Emerging Challenges In Primary Care: 2015

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Care Se'ng Emerging Challenges In Primary Care: 2015 Transitions of Care in Diabetes: Initiation and Intensification of Therapies Beyond Monotherapy 1 Faculty Mark Stolar, MD Associate Professor of

Beaser, MD Senior Staff Physician Joslin Diabetes Center Associate Clinical Professor of Medicine Harvard Medical School Boston, MA Robert S.

Disclosures Mark Stolar, MD serves as a speaker for and/or on the advisory board for Takeda, Sanofi, and Astra Zeneca. Richard S. Beaser, MD served as an academic participant for Glaxo Smith Kline.

1 Care Se'ng Emerging Challenges In Primary Care: 2015 Transitions of Care in Diabetes: Initiation and Intensification of Therapies Beyond Monotherapy 1 Faculty Mark Stolar, MD Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University Chicago, IL Richard S. Beaser, MD Senior Staff Physician Joslin Diabetes Center Associate Clinical Professor of Medicine Harvard Medical School Boston, MA Robert S. Busch, MD, FACE Director of Clinical Research Albany Med: Community Endocrine Group Albany, NY Jeff Unger, MD, ABFM, FACE Director, Unger Primary Care Medical Group Rancho Cucamonga, CA 2 Disclosures Mark Stolar, MD serves as a speaker for and/or on the advisory board for Takeda, Sanofi, and Astra Zeneca. Richard S. Beaser, MD served as an academic participant for Glaxo Smith Kline. Robert S. Busch, MD, FACE serves on the speakers bureau for Astra Zeneca, Eli Lilly, and Boehringer Ingelheim. Dr. Busch also serves on the advisory board for Amgen. Jeff Unger, MD, ABFM, FACE serves as a speaker for Novo Nordisk and Janssen and on the advisory board for Novo Nordisk, Janssen, Intarcia, and Abbott. Dr. Unger also receives research support from Abbott. 3 1

2 Learning Objectives Recognize the importance of early glycemic control for reducing microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM) Describe the role and demonstrate effective utilization of glucoretic agents in the management of T2DM Demonstrate an understanding of the role of incretin-based therapies in the management of T2DM Utilize diet/exercise history, home glucose logs of fasting and postprandial glucose and an understanding of mechanisms of action of current patient medications to adjust therapy based on physiologic needs rather than algorithmic choices Discuss the rationale for use of combination therapy for diabetes both as a means for more rapid achievement of glycemic targets and as a way to individualize care based on a logical assessment of 4 patient physiologic needs and therapeutic mechanism of action PRE-TEST QUESTIONS 5 Pre-test ARS Question 1 On a scale of 1 to 5, please rate how confident you are in intensifying treatment strategies beyond monotherapy in a patient with Diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 6 2

3 Pre-test ARS Question 2 Which one of the following patients with diabetes will be at high risk for progression to macrovascular and microvascular complications? year old patient on diet/exercise regimen and A1c=6.9% year old patient on metformin and A1c=6.4% year old on metformin and A1c=10% who will continue metformin therapy for 3 more months year old on metformin with A1c=8% who has a GLP-1 agonist therapy added 7 Pre-Test Question 3 How can glucoretic agents (SGLT-2 inhibitors) be used to improve therapy in the treatment of a 58 year old patient with type 2 diabetes on blood pressure medications? 1. Glucoretic therapy can not be started in patients naïve to medication therapy 2. Glucoretic therapy can be started regardless of the renal function of the patient 3. The fact that the patient is on diuretics for blood pressure prohibits the use of glucoretic therapy 4. After evaluation of renal function, SGLT-2 inhibitors can be started 1st line or 2nd line therapy in the treatment of T2DM 8 Pre-Test Question 4 How can incretin-based therapies improve glycemic control for a medication naïve 70 year old patient with type 2 diabetes and renal dysfunction BMI=31, A1c=7.5%? 1. Incretin-based therapy, specifically GLP-1 agonists, will increase insulin release, decrease glucagon release, may increase satiety and also has a glucose dependent affect 2. Incretin-based therapies specifically DPP-4 inhibitors will increase glucose release and reduce glucagon release, but also will increase the patient s weight 3. Incretin based therapies will only increase insulin release may, but can not be prescribed because of the patient s renal function 4. Incretin-based therapies, specifically GLP-1 agonists, will increase insulin release, decrease glucagon release, but may not 9 reduce A1c by more than 0.5% 3

Pre-Test Question 5 A 45 year old patient with diabetes complains of hypoglycemic symptoms every morning. He takes sulfonylurea and metformin after he exercises in the evening.

