Robert Tanenberg, MD, FACP Professor of Medicine Division of Endocrinology Brody School of Medicine Medical Director, Diabetes and Obesity Institute East Carolina University Medical Director, Inpatient Diabetes Program Pitt County Memorial Hospital Diabetes Drugs and Devices: A Guide to the Pharmacologic and Technologic Menagerie

Learning Objectives Describe the benefits and drawbacks of the incretin drugs vs.basal insulin in patients failing traditional oral agents Discuss stepwise therapy for patients who require more than basal insulin Demonstrate the usefulness of continuous glucose monitoring for patients on insulin

Disclosures Research Support  Medtronic  Johnson and Johnson  Eli Lilly  Sanofi  Novo-Nordisk Speaker’s Bureaus  Sanofi  Boehringer Ingelheim-Lilly

Overview Type 2 Diabetes: Type 2 Diabetes:

If the current "obesity epidemic" continues unchecked, 50% of the U.S. adult population will be obese -- with body mass index values of 30 or higher -- by 2030, researchers said. Wang and colleagues also projected that, as a result of the burgeoning obese population, the U.S. will see the following health impacts: 6 to 8.5 million more people with diabetes 5.7 to 7.3 million more cases of heart disease and stroke 490,000 to 670,000 additional cancers 26 to 55 million quality-adjusted life-years lost The economic burden of these increasing morbidities will be substantial, medical expenditures alone will be higher by $48 to $66 billion annually by 2030, without taking into account lost productivity and other indirect costs Reduced productivity would add another $390 to $580 billion to the annual tab Half of Americans Projected to Be Obese in 2030 Wang Y, et al "Health and economic burden of the projected obesity trends in the USA and the UK" Lancet 2011; 378:815-25

Prevalence of DM in US 2007: The Diabetes Belt 9.9% % > 11% 8.7% - 9.8% < 8.6% The Diabetes Belt is composed of counties with a prevalence of DM > 11%

Prevalence of Diabetes and Obesity in North Carolina by Region 2009 Eastern NC is #1 in Both Percentage DiabetesPercentage Obesity Obesity defined as a BMI > 30 Obesity data are from from NC Center for Health Statistics BRFSS Program and CDC. Diabetes data courtesy of D. Cummings, ECU Epidemiology

EASD: Diabetes Estimate Now 366 Million By Kristina Fiore, Staff Writer, MedPage Today Published: September 13, 2011 LISBON -- About 366 million people worldwide have diabetes, according to the latest figures from the International Diabetes Federation(IDF) released in advance of a United Nations summit on non-communicable diseases in New York next week. That's up from 300 million estimated in the 2009 edition of the organization's Diabetes Atlas. This year's edition will be published in mid- November. The new edition also estimates 4.6 million deaths from the disease annually, Jean Claude Mbanya, MD, president of the IDF, said during a press briefing at the European Association for the Study of Diabetes (EASD) meeting here. "We don't want world leaders to forget diabetes, which is a tsunami of the 21st century," Mbanya said regarding the early release of the figures.

Diabetes Facts 2011 About 366 million people worldwide have diabetes, according to the latest figures from the International Diabetes Federation (IDF) That's up from 300 million estimated in 2009 The new estimate from the IDF is 4.6 million deaths from the disease annually Numbers underestimated, not all countries have good data U.S. prevalence is 25.8 million (7 million undiagnosed) Estimated to affect nearly 600 million people within 20 years Global spending diabetes patient care at $465 billion/yr Sources: Kristina Fiore, Staff Writer, MedPage Today published: September 13, 2011 and CDC National Diabetes Fact Sheet

Costs of Diabetes Care in U.S. Continue to Soar The total annual economic cost of diabetes in 2007 was estimated to be $174 billion an increase of $42 billion since 2002 Factoring in the additional costs of undiagnosed diabetes, prediabetes, and gestational diabetes brings the total cost of diabetes in the United States in 2007 to $218 billion Medical expenditures totaled $116 billion and were comprised of $27 billion for diabetes care, $58 billion for chronic DM related complications, $31 billion for excess general costs Indirect costs unemployment disability, and loss of productive capacity due to early mortality totaled $58 billion The 2007 per capita annual costs of health care for people with diabetes is $11,744 a year, of which $6,649 (57%) is attributed to diabetes One out of every five US health care dollars is spent caring for someone with diagnosed diabetes. Accessed at:

Diabetes: Complications and Mortality Adults with diabetes have heart disease death rates ~ times higher than adults without diabetes The risk for stroke is 2 -4 times higher among people with diabetes ~73% of adults with diabetes have blood pressure > 130/80 or use prescription medications for hypertension Worldwide, total mortality attributable to higher-than-optimum blood glucose is 3.16 million, vs. 4.8 million from smoking, 3.9 million from high cholesterol, and 2.4 million from overweight and obesity* Lancet 2006; 368: Nov 17,2006

