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Primary Care Women’s Health Forum

Considerations for Screening and Managing T2DM in Female Patients Cheryl Lambing, MD Medical Director, Professional Education, Ventura County Health Care Agency Faculty, Family Medicine Residency Ventura County Medical Center Ventura, California Educational Objectives By the end of this activity, the participant should be better able to: 1. Describe the burden of diabetes with respect to sex‐specific risk factors and comorbid

disorders within the female population. 2. Outcome clinical data regarding novel insulin options for patients with diabetes, including

pharmacokinetic and pharmacodynamics profiles that infer reduced risk of hypoglycemia and weight gain.

3. Compare the mechanisms of action, safety, and efficacy of available incretin mimetic pharmacotherapies.

4. Employ targeted screening and patient‐centric strategies to effectively manage and reduce progression of diabetes in the female patient population.

Speaker Disclosure Dr. Lambing has disclosed that she has no actual or potential conflict of interest in relation to this topic. Supporter Disclosure This activity is supported by an educational grant from Novo Nordisk. It has been planned and produced by NACCME and Texas Academy of Family Physicians strictly as an accredited continuing medical education activity.

INTENDED LEARNERS

This activity is designed for primary care physicians, nurses, nurse practitioners, and physician assistants who treat female

patients.

Independent Clinical Reviewers: Cari Benbasset‐Miller, MD, Physician, Family Medicine, Cambridge, MA; Brian McDonough,

MD, Clinical Professor of Family Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; William C. Torrey,

MD, Medical Director, DHPA, Associate Professor of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New

Hampshire; Lorena A. Wright, MD, Clinical Assistant Professor Metabolism, Endocrinology and Nutrition, University of

Washington Medical Center/Roosevelt, Harborview Medical Center, Seattle, Washington.

Nurse Planner: Susie Seaman, NP, Sharp Rees‐Stealy Wound Clinic, San Diego, California

PLANNING COMMITTEE

The planning committee comprises of Cari Benbasset‐Miller, MD, Pamela Ellsworth, MD, Deborah Friedman, MD, Susan

Hutchinson, MD, W. Clay Jackson, MD, DIPTH, Cheryl L. Lambing, MD, FAAFP, Jeffrey Levine, MD, MPH, Brian McDonough, MD,

William C. Torrey, MD, Lorena A. Wright, MD; Susie Seaman, MSN, NP, CWOCN; Celeste Collazo, MD, MaryEllen Fama, Raquel

Gaerlan, Michael Kearney, Michelle Montgomery, Randy Robbin, and John Savage, NACCME. PRIMARY CARE WOMEN’S

HEALTH FORUM

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is not viewed as implying bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity of studies reported, and levels of evidence. Faculty presenter disclosures can be viewed within presentations. Additional planning committee disclosures are as follows: Ms. Seaman: Scientific advisor—Smith & Nephew, Inc., Promotional Speakers’ Bureau—Smith & Nephew, Inc. Dr. Benbasset‐Miller, Dr. McDonough, Dr. Torrey, and Dr. Wright have disclosed no relevant financial relationships with any commercial interests. Dr. Collazo, Ms. Fama, Ms. Gaerlan, Mr. Kearney, Ms. Montgomery, Mr. Robbin, and Mr. Savage have disclosed no relevant financial relationships with any commercial interests. NACCME requires faculty to inform participants whenever off‐label/unapproved uses of drugs and/or devices are discussed in their presentations. The faculty has disclosed that no off‐label/unapproved uses of drugs and/or devices will be discussed in the presentations. ADA STATEMENT

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NACCME. Clinical judgment must guide each professional in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and

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Developed in partnership with the Texas Academy of Family Physicians

Considerations for Screening and Managing T2DM in Female Patients

Supported by an educational grant from Novo Nordisk.

Faculty

Cheryl L. Lambing, MD, FAAFPClinical Professor

Department of Family MedicineUniversity of California, Los Angeles

Los Angeles, California Medical Director

Ventura County Health Care AgencyProfessional and Community Education and Outreach

Ventura, California

Faculty Disclosure

Dr. Lambing disclosed no relevant financial relationships with any commercial interests.

Learning Objectives • Describe the burden of diabetes with respect to sex-

specific risk factors and comorbid disorders within the female population

• Outline clinical data regarding novel insulin options for patients with diabetes, including pharmacokinetic and pharmacodynamic profiles that infer reduced risk of hypoglycemia and weight gain

• Compare the mechanisms of action, safety, and efficacy of available incretin mimetic pharmacotherapies

• Employ targeted screening and patient-centric strategies to effectively manage and reduce progression of diabetes in the female patient population

US Adult Population by Weight Classifications

Normal

(18.5–24.9)

31%

Overweight

(25.0–29.9)

34%

Obese

(≥30)35%

Class I

(30.0–34.9)21%

Class II

(35.0–39.9)8%

Class III

(≥40)6%

• Based on height and weight data for individuals ≥20 years of age from the 2011-2012 National Health and Nutrition Examination Survey

Jensen MD, et al. Obesity. 2014;22(Suppl 2):S1-S410. Ogden C, et al. JAMA. 2014;311:806-814.