4 Pre-Test Question 5 A 45 year old patient with diabetes complains of hypoglycemic symptoms every morning. He takes sulfonylurea and metformin after he exercises in the evening. How can a healthcare professional utilize diet/exercise history, home glucose logs, and understanding the mechanisms of action of current medication regimen to adjust therapy? 1. Diet and exercise history can not explain fluctuation in glycemic control 2. Home glucose logs without the history of diet/exercise can explain when the patient eats and takes medications 3. Home glucose logs can recommend how the patient should change eating behaviors to improve efficacy of medication therapy 4. Evaluation of diet/exercise history together with the understanding the mechanism of action of sulfonylureas and metformin will help prevent adverse effects and improve glycemic control 10 Pre-Test Question 6 What is the benefit of combination medication therapy in a patient with diabetes who failed to meet A1c goal on 1 st line therapy? 1. Combination medication therapy decreases the likelihood of dose titration of each single medication 2. Combination medication therapy may not be beneficial because it may reduce compliance with the regimen 3. Combination medication therapy allows for rapid achievement of glycemic targets and as a way to individualized care based on logical assessment of patients needs and mechanism of action of the component medications 4. Combination medication therapy will benefit a patient if medication choices follow algorithmic choices rather than 11 assessment of patient s physiologic needs Pathophysiologic Changes Affecting Blood Glucose in Patients with Type 2 Diabetes accessed August 2015 permission requested 12 4

5 Diabetes Mellitus A Constellation of Complications Peripheral Vascular Disease Gastropathy Dyslipidemia Erectile Dysfunction Cardiovascular Disease Renal Disease Diabetes Peripheral Neuropathy Retinopathy/ Macular Edema Autonomic Neuropathy Hypertension 13 United Kingdom Prospective (UKDPS) Diabetes Study : Effect of Earlier Glucose Control 10 year Follow up of T2DM Patients Intensive control group (insulin +sulfonylurea) Vs. control Risk for microvascular disease Risk for myocardial infarction Risk of death from any cause Intensive control group (metformin) Vs. control Risk for myocardial infarction Risk of death from any cause J Diabetes Sci Technol Nov;2(6): Percentage decrease in relative risk corresponding to a 1% decrease in HbA1C UKPDS: Reduction of A1C by 1% Reduces diabetes Complications Any diabetes- Diabetes- All Peripheral Microrelated related Myocardial cause vascular vascular Cataract death infarction endpoint mortality Stroke disease disease extraction 21% ** Observational analysis from UKPDS study data 21% ** ** 14% 14% Lower extremity amputation or fatal peripheral vascular disease *P = 0.035; **P < JAMA Intern Med August; 174(8): doi: /jamainternmed ** 12% * 43% ** 37% ** 19% ** 5

Despite Important Advances in Therapy, Glycemic Control for T2DM Is Not Optimal Inadequate glycemic control

in treatment intensification (inertia) Underuse of combination medication products Inadequate familiarity

Kidneys Sodium Glucose Transporters SGLT-2 inhibitors Hepatic glucose overproduction Metformin TZDs DPP-4

Sulfonylureas Meglitinides Gut DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.

inhibitors Metformin Colesevelam Muscle and fat Insulin resistance TZDs Metformin 17 Biguanides Metformin

hypoglycemia Disadvantage Gastrointestinal side effect Renal function monitoring GFR<45ml/min/1.