Glycemic Control and Vascular Complications in T2DM MICROVASCULARMACROVASCULARMORTALITY DCCT/EDIC UKPDS ACCORD ADVANCE VADT Observational follow-up UKPDS Group. Lancet 1998;352:837-53; Gerstein et al. New Engl J Med 2008;358: ; Duckworth et al. New Engl J Med 2009;360:129-39; Patel et al. New Engl J Med 2008;358: ; ACCORD Study Group. New Engl J Med 2010; 363:

UKPDS Intervention And Observation: Legacy Benefits After median 8.5 years post-trial follow up Aggregate endpoint Any diabetes-related endpoint RRR:12%9% Microvascular diseaseRRR:25%24% Myocardial infarctionRRR:16%15% All-cause mortalityRRR:6%13% RRR, relative risk reduction UKPDS 80. New Engl J Med 2008;359

Baseline Characteristics of the Landmark Trials in T2DM UKPDS Group. Lancet 1998;352:837-53; Gerstein et al. New Engl J Med 2008;358: ; Duckworth et al. New Engl J Med 2009;360:129-39; Patel et al. New Engl J Med 2008;358: ACCORDADVANCEVADTUKPDS Number of subjects10,25111,1401,7914,209 Gender (% male) Age (years) Diabetes duration (years) HbA 1c (%) CV events (%)~35~32~40unknown Insulin use (%)~35~1.5~500

Understanding Cardiovascular Outcome Studies in Type 2DM Schwartz S S, Kohl B A Mayo Clin Proc. 2010;85:S15-S26 © 2010 Mayo Foundation for Medical Education and Research

The Multifactorial Pathogenesis of Type 2 Diabetes: DeFronzo’s “Ominous Octet” Impaired insulin secretion and insulin resistance underlie all other pathophysiologic defects leading to hyperglycemia DeFronzo, R The American Journal of Medicine Volume 123, Issue 3, Supplement, March 2010, Pages S38-S48

Type 2 Diabetes Characterized by dual impairments: 1) Impaired ß-cell Function: Diminished Insulin Secretion IGT (pre-diabetes) occurs initially 2) Impaired Insulin Action: Increased Insulin Resistance Most often related to obesity May precede IGT by 10 or more years 1) Impaired ß-cell Function: Diminished Insulin Secretion IGT (pre-diabetes) occurs initially 2) Impaired Insulin Action: Increased Insulin Resistance Most often related to obesity May precede IGT by 10 or more years

Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota  20  Years of Diabetes Relative  -Cell Function Plasma Glucose Insulin resistance Insulin secretion Fasting glucose Post meal glucose 6-6 Natural History of Type 2 Diabetes  Over time most Type 2 patients lose insulin secretory capacity.  Insulin resistance precedes onset of DM  DM requires both IR and loss of insulin secretion 126 mg/dL

Beta-cell Function Progressively Declines Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58) HOMA, homeostasis model assessment Beta-cell function (%, HOMA) Extrapolation of beta-cell function prior to diagnosis –4–46–10–8–8–6–6–2– –128 Diabetes diagnosis Years from diagnosis

Type 2 diabetes Years from diagnosis Pre-diabetes Onset Diagnosis Insulin secretion Insulin resistance Postprandial glucose Macrovascular complications Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Fasting glucose Microvascular complications Natural History of Type 2 Diabetes N Engl J Med. 2002;347:

Diagnostic Criteria for Pre-diabetes and Diabetes A1C Fasting Plasma Glucose Test (FPG) 2-Hour Oral Glucose Challenge Normal< 5.6Below 100 mg/dlBelow 140 mg/dl Pre-diabetes5.7% - 6.4% mg/dl (IFG) mg/dl (IGT) Diabetes≥ 6.5%126 mg/dl or above200 mg/dl or above American Diabetes Association. Diabetes Care 2010; 33;(Suppl.1):S11-61

Treatment of Type 2 Diabetes Lifestyle Modification Lifestyle Modification

Lifestyle Modification: Good Dietary Habits Are Essential Always remember to send your patients to a diabetes educator for behavioral therapy (diet and exercise), instruction in glucose monitoring, insulin, treatment of hypoglycemia, foot care, etc.