2

1.47

2.51

1.37

2.93

0.5

1.5

2.5

3.5

15 20 25 30 35 40 45

Haz

ard

Rat

io BMI and All-Cause Mortality

Women Men

BMI Range (kg/m2)

Category BMI Range (kg/m) US Adults (%) Elevated Risk

Overweight 25.0–29.9 34 CVD

Obese, class I 30.0–34.9 21 CVD, all-cause mortality

Obese, class II 35.0–39.9 8 CVD, all-cause mortality

Obese, class III ≥40 6 CVD, all-cause mortality

Rationale for Weight Categories According to BMI

CVD = cardiovascular disease.Berrington de Gonzalez A, et al. N Engl J Med. 2010;363:2211-2219. Jensen MD, et al. Obesity. 2014;22(Suppl 2):S1-S410. Ogden C, et al. JAMA. 2014;311:806-814.

Medical Conditions Associated with Obesity in Women

• Diabetes mellitus

• Hypertension

• Coronary heart disease

• Stroke

• Venous thromboembolism

• Colorectal cancer

• Breast cancer

• Cervical cancer

• Endometrial cancer

• Infertility

• Urinary incontinence

• Sexual dysfunction

• Low back pain

• Knee osteoarthritis

• Depression

• Cognitive dysfunction

• Dementia

• Lower health-related quality of life

Kulie T, et al. J Am Board Fam Med. 2011;24(1):75-85.

Relationship between BMI and Percent Body Fat in Men and Women

Bod

y F

at (

%)

Body Mass Index (kg/m2)

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60

Women

Men

Adapted from Gallagher D, et al. Am J Clin Nutr. 2000;72(3):694-701.

Lipotoxicity Products of Fat Tissue

The link between pathophysiology of obesity and associated comorbid conditions

Adipose Tissue

Hypertension

Thrombosis

Inflammation

Type 2 diabetes

DyslipidemiaArthritis

Stroke

Heart attack

PVD

Asthma

Cancer

Sleep apnea

Fatty liver diseaseInsulin resistance

Adipsin

Resistin

Angiotensinogen TNF-α

TNF-β

IL-6

EGF PAI-1

FFA

Prostaglandins

Insulin

Estrogen

Adiponectin

Leptin CRP-1

Cortisol

CRP = C-reactive protein; EGF = epidermal growth factor; FFA = free fatty acids; PAI-1 = plasminogen activator inhibitor type 1; PVD = peripheral artery disease; TNF = tumor necrosis factor.

Waist Circumference Correlates with Visceral Adipose Tissue

• High risk for women WC >35 inches (88 cm) • High risk for men WC >40 inches (102 cm)

WC = waist circumference.Despres JP, et al. BMJ. 2001;322:716-720.

New Patients with Diabetes

EVERY

21SECONDS

someone is diagnosed with diabetes

New patient every 21 seconds = 3 patients/minute

1440 minutes/day × 3 patients/minute = 4320 patients/day

365 days/year × 4320 patients/day =1,576,800 new patients with diabetes/year

American Diabetes Association (ADA). www.diabetes.org/?loc=logo. Accessed March 23, 2015.

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Pathophysiological Defects in Hyperglycemia and Obesity

incretineffect

pancreaticinsulinsecretion

pancreaticglucagonsecretion

peripheralglucoseuptake

gutcarbohydratedelivery andabsorption

hepaticglucoseproduction

--

HYPERGLYCEMIAstress

hormones

Proinflammatory Cytokines

leptin

increased appetite

osteocalcin

Goldman's Cecil Medicine. 24th Edition. New York, NY: Elsevier Saunders; 2012.

Unique Risk Factors for Diabetes in Women

• Gestational Diabetes Up to 70% of women with gestational diabetes develop T2DM within 5

years of the pregnancy

• PreeclampsiaWomen with preeclampsia are 3.8 times more likely to develop

diabetes, and 11.6 times more likely to develop hypertension requiring drug treatment

• Polycystic Ovarian Syndrome (PCOS) 5-fold risk of developing T2DM compared with age- and weight-

matched control subjects Up to 70% have dyslipidemiaMetabolic syndrome is present in approximately 40%

T2DM = type 2 diabetes mellitus. Kim C, et al. Diabetes Care. 2002;25(10):1862-1868. Magnussen EB, et al. Obstet Gynecol. 2009;114(5):961-970. Wild R, et al. J Clin Endocrinol Metab. 2010;95(5):2038-2049.

Obesity and Diabetes Risk

• Diabetes in a biologic relative raises the risk2× increase with 1 DM parent (26% risk)5× increase with both DM parents3× increase with a DM sibling

• Heritability of DM is estimated to be 25%Genes explain <10% of overall DM heritability

• The socioenvironmental settingimpacts expression of genetic risk26% risk with a DM spouse

Genetics/ Heritability Socioenvironmental Influences

Leong A, et al. BMC Med. 2014;12:12. Baliunas DO, et al. Diabetes Care. 2009;32(11):2123-2132. American Association of Clinical Endocrinologists (AACE). www.aace.com/files/dm-guidelines-ccp.pdf. Accessed March 24, 2016. Jensen MD, et al. JAMA. 2014;311(1):23-24.

Obesity and Diabetes Risk

• Biologic clustering (family risk/genetic risk)

• “Social clustering” (not genetic/not related) Common living environment, resources, social habits, eating

patterns, physical activities, activity level, health behavior

• The best quality studies tested glucose tolerance 26% risk without adjustment for BMI 18% risk with adjustment for BMI (shared risk) Higher association for spousal dysglycemia (IFG/IGT) 26% risk of dysglycemia (“ripple effects”)

Genetics/ Heritability Socioenvironmental Influences: Clustering

IFG = impaired fasting glucose; IGT = impaired glucose tolerance.Leong A, et al. BMC Med. 2014;12:12. Baliunas DO, et al. Diabetes Care. 2009;32(11):2123-2132. American Association of Clinical Endocrinologists (AACE). www.aace.com/files/dm-guidelines-ccp.pdf. Accessed March 24, 2016. Jensen MD, et al. JAMA. 2014;311(1):23-24.