6 Despite Important Advances in Therapy, Glycemic Control for T2DM Is Not Optimal Inadequate glycemic control Inadequate understanding of T2DM pathophysiology Gaps in perception/knowledge of available therapies Delays in treatment intensification (inertia) Underuse of combination medication products Inadequate familiarity with treatment guidelines 16 Major Targeted Sites of Oral Drug Classes in the Treatment of Type 2 Diabetes Kidneys Sodium Glucose Transporters SGLT-2 inhibitors Hepatic glucose overproduction Metformin TZDs DPP-4 inhibitors GLP-1 analogues Amylin analogue Liver Beta-cell dysfunction Glucose level Glucose absorption Sulfonylureas Meglitinides Gut DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. SGLT-2=sodium glucose transport 2 inhibitors Pancreas DPP-4 inhibitors GLP-1 analogues Alpha-glucosidase inhibitors Metformin Colesevelam Muscle and fat Insulin resistance TZDs Metformin 17 Biguanides Metformin Mechanism Activates AMP-kinase insulin sensitivity hepatic glucose production Advantage No weight gain No hypoglycemia Disadvantage Gastrointestinal side effect Renal function monitoring GFR<45ml/min/1.73m 2 è 1000mg/day GFR<30ml/min/1.73m 2 è discontinue Vitamin b12 deficiency accessed July

Secretagogues Mechanism insulin secre4on Close K ATP Channel on β cell plasma membrane Class Compound Advantages Disadvantages Sulfonyureas Glyburide Glipizide Glimepiride Meglitinides Repaglinide

org/content/early/2012/04/17/dc12-0413.full.

7 Secretagogues Mechanism insulin secre4on Close K ATP Channel on β cell plasma membrane Class Compound Advantages Disadvantages Sulfonyureas Glyburide Glipizide Glimepiride Meglitinides Repaglinide Nateglinide Reduced microvascular risk Dosing flexibility Hypoglycemia Weight gain Hypoglycemia Weight gain Frequent dosing schedule accessed May Thiazolidinediones Mechanism insulin sensi4vity Compound Advantages Disadvantages Rosiglitasone No hypoglycemia Restricted in the U.S; withdrawn (Europe) LDL MI cases? Bone fractures Pioglitasone No hypoglycemia HDL TG CVD events Weight gain Edema/CHF Bone fractures Bladder cancer? accessed May Role of Incretins in Glucose Homeostatis Ingestion of food Pancreas GI tract Release of gut hormones Incretins Active GLP-1 & GIP DPP-4 enzyme Beta cells Alpha cells Glucosedependent insulin from beta cells (GLP-1, GIP) Glucose dependent glucagon from alpha cells (GLP-1) Glucose uptake by muscles Glucose production by liver Blood Glucose Inactive GLP-1 Inactive GIP DPP-4=dipeptidyl peptidase 4 GIP= Glucose-dependent insulinotropic peptide (GIP) Glucagon like product 1 (GLP-1) 21 Glucose GLP-1=glucagon-like peptide 1 7

The Incretin Effect is Diminished in Subjects With Type 2 Diabetes Control Subjects (n=8) Subjects With Type 2 Diabetes (n=14) IR Insulin, mu/l 80 60 40 20 Normal Incretin Effect 80 Oral glucose IV

secretion GIP/GLP-1 secreted upon the ingestion of food α-cells: Postprandial glucose secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Larsson H et al.

8 The Incretin Effect is Diminished in Subjects With Type 2 Diabetes Control Subjects (n=8) Subjects With Type 2 Diabetes (n=14) IR Insulin, mu/l Normal Incretin Effect 80 Oral glucose IV Glucose IR Insulin, mu/l Diminished Incretin Effect Oral glucose IV Glucose Time, min Time, min IR: immunoreactive Diabetes September; 61(9): doi: /db Incretin Based Therapies Affect on GIP and GLP-1 Β-Cell workload Β-Cell response Promotes satiety and reduces appetite Β-Cells: (GIP/GLP-1) Enhance glucosedependent insulin secretion GIP/GLP-1 secreted upon the ingestion of food α-cells: Postprandial glucose secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Larsson H et al. Acta Physiol Scand.1997;160: Drucker DJ. Diabetes. 1998;47: GLP-1 Infusion Has Glucose- Dependent Effects Effects of 4-hour GLP-1 infusion (1.2 pmol/kg/min) in 10 patients with type 2 diabetes. Glucose (mmol/l) Insulin (pmol/l) Glucagon (pmol/l) * * * * * * * Time (min) * * * * 10 * * * * Time (min) 20 * * * * Time (min) Placebo (PBO) Native human GLP-1 Mean (SE); n=10; *p< Prog Mol Biol Transl Sci. 2014; 121: doi: /B