Lifestyle Modification - Exercise Suggest Walking A Dog

Pharmacologic Treatment Options Treatment of Type 2 Diabetes

Increased β Cell Workload Decreased β Cell Response The Pathogenesis of Type 2 Diabetes  Insulin resistance - obesity  Food intake  Rate of nutrient absorption  Glucagon secretion  hepatic glucose output  Insulin secretion to  glucose  1 st phase insulin response Hyperglycemia results from an imbalance between β cell workload and β cell response

Increase Insulin Levels (  Supply )  Insulins  Sulfonylureas and  Meglitinides (stimulate ß cells) Increase Insulin Sensitivity (  Demand)  Biguanides (liver)  Thiazolidinediones (“Glitazones” or “TZDs”) (muscle) Delay /  Carbohydrate Absorption S. Intestine (  Demand)  Alpha-Glucosidase Inhibitors  Bile acid sequestrants Incretin Drugs (multiple effects: α /ß cells, liver, stomach, intestine, brain)  GLP-1 Agonists  DPP-4 Inhibitors  Amylinomimetics Antihyperglycemic Therapy for T2DM More Than 10 Different Drug Classes in US

ADA Algorithm for the Management of Type 2 Diabetes Reinforce lifestyle interventions at every visit and check HbA 1c every 3 months until HbA 1c is <7%, and then at least every 6 months. The interventions should be changed if HbA 1c is ≥7% Nathan et al. Diabetes Care 2008;31:1–11 a Sulfonylureas other than glibenclamide (glyburide) or chlorpropamide b Insufficient clinical use to be confident regarding safety Lifestyle and metformin + intensive insulin Lifestyle and metformin + basal insulin Lifestyle and metformin + sulfonylurea a At diagnosis: lifestyle + metformin Lifestyle and metformin + pioglitazone No hypoglycemia Edema/CHF; bone loss Lifestyle and metformin + GLP-1 agonist b No hypoglycemia; weight loss Nausea/vomiting Lifestyle and metformin + pioglitazone + sulfonylurea a Step 1Step 2Step 3 Lifestyle and metformin + basal insulin Tier 2:Less well-validated therapies Tier 1:Well-validated core therapies

AACE 2009 Algorithm A1c Goal < 6.5% Endocr. Pract. 2009; Sept/Oct V15 (No.6) Page 546

Early Aggressive Intervention May Improve Patients' Chances of Reaching Treatment Goal Schwartz S S, Kohl B A Mayo Clin Proc. 2010;85:S15-S26 © 2010 Mayo Foundation for Medical Education and Research ADA Algorithm AACE Algorithm

Ten Factors to Consider When Selecting a Drug for T2DM 1) Efficacy: What % A1c reduction expected 2) Safety: Hypoglycemic Potential 3) Effect on Weight: Gain, neutral or loss 4) Durability: How long does the drug keep working 5) Renal Function: Dose adjustments; contraindications 6) Cardiovascular Risk: Increase, neutral or decrease 7) Effect on Lipids: Positive, negative or neutral 8) Administration: Oral or injectable; qd vs. bid 9) Synergy: With other diabetes drugs 10) Cost: Affordability (insurance tier; generic option)

Difficulties in Achieving A1c Targets Challenges: Late diagnosis and initiation of therapy Therapeutic inertia Lack of lifestyle intervention Secondary drug failure (loss of insulin reserve) Role of postprandial glucose in failure Adverse events associated with diabetes drugs Complexity of care (Inadequate time and resources) Adapted from A Garber

8 ExenatidePioglitazone (A1c < 9.0) Metformin Sitagliptin 2.0 Efficacy: Comparison of A1c Reduction Between Selected Anti-Diabetic Agents (Monotherapy) %A1c  from baseline Glimepiride 2.2 Pioglitazone Insulin (A1c > 9.0) > 2.5

Increasing Weight with Intensification of SU Drug or Insulin Treatment in T2DM Intensifying treatment increasing weight Increasing weight= intensifying treatment Intensive Conventional HbA 1c Cross-sectional, median values HbA 1c (%) Years from randomization 6.2% upper limit of normal range Change in body weight Cross-sectional, mean values − Weight (kg) Years from randomization

Balancing Glycemic Control and Side-effects Clinicians must balance glycemic control with side effects associated with current type 2 diabetes treatments, including insulin

Newer Drugs for Diabetes Development of Therapeutic Agents Based on the GLP-1 Pathway

37 Definition of an Incretin In ● cre ● tin Intestine Secretion Insulin Gut-derived factors that increase glucose-stimulated insulin secretion Is a substance (hormone) originating in the GI tract and released during nutrient absorption Augments insulin secretion at physiologic concentrations Insulinotropic effects are glucose-dependent Some incretins also decrease glucagon secretion The most important incretin is GLP-1 (glucagon-like peptide) Creutzfeldt. Diabetologia. 1985;28:565. Pugh MB, et al, eds. Stedman’s Medical Dictionary. 27th ed Vilsbøll T, Holst JJ. Diabetologia. 2004;47:

The Incretin Effect Demonstrated as the Response to Oral vs. IV Glucose Mean ± SE; N=6; *P  0.05; =glucose infusion time. Venous Plasma Glucose (mg/dl) Time (min) C-Peptide (nmol/L) Time (min) Incretin Effect Oral Glucose IV Glucose * * * * * * * Nauck. J Clin Endocrinol Metab. 1986;63:492. Copyright 1986, The Endocrine Society.