T2DM Can Be Prevented or Delayed by Intervention

An Ounce of Prevention isWorth a Pound of Cure

Not all overweight or obese individuals have subclinical or clinical diabetes, but

weight gain increases their risk for diabetes, hypertension, and

hyperlipidemia

The American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(6):1388-1393.

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Gender Differences

• IFG Higher prevalence in men, increases with ageLower prevalence in women

• IGTHigher prevalence in women at all ages in some studiesNHANES data support equal prevalence in men and

women

NHANES = National Health and Nutrition Examination Survey.American Diabetes Association. Diabetes Care. 2005;28(Suppl 1):S37-S42. American Diabetes Association. Diabetes Care. 2014;37(Supp 1):S14-S80.

Screen for T2DM• BMI ≥25

• Family history (first-degree relative)

• Ethnicity (native American Indian, Latino, African-American, Asian, Pacific Islander)

• Women with previous gestational diabetes or >9 pounds childbirth weight

• Previously identified IFG or IGT (metabolic syndrome)

• Dyslipidemia (HDL ≤35 mg/dL and/or TG ≥250 mg/dL)

• Hypertension (BP >140/90)

• PCOS or acanthosis nigracans

• CVD disease

• Physically inactive

• Age ≥45 years (screen every 3 years)

• Patients taking glucocorticoids or antipsychotics

BMI • Normal 18.5–24.9• Overweight 25–29.9• Obesity >30

− Class I 30–34.9− Class II 35–39.9− Class III >40

• Extreme obesity 50 to >70

HDL = high density lipoprotein; TG = triglycerides; BP = blood pressure.Katznelson L, et al. Endocr Pract. 2011;17(4):636-646. Diabetes Care. 2016;39(Suppl 1).

Making the DiagnosisCriteria for the Diagnosis of Diabetes

1. • FPG ≥126 mg/dL (7.0 mmol/L)*• Fasting is defined as no caloric intake for at least 8 hours

OR

2. • 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT*• The test should be performed as described by the WHO, using glucose load

containing the equivalent of 75 g anhydrous glucose dissolved in waterOR

3. • HbA1c ≥6.5% (48 mmol/mol)*• The test should be performed in a laboratory using a method that is NGSP

certified and standardized to the DCCT assay

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L)

*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.DCCT = Diabetes Control and Complications Trial; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; OGTT = oral glucose tolerance test.Diabetes Care. 2016;39(Suppl 1).

ADA Clinical Practice Guidelines

• Increased risk for prediabetes IFG 100–125 mg/dL IGT 140–199 mg/dLHbA1c 5.7% to 6.4%

• Sensitivity, 66%; Specificity, 88%

• Predictive diabetes over thenext 6 years

• Risk is continuous

ADA = American Diabetes Association.American Diabetes Association. Diabetes Care. 2005;28(Suppl 1):S37-S42. American Diabetes Association. Diabetes Care. 2014;37(Supp 1).

Diabetes Prevention• The DPP studied the effects of 3 interventions in >3000 adults with

prediabetes over 3 years (A)Diet and exercise resulted in a 58% reduction in risk of

developing diabetesMetformin reduced the risk by 31% and TZDs by 23% (this arm

of the study was discharged after 10 months)• The use of metformin to prevent T2DM is especially beneficial for

those with a BMI >35, age <60, and women with prior gestational diabetes (A)

• Patients with IGT or IFG should be counseled to lose 5% to 10% of body weight and walk 150 minutes weekly (A)

DPP = Diabetes Prevention Program; TZD = thiazolidinediones.DPP Research Group. Diabetes Care. 2002;25(12):2165-2171. Diabetes Care. 2016;39(Suppl 1).

Diabetes Prevention (continued)

• Follow-up counseling is important for successful prevention (B), and patients with prediabetes should be monitored yearly for the development of overt T2DM (E)

• Education modalities (B)Self-management/support programs designed for

patients with diabetesoAppropriate for people with prediabetes

Technology-assisted tools useful to support lifestyle modification

5

Evaluate for other CVD risk factors (A)

DyslipidemiaHyperlipidemia

Hypertension Obesity Smoking

Lifestyle Modification (A)(including medically assisted weight loss)

• Evaluate for medications based on the presence and number of risk factors

• Intensify weight loss strategies

SmokingCessation (B)

Prediabetes Algorithm

Garber AJ, et al. Endocr Pract. 2013;19(3):536-557. Apovian CM, et al. J Clin Endocrinol. Metab. 2015;100(2):342-362.

Medical Treatment for Obesity

— Predominant Contributor to Development & Deterioration of Diabetes

Recent Advances in Obesity Management

• AMA now recognizes obesity as a disease

• CMS reimburses PCPs for “intensive behavioral therapy for obesity”

• New guidelines promote weight management as a path to disease managementAACE algorithmsAHA/ACC/TOS Guidelines on Obesity Management

• 2 new medications on market in 2012, 2 more approved by the FDA in 2014 and 2015; overlap with diabetes medications

AACE = American Association of Clinical Endocrinologists; ACC = American College of Cardiology; AHA = American Heart Association; AMA = American Medical Association; CMS = Centers for Medicare & Medicaid Services; PCP = primary care physician; TOS = The Obesity Society.