9 Incretin Based Therapies DPP- 4 Inhibitors GLP- 1 Receptor Agonists Mechanism of ac4on Compounds Inhibit DPP- 4 enzyme GIP/ GLP- 1 Insulin & glucagon Sitaglip4n Saxaglip4n Linaglip4n Aloglip4n Ac4vates GLP- 1 Insulin & glucagon & Sa4ety Exena4de Exena4de LAR Liraglu4de Albiglu4de Dulaglu4de Advantages Glucose dependent effect Glucose dependent effect Weight reduc4on Disadvantages Hypersensi4vity Renal dose adjustment (sitaglip4n, saxaglip4n, aloglip4n) liver dose adjustment (saxaglip4n) Pancrea44s? GI side effects Injectable Pancrea44s (black box label) Thyroid tumor (black box label) Renal dose adjustment (exena4de,exena4de LAR) Short Acting GLP-1 Vs. Long Acting GLP-1 Agonists Parameters Short-Acting GLP-1 Agonists Long-Acting GLP-1 Agonists Fasting blood glucose Modest reduction Strong reduction Post prandial blood glucose Strong reduction Modest reduction Body weight reduction 1-5 Kg (dose related) 2-5 kg (dose related) Induction of nausea 20-50%, attenuates slowly (weeks to several months) 20-40%, attenuates quickly (~4-8 weeks) accessed Jan Cardiovascular Effects of GLP-1 Analogs Beneficial BP effects May be direct vascular effects? Weight loss may contribute to sustained reductions Beneficial effects on lipids, other CVD risk factors Largely mediated through weight loss May have direct cardioprotective effects Cardiovasc Diabetol. 2013; 12:

MWP43DE71876_MMF4_R11.ppt 9/29/15 12:07 Glucoretic Therapy How Do Sodium Glucose Transport 2 (SGLT2) Inhibitors Work?

28 Glucoretic Based Therapies SGLT 2 Inhibitors Compounds Canagliﬂozin Dapagliﬂozin Empagliﬂozin Advantages Eﬀec4veness independent

Renal monitoring and dose adjustment Electrolyte imbalance Cost Diabetes Care 2014;37: S14-79.

$(dapagliflozin) (dapagliflozin) Risk for bone fracture 30 (canagliflozin) Invokana [package insert].$

10 MWP43DE71876_MMF4_R11.ppt 9/29/15 12:07 Glucoretic Therapy How Do Sodium Glucose Transport 2 (SGLT2) Inhibitors Work? Glucose in blood Glucosuria Chao EC, et al. Nat Rev Drug Discovery. 2010;9: permission requested. 28 Glucoretic Based Therapies SGLT 2 Inhibitors Compounds Canagliﬂozin Dapagliﬂozin Empagliﬂozin Advantages Eﬀec4veness independent of insulin Low risk for hypoglycemia Small amount of weight Small in blood pressure Disadvantages Adequate renal func4on required Renal monitoring and dose adjustment Electrolyte imbalance Cost Diabetes Care 2014;37: S Monitoring patient on SGLT2 Inhibitors Adverse reactions Precautions Hypotension Increased urination Impairment in renal Vaginal yeast function infections Hypoglycemia Urinary tract Hypersensitivity infections LDL (empagliﬂozin) Nasopharyngitis Bladder cancer (dapagliflozin) (dapagliflozin) Risk for bone fracture 30 (canagliflozin) Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc Farxiga [package insert. Wilmington, DE: AstraZeneca

Cardiometabolic Effects of SGLT-2 Inhibitors Beneficial BP effects Systolic blood pressure Weight reduction (2-4Kg) Drug Des Devel Ther 2014;8:1335-1380 31 Patient Centered Approach When Choosing

11 Cardiometabolic Effects of SGLT-2 Inhibitors Beneficial BP effects Systolic blood pressure Weight reduction (2-4Kg) Drug Des Devel Ther 2014;8: Patient Centered Approach When Choosing Medication Regimen Patient factors: Age A1c at baseline, duration of diabetes, goal and expect reduction Kidney or liver function or comorbidities Other concomitant medications Medication factors: -Efficacy (A1c lowering capabilities) Potential side effects Risk of hypoglycemia Renal or liver dose adjustment Cost 32 How Do We Choose Appropriate Medication Therapy? A1c 7% accessed March

