 years sustained Efficacy (Evidence based)

    3.3% A1c reduction from baseline 10%

    Comparable efficacy to Sulphonylurea without risk of hypoglycemia

  • Healthy eating, weight control, increased physical activity & diabetes education

    Metformin high low risk

    neutral/loss

    GI / lactic acidosis

    low

    If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    high low risk

    gain

    edema, HF, fxs

    low

    Thiazolidine- dione

    intermediate low risk

    neutral

    rare

    high

    DPP-4 inhibitor

    highest high risk

    gain

    hypoglycemia

    variable

    Insulin (basal)

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Basal Insulin +

    Sulfonylurea

    +

    TZD

    DPP-4-i

    GLP-1-RA

    Insulin

    or

    or

    or

    or

    Thiazolidine-dione

    + SU

    DPP-4-i

    GLP-1-RA

    Insulin

    TZD

    DPP-4-i

    GLP-1-RA

    high low risk

    loss

    GI

    high

    GLP-1 receptor agonist

    Sulfonylurea

    high moderate risk

    gain

    hypoglycemia

    low

    SGLT2 inhibitor

    intermediate low risk

    loss

    GU, dehydration

    high

    SU

    TZD

    Insulin

    GLP-1 receptor agonist

    +

    SGLT-2 Inhibitor +

    SU

    TZD

    Insulin

    Metformin +

    Metformin +

    or

    or

    or

    or

    SGLT2-i

    or

    or

    or

    SGLT2-i

    Mono- therapy

    Efficacy* Hypo risk

    Weight

    Side effects

    Costs

    Dual therapy

    Efficacy* Hypo risk

    Weight

    Side effects

    Costs

    Triple therapy

    or

    or

    DPP-4 Inhibitor

    + SU

    TZD

    Insulin

    SGLT2-i

    or

    or

    or

    SGLT2-i

    or

    DPP-4-i

    If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

    If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

    Metformin +

    Combination injectable therapy

    GLP-1-RA Mealtime Insulin

    HbA1c9%

    Me orminintoleranceor

    contraindica on

    Uncontrolledhyperglycemia

    (catabolicfeatures,BG300-350mg/dl,HbA1c10-12%)

    Insulin (basal)

    +

    or

    or

    or

    Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0 American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1)

    Guidelines recommend the combination

    MANAGE EARLY AND TIGHTLY

  • Healthy eating, weight control, increased physical activity & diabetes education

    Metformin high low risk

    neutral/loss

    GI / lactic acidosis

    low

    If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    high low risk

    gain

    edema, HF, fxs

    low

    Thiazolidine- dione

    intermediate low risk

    neutral

    rare

    high

    DPP-4 inhibitor

    highest high risk

    gain

    hypoglycemia

    variable

    Insulin (basal)

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Metformin +

    Basal Insulin +

    Sulfonylurea

    +

    TZD

    DPP-4-i

    GLP-1-RA

    Insulin

    or

    or

    or

    or

    Thiazolidine-dione

    + SU

    DPP-4-i

    GLP-1-RA

    Insulin

    TZD

    DPP-4-i

    GLP-1-RA

    high low risk

    loss

    GI

    high

    GLP-1 receptor agonist

    Sulfonylurea

    high moderate risk

    gain

    hypoglycemia

    low

    SGLT2 inhibitor

    intermediate low risk

    loss

    GU, dehydration

    high

    SU

    TZD

    Insulin

    GLP-1 receptor agonist

    +

    SGLT-2 Inhibitor +

    SU

    TZD

    Insulin

    Metformin +

    Metformin +

    or

    or

    or

    or

    SGLT2-i

    or

    or

    or

    SGLT2-i

    Mono- therapy

    Efficacy* Hypo risk

    Weight

    Side effects

    Costs

    Dual therapy

    Efficacy* Hypo risk

    Weight

    Side effects

    Costs

    Triple therapy

    or

    or

    DPP-4 Inhibitor

    + SU

    TZD

    Insulin

    SGLT2-i

    or

    or

    or

    SGLT2-i

    or

    DPP-4-i

    If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

    If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insuli