Obesity and Diabetes: Lifestyle Intervention

• Diet and nutrition education/counseling

• Frequent contact with medical professional

• Active and long-term management; chronic disease model

• Exercise and increased daily activities Current guidelines: 30 minutes of physical activity “most days,” “every

day,” “5 days a week” or “150 minutes a week”, which is enough to reduce cardiovascular risk; not enough to impact weight reduction Institute of Medicine recommends 60 minutes of moderate activity for

weight maintenance Treating obesity requires 90 to 120 minutes of daily moderate

exerciseAmerican Diabetes Association. Diabetes Care. 2014;37(1):S14-S80. Rogovik AL. Canadian Family Physician. 2009;55(3): 257-259. Yanovski SZ, et al. JAMA. 2014;311(1):74-86. Brooks GA, et al. Am J Clin Nutr. 2004 79(5):921S-930S. American Diabetes Association. Diabetes Care. 2014;37(1):S14-S80. Apovian CM, et al. J Clin Endocrinol Metab. 2015;100(2):342-362.

Challenges Associated with Weight Reduction

• Altered physiology• Longer term and persistent changes • Adaptive responses to weight loss result in altered total/resting

energy expenditure Persist as long as reduced weight is maintained To maintain stable weight, must actively eat less and exercise more,

regardless of new weight• Appetite-related hormones remain altered for greater than 12

months after weight reduction Functions to promote increased energy intake and weight regain

• Increased hunger and decreased satiety (altered 24-hour circulating leptin, CCK, insulin) Basal and reactive responses

Apovian CM, et al. J Clin Endocrinol Metab. 2015;100(2):342-362. Grundy, SM, et al. J Am Coll Cardiol.2012;59(7):635-643.

Obesity Therapies: Medications

• Many cannot lose sufficient weight to impact health with lifestyle interventions

• In 2011, 3% (2.74 million) of obese adults used obesity medications

• Lifestyle interventions may be combined with short-term weight loss agents or longer use agents following guidelines

• Lifestyle interventions and/or medications may impact patient progression to diabetes and CVD risk factors

Ogden CL, et al. NCHS Data Brief. 2012;(82):1-8. Hampp C, et al. Pharmacotherapy. 2013;33(12):1299-1307. Yanovski SZ, et al. JAMA. 2014;311(1):74-86.

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Obesity Therapies: Medications

•Weight loss medications do not work as a stand-alone method or treatment

•Weight loss medications have not been shown to reduce CVD morbidity/mortality

•Weight loss must be persistent to achieve longer term benefits- Sustained weight loss of 3% may improve CVD risk, but ≥5% is clinically meaningful

Ogden CL, et al. NCHS Data Brief. 2012;(82):1-8. Hampp C, et al. Pharmacotherapy. 2013;33(12):1299-1307. Yanovski SZ, et al. JAMA. 2014;311(1):74-86.

Clinically Meaningful Weight Loss•Weight loss of at least 5%May be achieved 12 weeks or 1 year

•The FDA efficacy trial benchmarks for weight loss compared to placebo (for FDA approval)≥35% of study patients lose ≥5% of their initial weight

compared to approximately 15% placebo patients

Yanovski SZ, et al. JAMA. 2014;311(1):74-86.

Obesity Therapies: Medications• Short-term (≤12 weeks): 4 centrally mediated noradrenergic

agents with FDA approval prior to new requirementsPhentermineDiethylpropionPhendimetrazineBenzphetamine

• Long-term: FDA-approved agents OrlistatLorcaserinPhentermine plus topiramate-ERNaltrexone-bupropionLiraglutide

Yanovski SZ, et al. JAMA. 2014;311(1):74-86.

Liraglutide: GLP-1 Receptor Agonist

• Subcutaneous injection, pre-filled, multi-dose pen• SCALEAverage weight loss of 4.5% compared to placebo after 1

yearo62% of patients treated lost 5% of body weighto34% of patients lost 10% of body weight

• Boxed warning: increased risk of thyroid C-cell tumors• AE include nausea, diarrhea, constipation, vomiting, low blood

sugar (hypoglycemia), and decreased appetite• Contraindications: family Hx of MTC or MEN2• REMS developed—physician training• FDA requested post-market study

MTC = medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia syndrome type 2. FDA News Release. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427913.htm.

Care of the Obese PatientPrimary care/specialists that work in cooperation

with nutritionists and exercise physiologists

Goal • Nonoperative weight loss of

10% original body weight

• Treat comorbid conditions

Less than 5% to 10% loss• Revaluate treatment options

• Intensify behavioral strategies

• Consider risks/benefits of obesity medications

Consider surgical treatment of obesity

Medication trial12 weeks

Reevaluate

Longer term use Long-term managementRescue

strategies

Apovian CM, et al. J Clin Endocrinol. Metab. 2015;100(2):342-362. American Diabetes Association. Diabetes Care. 2014;37(1):S14-S80. Diabetes Care. 2016;39(Suppl 1). American Association of Clinical Endocrinologists (AACE). www.aace.com/files/dm-guidelines-ccp.pdf. Accessed March 24, 2016. Yanovski SZ, et al. JAMA. 2014;311(1):74-86.