12 Profile of Antidiabetic Medications Met GLP- 1 SGLT- 2 DPP- 4 AGI Hypo Neutral Neutral Neutral Neutral Neutral Weight Loss Loss Loss Neutral Neutral Renal CI in CKD CI exena4de Crcl<30 CI in renal dz product specific Dose adjustment (except linaglip4n) GI Moderate Moderate Neutral Neutral Moderate CHF Neutral Neutral Neutral Neutral Neutral CVD Benefit Neutral LDL Neutral Neutral Hypo: hypoglycemia, GI: gastrointestinal, CHF: congestive heart failure, CVD: cardiovascular disease, CI: contraindicated, CKD: chronic kidney disease,dz:disease Met: metformin, AGI: alpha glucosidase inhibitors permission requested July Profile of Antidiabetic Medications (Continue) TZD SU/GLN Colv BCR Pram Hypo Neutral Moderate/ mild Neutral Neutral Neutral Weight Gain Gain Neutral Neutral Loss Renal Fluid reten4on? Hypo risk Neutral Neutral Neutral GI Neutral Neutral Mild Moderate Moderate CHF Moderate Neutral Neutral Neutral Neutral CVD Neutral? Neutral Safe Neutral TZD: thizolididiones, SU/GLN: sulfonylureas/meglitinides, Colv: colvesalem, BCR: bromocriptine, Pram: pramlintide permission requested July Standards of Care Adults American Diabetes Associa4on (ADA) A1C 7% FPG: mg/dl PPG<180 mg/dl American Associa4on of Clinical Endocrinologists (AACE) A1C 6.5% FPG<110 mg/dl PPG<140 mg/dl Pediatric/pregnancy American Diabetes Associa4on (ADA) Pediatric A1C <7.5% FPG:90-130mg/dL Bed4me:90-150mg/dL Pregnancy A1C<7% before concep4on A1c<6% during pregnancy FPG/bed4me: mg/dl PPG: mg/dl The American Diabetes Association Diabetes Care Jan accessed March 2015 hnp:// with- diabetes/complica4ons/pregnancy/prenatal- care.html accessed March

13 Glycemic Control for Older Adults PaHents characterishcs Few chronic condi4ons Cogni4ve impairment, arthri4s, hypertension, chronic kidney disease, mild CHF Severe CHF, oxygen dependent lung disease, dialysis, advanced stage cancer A1c goal (%) Pre- prandial goal (mg/dl) BedHme goal (mg/dl) < < < The American Diabetes Association Diabetes Care Jan American Diabetes Association Algorithm 3 months A1C>7% Met+Lifestyle modificahons 3 months A1C>7% For 2 drug combinahon add either Su/Th/DP/GL/SGLT/In (do not add GL to DP) 3 months A1C>7% 3 months A1C>7% For 3 drug combinahon add either Su/Th/DP/GL/In/SGLT (do not add GL to DP) 3 months A1C>7% In basal+ In mealhme or GL Met=metformin, SU=sulfonylureas, Th:thiazolidinedione, DP=DPP-4 inhibitors, GL=GLP-1 receptor agonists, In=insulin, SGLT:sodium glucose transporter inhibitors 2 38 Diabetes Care Jan 2015;38(1): S48 AACE/ACE Glycemic Control Algorithm Change therapy if not in goal in 3 months A1c<7.5% A1c>7.5% Monotherapy Dual therapy Triple therapy A1c>9% Symptoms No Yes Met SGLT-2 DPP-4 AGI TZD SU/GLN Met+ GLP-1 or SGLT-2 DPP-4 or TZD Basal insulin Colv or BCR AGI or SU/GLM Met+ 1 st line +2 nd line agent Titrate Insulin therapy combination If not at goal in 3 months accessed March

14 Test Your Knowledge Case 1 Dan 42 year old WM, 270 lb, 70, 5 year history of type 2 diabetes. Current medication regimen: metformin 1000mg BID, glipizide ER 10mg daily. No episodes of hypoglycemia, weight gain - A1C 8.0%, FPG 110 mg/dl and PPG 240 mg/dl, Scr=1.4mg/dL When will you initiate a change in therapy: 1. Wait 3 more months 2. Discuss diet and exercise first for 6 months 3. Refer him to an endocrinologist 4. Augment therapy at this visit 40 Dan Question 2: Case 1 Which of the following is a good choice for therapy according to the ADA algorithm? and how would you change therapy? 1. Add DPP-4 inhibitor & keep glipizide dose the same 2. Increase doses of metformin & glipizide 3. Add GLP-1 agonist & cut in half dose of glipizide 4. Add SGLT-2 inhibitor & half the dose of metformin 41 Combination Therapy Better Glycemic Control Initial A1c >7.5% start dual therapy Target A1c not reached in 3 months with metformin add second agent SGLT2/DPP-4 inhibitors GLP1-agonists studies have demonstrated improved glycemic control with combination and add-on therapy Metformin Sulfonylurea Thiazolidinedione Insulin Diabetes Care 2014;37: S J Gen Intern Med April; 29(Suppl 1):