GLP-1: An Intestinal Hormone Secreted from L cells of the ileum with meals. Effects Stimulates insulin secretion Suppresses glucagon secretion Delays gastric emptying Enhances satiety Enhances  -cell mass/replication in animals Rapidly degraded by an enzyme known as protease dipeptidyl peptidase IV (DPP-IV) GLP-1 levels reduced in IGT and T2DM Drucker. Diabetes Care. 2003;26:2929.

Abu-Hamdah, R. et al. J Clin Endocrinol Metab 2009;94: GLP-1 Actions on Peripheral Tissues

41 Glycemic Response to Exogenous IV GLP-1 Infusion Rachman J, et al. Diabetologia. 1997;40: Glucose (mmol/L) DM, Saline DM, GLP-1 Control

Therapy with GLP-1: A Major Problem DPP4 Degradation Leads to a Short Plasma Half Life: Not Suitable for Subcutaneous Injection GLP-1(7-36) amideGLP-1(9-36) amide Dipepidyl pepidase IV Active Inactive 1)Naturally occurring GLP-1 analogues with longer half-life (e.g., exenatide) 2)Inhibit DPPIV (incretin enhancers, e.g., sitagliptin) 3)Synthesize DPPIV-resistant analogues (e.g., liraglutide) : U. of Surrey, UK 3 Solutions:

GLP-1 Agonists Exenatide (Byetta) Liraglutide (Victoza) Best Candidates Overweight / Obese Recent onset DM Patients making insulin Patients on metformin Good insurance Unable to lose wt. on diets Willing to take injections Cautions / Contraindications * Hx or risk of pancreatitis Prone to nausea (relative) Hypoglycemia (w/ SU drugs) CKD 3-5 Gastroparesis Patients on mealtime insulin Hospitalized patients Hx Medullary CA thyroid (V) * Do not use if GFR < 30 mL/min. In patients with moderate renal impairment (GFR 30 to 50) monitoring of serum creatinine is warranted when initiating therapy and after the dose increases

DPP-4 Inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Best Candidates Recent onset DM Patients making insulin Patients on metformin Patients who comply with once a day meds Normal weight /overweight Patients with postprandial hyperglycemia Unable to take other OADs Good insurance Cautions / Contraindications* Hx or risk of pancreatitis Patients on mealtime insulin Hypoglycemia (w/ SU drugs) Liver disease (severe) CKD (dose adjustment ) Drug interactions (CYP34A) Hx of angioedema ? Immunosuppressed patients * These drugs may be at any GFR including CKD 5. In patients with moderate renal impairment (GFR < 60) reduce dose; except no dosage reduction needed for linagliptin (GI excretion )

When Patients Fail Conventional Oral Drugs: What Are The Next Options?

55 y/o female with T2DM, obesity(BMI=31) & HTN DM meds: metformin 1gr BID & glipizide 10mg BID Glycemia and Labs HbA 1c 8.1% FPG mg/dL S. Creatinine = 0.9, normal LFTs What is the next best glycemic treatment option? a) TZD b) NPH insulin at bedtime c) Exenatide SQ BID Goldberg et al. New Engl J Med 2008;358: Treatment Options for T2DM: Hypothetical Case Presentation

North American Diabetologists 53% 15% 32% 6455 participants: Diabetologists 18%, Other specialties 49%, House Staff 17%, Other Health Professionals 16% Management of T2DM: Polling Results Goldberg et al. New Engl J Med 2008;358:

What drug classes and other treatments will lower this patient’s A1c from 8.1 to under 7.0%? a) TZDs (30 mg pioglitazone) b) Insulin (NPH, Glargine, Detemir) c) GLP-1 Agonists (Exenatide, Liraglutide) d) DDP-4 Inhibitors – maybe e) Behavioral changes Diet: stop sweet tea, regular sodas, junk food etc Weight loss Exercise 30 min > 3 times a week f) If OSA is present, nightly C-Pap g) Bariatric surgery (DM remits in 85% GOP and 65% banding) Treatment Options for T2DM: Hypothetical Case Presentation