Treatment of Diabetes in Obese Patients

Female Patient-Centric Approach to T2DM Management

7

Gender-Based Differences Impact on T2DM Management in Women

Gender-related• Differences in body fat distribution• Hormones• Slower glucose absorption in women• Greater (age) post-menopausal metabolic deterioration (B cell function and insulin resistance)

• Greater weight gain and risk for hypoglycemia with women

Kautzky-Willer A, et al. Diabetes Obes Metab. 2015;17(6):533-540.

Gender Differences in Disease Course and Outcomes

T2DM affects women disproportionately

• Poorer glycemic control

• Less likely to achieve HbA1c goal

• CVD risk remains elevated

• Higher all cause morbidity and mortality

• Emerging data for individualized management in women

• Guidelines for diabetes treatment do not differentiate between sexes

Kautzky-Willer A, et al. Diabetes Obes Metab. 2015;17(6):533-540. Arnetz L, et al. Diabetes Metab Syndr Obes. 2014;7:409-420.

2016 Management of T2DM Approach

CombinableInjectable Therapy

Triple Therapy

Dual Therapy

Monotherapy Efficacy (HbA1c)HypoglycemiaWeightMajor side effect(s)Costs

HighLow riskNeutral / lossGI / lactic acidosisLow

Metformin

If A1C target not achieved after ~3 months of monotherapy, proceed to 3-drug combination (order not meant to denoteany specific preference – choice dependent on a variety of patient – and disease specific factors):

Efficacy (HbA1c)HypoglycemiaWeightMajor side effect(s)Costs

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

SulfonylureaHighModerate riskGainHypoglycemiaLow

ThiazolidinedioneHighLow riskGainEdema, HF, fx’sHigh

DPP-4 InhibitorIntermediateLow riskNeutralRareHigh

SGLT2 InhibitorIntermediateLow riskLossGU, dehydrationHigh

GLP-1 receptor agonistHighHigh riskLossGIHigh

If needed to reach individualized A1C target after~3 months, proceed to three-drug combination(order not meant to denote any specific preference)

Sulfonylurea+

Thiazolidinedione+

DPP-4 Inhibitor+

SGLT2 Inhibitor+

GLP-1 receptor agonist+

IF A1C target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1 RA, addbasal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL2-I:

Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

SU

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

TZD

Insulin

Or

Or

SU

TZD

Insulin

Or

Or

SUTZD

Insulin

Or

Or

SU

Basal Insulin + or

Insulin (basal)HighHigh riskLossGIHigh

Metformin+

Insulin (basal)+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Or

Or

SLG2-IOr

Healthy eating, weight control, increased physical activity, and diabetes education

SLG2-IOr SLG2-IOr DPP-4-iOr SLG2-IOr

Metformin+

Mealtime Insulin GLP-1-RA

Diabetes Care. 2016;39(Suppl 1). Diabetes Care. 2016;39(Suppl 1).


Monotherapy Efficacy (HbA1c)HypoglycemiaWeightMajor side effect(s)Costs

HighLow riskNeutral / lossGI / lactic acidosisLow

Metformin

If A1C target not achieved after ~3 months of monotherapy, proceed to 3-drug combination (order not meant to denoteany specific preference – choice dependent on a variety of patient – and disease specific factors):

Healthy eating, weight control, increased physical activity, and diabetes education


Triple Therapy

Dual Therapy


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+







Sulfonylurea+

Thiazolidinedione+

DPP-4 Inhibitor+

SGLT2 Inhibitor+



Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

SU

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

TZD

Insulin

Or

Or

SU

TZD

Insulin

Or

Or

SUTZD

Insulin

Or

Or

SU

Basal Insulin + or


Metformin+

Insulin (basal)+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Or

Or

SLG2-IOr SLG2-IOr SLG2-IOr DPP-4-iOr SLG2-IOr

Metformin+


Diabetes Care. 2016;39(Suppl 1).

2016 Management of T2DM Approach Antihyperglycemic Agents Added to Metformin: Weight Changes

3.41

2.462.17

1.40 1.38

0.23

-1.01-1.66

-3.50

-5

-4

-3

-2

-1

0

1

2

3

4

BiphasicInsulin

TZD SU BasalInsulin

DPP-4i AGI GLP-1RA

SGLT-2iGlinide

GLP-1 RA, DPP-4 Inhibitors, SGLT-2 InhibitorsHighlighted for Avoiding Weight Gain

AGI = alpha-glucosidase inhibitor; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SGLT-2i = sodium-glucose co-transporter 2 (SGLT2) inhibitors; SU = sulfonylurea.Liu S, et al. Diabetes Obes Metab. 2012;14:810-820.

8

Antihyperglycemic Agents Added to Metformin: Hypoglycemic Risk

17.8

10.58.9

4.8

1.1 0.9 0.5 0.4 0.60

5

10

15

20

25

BiphasicInsulin

TZD SU BasalInsulin

DPP-4i AGI GLP-1RA

SGLT-2iGlinide

Increased Risk vs Placebo

No Increased Risk vs Placebo

Od

ds

Rat

io v

s P

lace

bo

Liu S, et al. Diabetes Obes Metab. 2012;14:810-820.