15 Case 2 George 65 years old, medication naïve A1c=10%, 210Lb, 5 2, BP=155/67, egfr=60ml/min, exercise: min/day Other medications: Hydrochlorothiazide 25mg daily, Lisinopril 5mg daily Atovastatin 10mg daily, Aspirin 81mg daily Date Before break- fast Before dinner Before Bed Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day Questions Initiation of Therapy What A1c goal would you aim at: 1. A1c<7% 2. A1c<8% 3. A1c<6.5% 4. A1c<7.5% 44 Questions (Cont) Initiation of Therapy What medication would you use initially: 1. Metformin 2. Metformin+GLP-1 3. Metformin+SGLT-2 4. Metformin+GLP-1+SGLT

16 Questions (Cont) Initiation of Therapy How would you monitor for adverse affects and improved glycemic control: 1. A1c only 2. A1c, FPG, PPG 3. Patient s report 4. Option 2 and 3 46 Case 2 George (continued) 3 months later, the patient is on metformin 1000mg bid+glp-1 agonist A1c=8%, BP=145/77 on diet/exercise Date Day 1 Day2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Before breakfast Before lunch Before dinner How will you augment combination medication therapy? 1. Metformin+SGLT-2 +DPP 4 2. Metformin +GLP-1+DPP-4 3. Metformin+SGLT-2+AGI or sulfonylurea 4. Metformin+SGLT-2+GLP-1 47 Utilization of Diet, Exercise & Home Glucose Logs History Addresses the patient s physiological needs Discloses information about patient s lifestyle Evaluates causes for hypoglycemia Evaluates causes for hyperglycemia Improves glycemic control Prevent wild fluctuation in glycemic control Ensures patient satisfaction Reduces chance for adverse effects 48 16

17 DPP-4 Inhibitors Benefits in Combination Therapy Part of 2 medicahon therapy Vs 1 medicahon therapy Part of 3 medicahon therapy Vs 2 medicahon therapy In addihon to MeXormin + basal insulin Vs. mexormin+ basal insulin A1c* A1c A1c FPG/PPG* FPG/PPG FPG/PPG Hypoglycemia Hypoglycemia Hypoglycemia *Results seen in treatment naïve patients FPG: Fasting plasma glucose PPG: Post prandial plasma glucose Package inserts.bms.com/pi/pi_onglyza Jul 2007 Hermansen K et al. Diabetes Obes Metab Rosenstock Diabetes Obes Metab 2010 Benefits of GLP-1 Agonists in Combination Medication Regimen GLP-1 in combination with 2-3 oral medications Vs. placebo A1c FPG Weight LA GLP-1 Vs. IR GLP-1 A1c FPG Weight GLP-1 Vs. basal insulin Non-inferiority (A1c reduction) Weight Diabetes Obes Metab June; 15(6): Drugs Context. 2015; 4: LA: long acting, IR: immediate release 50 SGLT2 Combination Medication Products Average Reduction of A1c Vs Monotherapy (metformin, sulfonylurea, DPP-4 Inhibitor) A1c% Drug Des Devel Ther 2014;8:

SGLT2 Combination Medication Products Average Reduction of Fasting Glucose Vs Monotherapy (metformin, sulfonylurea, DPP-4 Inhibitor) FPG (mg/dl) Drug Des Devel Ther

addressing different core defects of diabetes Glycemic control is further improved with combination medications>monotherapy Decision on diabetes therapy Individualized