Type 2 DM A1c Levels and Obstructive Sleep Apnea (OSA) J Respir Crit Care Med : Compared with patients without OSA, the adjusted mean A1c was increased by: 1.49% (P< ) in patients with MILD OSA, 1.93% (P< ) with MODERATE OSA (P< ) with SEVERE OSA AHI = Apnea, Hypopnea Index MILD AHI = 5-15 MODERATE AHI = SEVERE AHI > 30 ½½

Some Diabetes Drugs Cause Weight Gain WT. GAIN Insulins Sulfonylureas (SU) Meglitinides Actos, Avandia Combos with SU or TZD: Glucovance* Metaglip* Duetact Avandamet* Avandaryl Actoplusmet* WT NEUTRAL/LOSS Metformin (+/-wt loss) Precose, Glyset Byetta (wt loss) Victoza (wt loss) Symlin (wt loss) Januvia, Onglyza Welchol Cycloset Combos w/out SU or TZD: Janumet Kombiglyze * Metformin may offset wt. gain from SU, TZD or insulin

Some Diabetes Drugs May Induce Hypoglycemia Insulins Less hypos with basal than premix Sulfonylureas Common in elderly and those with CKD Short acting glipizide safest Meglitinides Good option for those who skip meals Combination Drugs with sulfonylureas Glucovance, Metaglip, Avandaryl, Duetact)

Diabetes Drugs to Avoid or Adjust Dosage in Diabetic Patients with Renal Impairment Metformin and its combination drugs* Safe if GFR > 40 Long acting sulfonylureas glyburide, glimepiride Insulin Lower dose (e.g. 0.3 units /kg if CKD) TZDs if nephrotic syndrome Incretin drugs GLP-1 agonists: avoid if GFR < 30 DPP4-I : If GFR < 60: adjust dose except for linagliptin (*Trade names: Glucovance, Metaglip, Actoplusmet, Janumet, Kombiglyze, Avandamet)

Diabetes Drugs to Avoid in Diabetic Patients with Congestive Heart Failure Pioglitazone (Actos) Rosiglitazone (Avandia) Metformin Combination Drugs (all have MF or a TZD) Glucovance Avandamet Metaglip Actoplusmet Duetact Avandaryl Janumet Note: The recent literature supports the use of metformin in stable or compensated CHF (Cardiology in Review 2008;16: 269–272)

Drs. Banting and Best (University of Toronto) “Marjorie” Dog # 33 lived 70 days on insulin extract First insulin injected into a human Jan. 11, 1922

Prescribe Insulin ASAP for “Severely Uncontrolled” Diabetes (from: 2008 ADA Consensus for T2DM) Defined as one or more of the following: Fasting glucose > 250 mg/dl Random glucose > 300 A1c > 10% Ketonuria Symptomatic (polyuria, polydipsia, and weight loss) Therapeutic recommendations: Rapidly titrate insulin to achieve glucose targets After glucose controlled, oral agents may be added Diabetes Care 31:1-11, 2008

Benefits of Insulin Therapy for Type 2 Diabetes Biologic replacement of deficient hormone High safety profile Easy to titrate No contraindications No dose limits Therapy will decrease A1c to < 7% in most cases Corrects hyperglycemia and reduces glucotoxicity Increases glycolysis and reduces production of oxidative stressors Inhibits FFA production Improves endothelial dysfunction Increases vasodilatation and slightly lowers BP Reduces inflammatory markers May be antithrombotic Adapted from: Gerstein, H.C. Diabetes Digest 7:2 (2003)

4: :0012:0016:0020:0024:004:00 BreakfastLunch Dinner Plasma insulin (U/ml) Plasma insulin (µU/ml) Time 8:00 Physiological Serum Insulin Secretion Profile Fasting

The Basal Insulin Concept Amount of insulin required when food is not absorbed to regulate endogenous glucose output Suppresses glucose production between meals and overnight Specifically suppresses hepatic glycogenolysis Prevents lipolysis in DM 1 Nearly constant levels ~50% of daily needs In outpatient setting, usually begun at 0.2 units/kg Bedtime basal insulin should target a FPG of Continue metformin, if possible, to offset weight gain If continue SU and TZD caution for increased side effects

Insulin Characteristic NPH Humulin N Novolin N Glargine Lantus Detemir Levemir Onset (hrs) Peak (hrs) 6-14No Sig. PeakRelatively Flat Mean Duration of Action (hrs) (dose dependent) Dosing (hrs) q. 8-12q. 24 hrsq Cost $$$$ Comments Nocturnal hypoglycemia am. hyperglycemia intersubject variability Less hypo vs. NPH Less hypo vs. NPH Slightly less wt. gain Basal Insulins From Prescriber's Letter March 2006 Vol. 22 Number

Option 1: Add an Incretin When Patients Fail Basal Insulin + Oral Drugs: What Are The Next Options?