Triple Therapy

Dual Therapy


Metformin+

Metformin+

Metformin+

Metformin+

Metformin+







Sulfonylurea+

Thiazolidinedione+

DPP-4 Inhibitor+

SGLT2 Inhibitor+



Metformin+

Metformin+

Metformin+

Metformin+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

SU

DPP-4-i

GLP-1-RA

Insulin

Or

Or

Or

TZD

Insulin

Or

Or

SU

TZD

Insulin

Or

Or

SUTZD

Insulin

Or

Or

SU

Basal Insulin + or


Metformin+

Insulin (basal)+

Metformin+

TZD

DPP-4-i

GLP-1-RA

Or

Or

SLG2-IOr SLG2-IOr SLG2-IOr DPP-4-iOr SLG2-IOr

Metformin+


Diabetes Care. 2016;39(Suppl 1).


DPP-4 Inhibitors (Gliptins)• Sitagliptin 25 mg, 50 mg, and 100

mg Once-daily dosingDose adjustment in

renal impairment

• Saxagliptin 2.5 mg and 5 mgOnce-daily dosingDose adjustment in

renal impairment

• Linagliptin 5 mgOnce-daily dosing

• Alogliptin 6.25 mg, 12.5 mg, and

25 mg Once-daily dosingDose adjustment in

renal impairment

Cornell S, et al. Postgrad Med. 2012;124(4):84-94.

DPP-4 Inhibitors (Gliptins)• Inhibits DPP-4 enzyme in the GI tract that breaks down GLP-1

resulting in ↑ endogenous GLP-1 (fixes 2 broken organs)Glucagon suppression results in ↓ liver glucose production Enhances appropriate insulin and amylin secretion from the pancreas Can be used thru duration provided insulin is present

oPromising durability

• Lowers postprandial glucose Decrease A1c by 0.5% to 0.7% ( ~15–20 mg/dL; most postprandial)

• Most common side effects Stuffy, runny nose Headache Upper respiratory tract infection

GI = gastrointestinal.Cornell S, et al. Postgrad Med. 2012;124(4):84-94.

GLP-1 Receptor AgonistsShort-Acting GLP-1

Agonists

• Exenatide 5 mcg and 10 mcgTwice-daily dosing

Long-Acting GLP-1 Agonists

• Liraglutide 0.6 mg, 1.2 mg, and 1.8 mg Once-daily dosing

• Exenatide 2 mg Once-weekly dosing

• Albiglutide 30 mg and 50 mg Once-weekly dosing

• Dulaglutide 0.75 mg and 1.5 mg Once-weekly dosing


GLP-1 Receptor Agonists• GLP-1 agonists “fix” 4 dysfunctional organs in T2DM Glucagon suppression

oResults in ↓ liver glucose production Enhances appropriate insulin and amylin secretion from the pancreas

oResults in brain satiety Regulates the GI tract to slow gastric emptying time Can be used thru duration provided insulin is present

oPromising durability• Short-acting agonists lower postprandial glucose Decreases A1c by 0.8% to 1.5% (~20–45 mg/dL; most postprandial)

• Long-acting agonists lower fasting and postprandial glucose Decreases A1c by 0.8% to 1.8% (~20–50 mg/dL)

• Most common side effectsWeight loss Stomach upset Caution in patients at risk for pancreatitis


9

SGLT-2 Inhibitors• ↓ Renal glucose reabsorption in the early proximal tubule of the kidney ↓ Body fat – possibly due to ↑ water and fat urination (elimination)

• Lowers fasting glucose Decreases A1c by 0.7% to 1% (~20–30 mg/dL)

• Most common side effectsWeight loss Vaginal and male genital infections Rash UTI Frequent urination Increased thirstGI problems (when combined with metformin)

• FDA-approved agents Canagliflozin Dapagliflozin Empagliflozin

UTI = urinary tract infection.List JF, et al. Diabetes Care. 2009;32:650-657. Wilding JP, et al. Diabetes Care. 2009;32:1656-1662.

Agent Favor Avoid

DPP-4s • Close to A1c target • High PPG• Advanced CKD (dose adjust)• ‘Side-effect prone’

• h/o pancreatitis• h/o urticaria, angioedema • Self-pay

GLP-1s • Obese• ‘Weight-obsessed’ • High PPG (shorter acting)• High FPG (longer acting)

• ‘Needle-phobes’• h/o pancreatitis• CKD (eGFR<30) – exenatide• Baseline GI disease/ Sxs• Gastroparesis• Medullary ca / MEN-2• Self-pay

SGLT-2s • Obese• High FPG• Need additional BP reduction • ? Heart failure

• h/o yeast infections• h/o UTIs (?)• CKD (eGFR<45)• Baseline orthostatic Sxs• h/o stroke (?)• Self-pay

Considerations with Newer Agents

Cornell S, et al. Postgrad Med. 2012;124(4):84-94. Sheen AJ. Drugs. 2015;75(1):33-59.

A Practical Approach

Metformin

Orals

SU TZD DPP-4 SGLT-2

Injectables

GLP-1Novel Insulin

Options

New Interest in Novel Extended Time-Action Insulin Profiles

• Pharmacodynamics rely on decreased solubility at the site of injection or shift in absorption/bioavailability

• Advances in synthetic chemistry and biosynthesis has allowed optimization of the insulin molecule for enhanced efficacy and safety

• New emerging evidence suggests early consideration of insulin therapy

• Extended time-action may improve patient acceptance and/or adherence

• May lead to improved treatment outcome – thus a focus for ongoing research

Greenhill C. Nat Rev Endocrinol. 2016;[Epub ahead of print].