18 SGLT2 Combination Medication Products Average Reduction of Fasting Glucose Vs Monotherapy (metformin, sulfonylurea, DPP-4 Inhibitor) FPG (mg/dl) Drug Des Devel Ther 2014;8: Summary Early glycemic control è risk for diabetes complications Incretin-based therapies and glucoretic therapy have a role in diabetes therapy by addressing different core defects of diabetes Glycemic control is further improved with combination medications>monotherapy Decision on diabetes therapy Individualized Requires evaluation of diet/exercise history and mechanism of action of medications Based on the physiological needs of the patient rather than algorithmic choices 53 Post-Test Questions 54 18

19 Post-test Question 1 Which one of the following patients with diabetes will be at high risk for progression to macrovascular and microvascular complications? year old patient on diet/exercise regimen and A1c=6.9% year old patient on metformin and A1c=6.4% year old on metformin and A1c=10% who will continue metformin therapy for 3 more months year old on metformin with A1c=8% who has a GLP-1 agonist therapy added 55 Post-Test Question 2 How can glucoretic agents (SGLT-2 inhibitors) be used to improve therapy in the treatment of a 58 year old patient with type 2 diabetes on blood pressure medications? 1. Glucoretic therapy can not be started in patients naïve to medication therapy 2. Glucoretic therapy can be started regardless of the renal function of the patient 3. The fact that the patient is on diuretics for blood pressure prohibits the use of glucoretic therapy 4. After evaluation of renal function, SGLT-2 inhibitors can be started 1st line or 2nd line therapy in the treatment of T2DM 56 Post-Test Question 3 How can incretin-based therapies improve glycemic control for a medication naïve 70 year old patient with type 2 diabetes and renal dysfunction BMI=31, A1c=7.5%? 1. Incretin-based therapy, specifically GLP-1 agonists, will increase insulin release, decrease glucagon release, may increase satiety and also has a glucose dependent affect 2. Incretin-based therapies specifically DPP-4 inhibitors will increase glucose release and reduce glucagon release, but also will increase the patient s weight 3. Incretin based therapies will only increase insulin release may, but can not be prescribed because of the patient s renal function 4. Incretin-based therapies, specifically GLP-1 agonists, will increase insulin release, decrease glucagon release, but may not 57 reduce A1c by more than 0.5% 19

20 Post-Test Question 4 A 45 year old patient with diabetes complains of hypoglycemic symptoms every morning. He takes sulfonylurea and metformin after he exercises in the evening. How can a healthcare professional utilize diet/exercise history, home glucose logs, and understanding the mechanisms of action of current medication regimen to adjust therapy? 1. Diet and exercise history can not explain fluctuation in glycemic control 2. Home glucose logs without the history of diet/exercise can explain when the patient eats and takes medications 3. Home glucose logs can recommend how the patient should change eating behaviors to improve efficacy of medication therapy 4. Evaluation of diet/exercise history together with the understanding the mechanism of action of sulfonylureas and metformin will help prevent adverse effects and improve glycemic control 58 Post-Test Question 5 What is the benefit of combination medication therapy in a patient with diabetes who failed to meet A1c goal on 1 st line therapy? 1. Combination medication therapy decreases the likelihood of dose titration of each single medication 2. Combination medication therapy may not be beneficial because it may reduce compliance with the regimen 3. Combination medication therapy allows for rapid achievement of glycemic targets and as a way to individualized care based on logical assessment of patients needs and mechanism of action of the component medications 4. Combination medication therapy will benefit a patient if medication choices follow algorithmic choices rather than 59 assessment of patient s physiologic needs Post-test Question 6 On a scale of 1 to 5, please rate how confident you are in intensifying treatment strategies beyond monotherapy in a patient with Diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 60 20

Post-test Question 7 Which of the statements below describes your approach to intensifying treatment strategies beyond monotherapy in a patient with diabetes? 1.

21 Post-test Question 7 Which of the statements below describes your approach to intensifying treatment strategies beyond monotherapy in a patient with diabetes? 1. I do not participate in the diagnosis and treatment of diabetes, nor do I plan to this year. 2. I did not manage diabetes beyond monotherapy before this course, but as a result of attending this course I m thinking of doing this now. 3. I do manage diabetes beyond monotherapy and I now plan to change my treatment methods based on completing this course. 4. I do manage diabetes beyond monotherapy and this course confirmed that I don t need to change my methods. 61 Questions!!! 62 21

Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes

Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes Genetics, environment, and lifestyle (obesity, inactivity, poor diet) Impaired fasting glucose Decreased β-cell