Maximizing the Impact on Glycemic Control 1) Basal Insulin is Effective in Reducing FPG > PPG 2) GLP-1-Based Therapies Improve PPG ≥ FPG Combined Therapy Has the Potential to Reduce A 1c While Limiting Hypoglycemia and Weight Gain (Combination is currently off-label) FPG=fasting plasma glucose PPG=postprandial glucose

Adding Sitagliptin to Insulin Reduces A 1c with a Minimal Increase in Hypoglycemia vs. Placebo Weeks HbA 1c (%) Incidence of hypoglycemia (events/patient/year) Sitagliptin 100 mg/day + insulin* Placebo + insulin Vilsbøll et al. Diabetes Obes Metab 2010;12:167–77 *long-acting, intermediate-acting or pre-mixed insulin Placebo + insulin Sitagliptin 100 mg/day + insulin* % Reduced A1c 0.6%

Exenatide Added to Insulin Glargine Reduces A 1c and Weight with Low Risk of Hypoglycemia (off-label) HbA 1c Hypoglycemia Weigh t ΔHbA 1c (%) Minor hypoglycemia (Events/patient/year) ΔWeight (kg) Insulin glargine + exenatide ± OADs (n=137) Insulin glargine + placebo ± OADs (n=122) Two major hypoglycemic episodes in the placebo group 30-week double-blind study comparing twice-daily exenatide vs. placebo as add-on to insulin glargine ± OADs Buse et al. Ann Intern Med Jan 18;154(2): OAD, oral anti-diabetic drug

12 Week Study Adding GLP-1-based Therapies to Glargine Insulin and Metformin (off-label) A 1c Hypoglycemia Weight ΔHbA 1c (%) Minor hypoglycaemia (events/patient/year) ΔWeight (kg) p= p= Insulin + metformin + exenatideInsulin + metformin + sitagliptinInsulin + metformin Arnolds et al. Diabetes Care 2010;33:1509–15 E+ME+M E+ME+M E+ME+M S+MS+M S+MS+M S + M M M M

Drugs Plus Insulin for T2DM Drugs / ClassGlycemic Synergy Effect on Weight Comments MetforminYesNeutral / Decrease Must drug for all DM 2 unless CKD SulfonylureasNo2+ IncreaseUse with basal insulin PioglitazoneYes4+ IncreaseFluid retention and CHF Sitagliptin Saxagliptin * Linagliptin * YesNeutralUse with basal insulin Exenatide * Liraglutide * YesNeutral / Decrease Use with basal insulin * Off Label

Option 2: Add Prandial (Bolus) Insulin to One or More Meals When Patients Fail Basal Insulin + Oral Drugs: What Are The Next Options?

The Bolus Insulin Concept Amount of insulin needed in relation to normal meals to promote conversion of digested nutrients into storage forms of energy Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour ~50% of daily needs Can give as prandial and/or correctional insulin Analogues are better for meals Dose can be adjusted based on carbohydrate ratios In patients with poor intake, analogues can be given just after meals

Insulin Characteristic Regular Humulin Novolin Lispro Humalog Aspart Novolog Glulisine Apidra Mean Duration of Action (hrs) Onset (Min) Peak (hrs) Cost $$$$ Comments Inject minutes a.c. Use in IV insulin infusions Cartridge pen with memory or disposable pen Disposable pen. ? better absorption in obese; equivalent p.c. dosing Bolus Insulins From Prescriber's Letter March 2006 Vol. 22 Number

Time 4:008:0012:0016:0020:0024:004:008:00 BreakfastLunchDinner Short acting analog e.g. Lispro Basal analog e.g. Glargine Skyler J, Kelley’s Textbook of Internal Medicine Basal/Bolus Insulin Absorption Pattern with Analogue Insulin Preparations

Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A Stepwise Approach to Insulin Therapy in Patients with Type 2 Diabetes Failing Basal Insulin Treatment. Endocr Pract May-Jun;17(3): Adding Short Acting Insulin to Basal: A Stepwise Approach

Data from studies by Monnier reveal the following about A1C levels in diabetic patients: A1c > 10% ~70% of value is from the fasting BG A1c ~ 8.5% ~50% of value from FPG and ~50% from PPG* A1c < 7.3% ~30% of value from FPG and ~70% from PPG Bolus insulin therapy should be added to T2DM patients if the A1C >7.0% despite achieving a target fasting BG of 110 mg/dl Further increases in basal insulin therapy when the A1c approaches 7.0% will increase the chances of hypoglycemia with minimal improvement in overall glycemic control In most of these studies, patients remain on OADs except for sulfonylureas Diabetes Care 2003 Mar;26(3):881-5 * PPG=postprandial glucose Stepwise Study: Background: Basal-Bolus Therapy