Novel and Emerging Insulins

2 Major Classes of Insulin Analogues

• Fast-acting meal-time (lispro, aspart, glulisine)

• Basal long-acting and ultra-long-acting (glargine, detemir, degludec)


Current and Emerging Prandial Insulins: United States

Prandial

Human insulins (short acting)

Regular human insulin (RHI)

U-100 RHI

U-500 RHI

Analogues (rapid acting)

Lispro

U-100 lispro

U-200 lispro†

Aspart Glulisine

Analogues (ultrarapid

acting)

Technosphere inhaled insulin*

*Approved by the FDA since June 2014. †Approved by the FDA in May 2015.US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

10

Rationale for and Limitations of Prandial Insulin Therapy in T2DM

• Aspart, glulisine, and lispro more nearly resemble physiological prandial insulin than regular human insulin, but they3

May not be absorbed rapidly enough, resulting in postprandial hyperglycemia May peak late (up to 120 min postinjection), resulting in hypoglycemia hours

after a meal

400

300

200

100

06:00 10:00 14:00 18:00 22:00 02:00 06:00

Glu

co

se

(m

g/d

L)

T2DMControl

Bolus (prandial) insulin therapy should reduce postprandial glucose excursions1,2

Time

Arrows above graph denote meal times.1Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. 2Zinman B. N Engl J Med. 1989;321(6):363-370. 3Cobelli C, et al. Diabetes. 2011;60(11):2672-2682.

U-200 LisproPharmacokinetics Pharmacodynamics

Potentially offers the advantage of a smaller injection volume for patients with high prandial insulin requirements

0 240 360 480300 420

Time (min)120 18060

250

200

150

100

0

Blo

od

Glu

co

se

(m

g/d

L)

50

LIS 0.2 U/kg (n = 10)RHI (n = 10); mean dose, 15.4 U

0 240 360 480300 420

Time (min)120 18060

80

70

50

30

0

10

20

40

60

Se

rum

Fre

e In

su

lin

C

on

ce

ntr

ati

on

(m

U/L

)

LIS 0.2 U/kg (n = 10)

RHI (n = 10);mean dose, 15.4 U

PK/PD data generated from a study of 10 patients with T1DM.US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Current and Emerging Basal Insulins: United States

Basal insulins

Human insulins

(intermediate acting)

NPH

Analogues

(long- acting)

U-100 glargine

Detemir

Analogues

(ultra-long-acting)

U-300 glargine*

Degludec†

*Approved by the FDA since February 2015. †Approved by the FDA since September 2015.US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Limitations of Current Basal Insulin Therapy in T2DM

Detemir and glargine more nearly resemble physiological basal insulin than NPH, but they

• May not have 24-hour duration of action

• Substantial within-patient reliability

• Clinically meaningful rates of nocturnal hypoglycemia

NPH = neutral protamine hagedorn.Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. Zinman B. N Engl J Med. 1989;321(6):363-370. Garber AJ. Diabetes Obes Metab. 2014;16(6):483-491.

Emerging Basal Insulin Analogues: Novel Mechanisms of Action

Insulin Degludec• Dihexamers (69 kDa) form

soluble multihexamers after injection

• Multihexamers (>5000 kDa) disassemble slowly

• Monomers are released rapidly after hexamers disassemble

• Glucose-lowering effect that persists for up to 42 hours

• FDA approved September 2015

Long multihexamer chainsassemble

Phenol from the vehiclediffuses quickly, and insulindegludec links up via single

side-chain contacts

Insulin degludec injected

Jonassen I, et al. Pharm Res. 2012;29(8):2104-2114. Haahr H, et al. Clin Pharmacokinet. 2014;53(9):787-800.

Ultra-Long-Acting Insulins

• Subcutaneous insulin injection does not exactly mimic endogenous insulin secretion

• Ultra-long-acting basal insulins have a flatter time-action profile and may be even less likely to cause nocturnal hypoglycemia than first-generation insulin analogues

• Several insulins designed for once-weekly administration are in early development

U-300 Glargine

• Approved• Same molecule as U-100

glargine• Compared with U-100 glargine:

• Equally effective• Less nocturnal hypoglycemia• Equivalent weight gain

Degludec

• Approved• Forms multihexamers for slow

release• Compared with U-100 glargine:

• Equally effective• Less nocturnal hypoglycemia• Equivalent weight gain

11

Investigational and Evolving Options

• Ultra-long dosing (>24 hours, weekly)

• Alternative delivery systems (oral, patch, inhaled)

• Designed to address flexibility, number of administrations, regimen complexity


Inhaled Insulin in T2DM

• Inhaled administration options

• Peak levels achieved in approximately 15 minutes

• Add-on to other T2DM medications

• Safety considerations include lung disease (contraindicated in asthma, COPD; perform spirometry prior to use, monitor for symptoms of CHF, hypoglycemia)

Treatment-Induced Hypoglycemia in WomenHypoglycemia—Significant Limiting Factor in

Diabetes Management

• More common, more severe, more severe nocturnal hypoglycemia

• Lower counter-regulatory responses to hypoglycemia

• Fear, anxiety, reduced quality of life/productivity related to episodes; important underlying reason for unwillingness to adhere to intensive insulin regimens (in studies women taking significantly higher insulin dose/kg compared to men yet less likely to achieve HbA1c goal)

• Advances in temporal profile, predictability of insulin preparations, less weight impact and novel mechanisms positively impact treatment of T2DM in women while reducing treatment-related hypoglycemia

Anderson M, et al. Diabetes Metab Syndr Obes. 2014;7:85-94. Kautzky-Willer A, et al. Diabetes Obes Metab. 2015;17(6):533-540.