Methods (Glargine Dosing) Stepwise Study: Methods (Glargine Dosing) Over 600 patients with T2DM failing 2 oral agents Baseline A1c ~10% Initial dose = 10 units glargine Glargine given at hs or am – time kept constant Patient instructed in the use of a meter to check self-monitored blood glucose (SMBG) per protocol Target Fasting Blood Glucose (FBG) < 110 FBG target range = Patient to increase dose every 3 rd day per algorithm to achieve target FBG Nurse coordinator reviewed dosing adjustments weekly Patients required to contact nurse if FBG > 250 or < 70. Endocr Pract May-Jun;17(3):

Stepwise Study: Methods (Randomization) After the run-in period subjects not at goal (A1C<7.0%) at week 0 were randomized to one of three 24-week intensified regimens Glulisine (Glu) insulin was given 0-15 min. a.c. The 3 regimens (arms) were Glu injected a.c. 1 meal (Glu-1) Glu injected a.c. 2 meals (Glu-2) Glu injected a.c. 3 meals (Glu-3) Insulin was given to target meals with maximum glycemic impact Glu-1 mostly ac supper meal Glu-2 either ac breakfast or lunch meal plus supper All subjects remained on insulin Glargine qhs/am Glulisine titrated to achieve Glucose < 110 ac / < 140 HS Endocr Pract May-Jun;17(3):

A1c Results for 14 Week Run-In Phase and 24 Week Post Randomization Phase Subjects Not at goal (63%) Randomized to 3 groups Rx Glargine Add Glulisine Subjects < 7.0% End Study (37%)

Stepwise Study: Summary and Conclusion A1C < 7.0% in 37% Glargine alone at 14 weeks (mean 0.58U/kg) A1C improved from baseline to week 24 in all groups The percentage of patients achieving A1C<7.0% at week 24 was greater in Glu-3 vs. Glu-1 (P=0.017) and Glu-2 (P=0.045) Glargine dose and weight did not differ significantly among the 3 arms There was a non-statistically significant trend for more severe hypoglycemia in Glu-3 vs. Glu-1 and Glu-2 72% of all study completers achieved an A1c of <7.0% at the end These results confirm the efficacy of Glargine in reducing A1C in patients failing >2 OADs These results support initiating prandial insulin with 1 injection, increasing to 2, and then 3 only if the A1C goal is not reached This method simplifies the basal-bolus regimen when further intensification of insulin is required Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A Stepwise Approach to Insulin Therapy in Patients with Type 2 Diabetes Failing Basal Insulin Treatment. Endocrine Practice 2011 May-Jun;17(3):

Treatment Plan for Basal Bolus Therapy in T2DM Continue 1-3 oral agents (especially metformin) Start with an analogue basal insulin (or NPH) at h.s Slowly increase the basal dose to achieve target FPG If fasting in target ( ) most days, recheck A1c q 3 mo. If A1c between % add rapid acting analogue insulin (RAI) before the largest meal (usually supper) and titrate to achieve a BG of at h.s or next meal If A1c > 8.5% or unable to get fasting BG to target add RAI injections before all meals and titrate to target If still not successful recheck patient dietary and medication compliance and if acceptable, evaluate for insulin resistance

ADA Insulin Initiation and Titration Algorithm Diabetes Care. 2009;32:

“ Ketoacidosis may kill a patient but frequent hypoglycemic reactions will ruin him.” E.P. Joslin ( )

Iatrogenic Hypoglycemia Common in patients on insulin or SU drugs Common causes in treated diabetic individuals Too much insulin (MD and patient dosing errors) Inadequate food intake, or poor timing of meals (insulin - food mismatch) Exercise without adequate adjustments (insulin - exercise mismatch) CKD Gastroparesis G.I. disorders (vomiting, diarrhea, malabsorption) Alcohol use/abuse

Thresholds in Response to Hypoglycemia in Normal Subjects Plasma Glucose (mg/dl) Clinical Response < 60diaphoresis, anxiety, palpitations, hunger, tremor < 55early cognitive dysfunction < 50lethargy and obtundation < 30coma < 20convulsions, death  = Neuroglycopenia  (adapted from McCulloch, 1998)

Severe Hypoglycemia: Definition An episode of neuroglycopenia so severe that another person is required for treatment Symptoms include: disoriented behavior loss of consciousness inability to arouse from sleep seizures

Thresholds in Response to Hypoglycemia in Normal Subjects Plasma Glucose (mg/dl)Hormonal Response < 80insulin secretion suppressed < 70glucagon and epinephrine increased < 60growth hormone and cortisol increased (adapted from McCulloch, 1998)

Impaired Counter-regulation in T1DM and Some T2DM Patients Deficient glucagon response to hypoglycemia is the rule Deficient epinephrine response to hypoglycemia (“HYPOGLYCEMIC UNAWARENESS”) Patients with diminished glucagon and epinephrine response have a 25 fold increase in the frequency of severe hypoglycemia Sleep or sedation further impairs epinephrine response to hypoglycemia Non-selective beta blockers impair the secretion of epinephrine and the patients ability to sense low BGs

Real-time Glucose Sensors are the Newest Devices That Can Prevent Severe Hypoglycemia for Patients Requiring Insulin

How Does a Real-time Glucose Sensor Work? A Real-time Sensor is a Continuous Glucose Monitoring (CGM) system comprised of a small glucose sensor, wireless transmitter, and portable monitor The sensor contains a platinum electrode that is inserted into the subcutaneous tissue Interstitial glucose is converted into H and gluconic acid H reacts with the platinum to generate an electrical current The sensor attaches to a small, lightweight transmitter, which sends glucose sensor data wirelessly to the monitor By calibrating the sensor value to a fingerstick glucose meter (plasma) value the sensor glucose value is converted into an equivalent plasma glucose value with a range of mg/dl

How Does a Real-time Glucose Sensor Work?  The sensor measures the interstitial glucose continuously and reports values q5 minutes - up to 288 readings a day. It plots trend lines to see how blood glucose levels may be affected by food, medications, and activities. CGM devices have built in alarms that go off if the Sensor Glucose falls below any set level (e.g. 70) alerting the patient to take actions to fend off impending hypoglycemia Patients must check fingerstick glucose at least 2 times a day to calibrate the sensor It is recommended that patients confirm low and high sensor glucose reading with their glucometer

Medtronic™ Real-Time Glucose Sensor Disposable Sensor and Transmitter Unit Receiver Unit with Screen Display and Multiple Functions Including Trend Graph and Alarms for High and Low Glucose Readings

Dex-Com™ Real-Time Glucose Sensor

Glucose Profiles in a Patient with Type 1 Diabetes vs. a Non-diabetic (Medtronic) Glucose Concentration (mg/dl) Midnight Noon Meal Type I Diabetic - Sensor Type I Diabetic - Blood Type I Diabetic - Finger Stick Non-Diabetic - Blood

Dex-Com™ 7 Day Tracking Graph in a Patient with TDM1 x 10 years (A1c=6.3%) The YSI reference value was measured on Day 7 in-clinic. Bailey TS Zisser H Chang A Diabetes Technology and Therapeutics 2009: 11 (12)

Sensor Economics 2011 Real-time monitors cost about $750 and the renewable sensors last 3-7 days cost ~$30 each ($10/day) Currently some BCBS, commercial plans and Tricare will pay for the sensors in patients with a documented history of hypoglycemia These devices can be life-saving for patients with hypoglycemic unawareness Medicare will NOT pay for real-time sensors but will pay physicians to administer and interpret recordings from non-real-time (3-7 day) sensor recordings Currently only the Medtronic insulin pump offers a real-time sensor option (sensor-augmented insulin pump)

Medtronic™ Paradigm Pump with Real-Time Glucose Sensor ( Sensor Augmented-Pump)

Summary and Conclusions Diabetes has become a costly epidemic in our society Behavioral modifications are a critical component of treatment but rarely control T2DM Consider testing for sleep apnea (OSA) in obese snorers Refer patients to a diabetes educator (CDE) as soon as possible to learn to use a glucometer, inject insulin, treat hypoglycemia, foot care rules, etc. Most traditional therapies for T2DM are often associated with weight gain, hypoglycemia, failure to maintain glycemic control over time Newer agents have better profiles and more durability but are expensive and most are off-label for use with insulin Start insulin for patients who are symptomatic (polyuria, weight loss) and/or have labs c/w poor control (any BG > 300, FPG >250 or A1c >10%) OR if patients cannot get A1c < 7% on 2-3 drugs

Summary and Conclusions  Set an appropriate A1c target: < 6.5% in early T2DM if not using SU drugs or insulin < 7% most patients with T1DM and T2DM 7.5 or 8.0% if elderly, at high risk for hypoglycemia, or have significant co-morbidities When patients fail basal insulin plus orals add a short acting analogue to the largest meal first and progress if needed Refer patients with recurrent or severe hypoglycemia to a diabetes specialist for consideration of real-time glucose sensors w/alarms Never forget non-glycemic therapies (e.g. statins, ACE-I, ASA, and smoking cessation) to reduce CVD risk

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