Final Comments on Medications• New medications only recently available. We are in the

dawn of developing these varied approaches

• There is no perfect medication; every patient profile is different and must be matched to the drug profile

• As in all treatments, prescribing is shared decision making

• The future points to using medications in combination, mimicking the biologic effects; improving management of hyperglycemia and patient outcomes

• Physicians must learn to prescribe appropriately to prescribe safely. In appropriate patients, medications can bring needed help to struggling patients

Take Home• Assess insight regarding their physiology and related health

risks (WHAT)

• Assess their readiness to change

• Identify their WHY goals and set realistic expectations

• Plan a management and follow-up strategy together – HOW(shared decision making)

• Enlist help of trusted colleagues (nutritionists, behaviorists, educators, trainers, etc.)

• Learn and utilize helpful community resources / online tools

• Schedule frequent follow-up visits as needed (promote positive attitude)

• Integrate successful strategies into their long-term lifestyle

Shared Decision Making

Health Care Provider:

Treatment options risks and benefits

experience and skill

Patient:

Personal preferences

values and concerns

lifestyle choicesMutually

Acceptable Decision

2016 Managem

ent of T2DM

Approach

Com

binableInjectable Therapy

Triple Therapy

Dual Therapy

Monotherapy

Efficacy(H

bA1c)H

ypoglycemia

Weight

Major side effect(s)

Costs

High

Low risk

Neutral / loss

GI / lactic acidosis

Low

Metform

in

If A1C

target not achieved after ~3 months of m

onotherapy, proceed to 3-drug combination (order not m

eant to denoteany specific preference –

choice dependent on a variety of patient –and disease specific factors):

Efficacy(H

bA1c)H

ypoglycemia

Weight

Major side effect(s)

Costs

Metform

in+

Metform

in+

Metform

in+

Metform

in+

Metform

in+

SulfonylureaH

ighM

oderate riskG

ainH

ypoglycemia

Low

ThiazolidinedioneH

ighLow

riskG

ainEdem

a, HF, fx’s

High

DPP-4 Inhibitor

Intermediate

Low risk

Neutral

Rare

High

SGLT2 Inhibitor

Intermediate

Low risk

LossG

U, dehydration

High

GLP-1 receptor agonist

High

High risk

LossG

IH

igh

If needed to reach individualized A1Ctarget after~3 m

onths, proceed to three-drug combination

(order not meant to denote any specific preference)

Sulfonylurea+

Thiazolidinedione+

DPP-4 Inhibitor

+SG

LT2 Inhibitor+

GLP-1 receptor agonist

+

IF A1C

target not achieved after ~3 months of triple therapy and patient (1) on oral com

bination, move to injectables; (2) on

GLP

-1 RA

, addbasal insulin; or (3) on optim

ally titrated basal insulin, add GLP

-1-RA

or mealtim

e insulin. In refractory patients consider adding TZD or S

GL2-I:

Metform

in+

Metform

in+

Metform

in+

Metform

in+

Metform

in+

TZDD

PP

-4-i

GLP-1-R

AInsulin

Or

Or

Or

SUDP

P-4-i

GLP-1-R

AInsulin

Or

Or

Or

TZD

Insulin

Or

Or

SUTZDInsulin

Or

Or

SUTZD

Insulin

Or

Or

SU

Basal Insulin + or

Insulin (basal)H

ighH

igh riskLossG

IH

igh

Metform

in+Insulin (basal)

+ Metform

in+TZD

DP

P-4-i

GLP-1-R

A

Or

Or

SLG2-I

Or H

ealthy eating, weight control, increased physical activity, and diabetes education

SLG2-I

Or

SLG2-I

Or

DP

P-4-i

Or

SLG2-I

Or

Metform

in+

Mealtim

e InsulinG

LP-1-RA

Diab

etes Care. 2016;39(Suppl1).

Medication Index

Primary Care Women's Health Forum: Considerations for Screening and Managing T2DM in

Female Patients

Generic Name Trade Name

Albiglutide Tanzeum

Alogliptin Nesina

Benzphetamine None

Canagliflozin Invokana

Dapagliflozin Farxiga

Diethylpropion Tinuate

Dulaglutide Trulicity

Empagliflozin Jardiance

Exenatide Byetta

Inhaled Insulin Recombinant Human Afrezza

Insulin Aspart Novolog

Insulin Degludec Tresiba

Insulin Detemir Levemir

Insulin Glargine Basaglar, Lantus, Toujeo Solostar

Insulin Glulisine Apidra

Insulin Lispro Humalog

Insulin Recombinant Human Humulin R, Novolin R

Linagliptin Tradjenta

Liraglutide Saxenda, Victoza

Lorcaserin Belviq

Metformin Fortamet, Glucophage, Glumetza, Riomet

Naltrexone/Bupropion Contrave

Orlistat Alli, Xenical

Phendimetrazine Bontril PDM

Phentermine Adipex‐P, Suprenza

Phentermine/Topirmate Qysmia

Saxagliptin Onglyza

Sitagliptin Januvia

The following medications were discussed in this presentation. The table below lists the

generic and trade name(s) of these medications.

considerations for screening and managing t2dm in · pdf fileconsiderations for screening and...

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