Clinical Diabetes basic training Eden Miller D.O.

Global Prevalence of Diabetes Projected to More Than Double by 2030 Europe: 2000: 33 million 2030: 48 million Africa and Middle East 2000: 22 million 2030: 61 million Asia and Australia 2000: 83 million 2030: 190 million The Americas 2000: 33 million 2030: 67 million The projections illustrated in this slide, based on World Health Organization data, are for the year 2030, when diabetes is predicted to affect some 366 million people worldwide, or more than twice as many as in 1995, when 135 million patients had (documented) diabetes.1-3 [1/8; 2/1047/Abstract; 3/1416/1/3] Although the prevalence of diabetes is expected to increase worldwide, the countries with the greatest numbers of people with diabetes are now—and will be in the year 2030—India, China, and the US.3 [3/8] 1WHO. Diabetes Action Now. 2004. 2Wild S, et al. Diabetes Care. 2004:27:1047-1053. 3King H, et al. Diabetes Care. 1998;21:1414-1431. World 2000: 171 million 2030: 366 million <2% 2%-5% 5%-8% 8%-11% 11%-14% Nationwide Diabetes Prevalence Categories WHO. Diabetes Action Now. 2004.

What is diabetes? An impairment of the body’s ability to effectively transport glucose into the cell so it may be utilized for fuel. Insulin, the body hormone responsible for the transport of glucose, is either less potent, decreased, or absent in a diabetic individual.

A touch of Sugar (fasting serum) Glucose intolerance: 1O5-113 Pre diabetes: 114-125 Diabetes: 126 or greater

Hemoglobin A1C, its just an average What is it- the measured percentage of glucose attached to a red cell. It is a representative of the average blood sugars over a 2-3 month period. Why 3 months- the body replaces the blood volume every 3 months. Why measure- it may assist in the diagnosis of diabetes. Typically used to monitor overall diabetes control. Often a measure used in research.

A1C what should it be? A.D.A.- less than 7% A.C.E.- less than 6.5% What does that percentage mean in terms of numbers. 6%-135 7%-170 8%-205 9%-240 10%-275 11%-310 12%-345

A1C Goals: Aim for the Lowest A1C Possible Presenter reviews ADA and ACE targets

Glucose Fluctuations Are Not Adequately Measured by A1C Mean A1C = 6.7% 400 300 Optional DISCUSSION POINTS: Excessive glucose fluctuations are common in diabetes and are not measured by the A1C. People without diabetes are able to maintain their glucose concentrations within a narrow band (approximately 80 to 140 mg/dL) throughout the day. For patients with diabetes, this level of glucose control is difficult. Even “optimally-treated” patients, whose A1C would predict near target glucose control, can experience wide glucose fluctuations throughout the day. In a recent study, Amylin Pharmaceuticals, Inc. assessed 24-h glucose profiles of 9 subjects with type 1 diabetes whose A1C averaged 6.7% (range of 5.8% to 7.1%), near or within the ADA A1C target range. Subjects used insulin lispro in their insulin pumps. Click: The individual glucose profiles of the 9 patients appear on the graph Despite excellent A1C levels, these patients experienced wide glucose fluctuations throughout the day as measured with continuous glucose monitoring system (CGMS) SLIDE BACKGROUND: CGMS = Medtronic MiniMed Continuous Glucose Monitoring System Mean duration of diabetes for these 9 subjects was 21.5 years (range 2.5 to 40.4 years). Glucose Concentration (mg/dL) 200 100 12 AM 4 AM 8 AM 12 PM 4 PM 8 PM 12 AM Type 1 diabetes, N = 9 24-h CGMS glucose sensor data Data on file, Amylin Pharmaceuticals, Inc.

Relative Contribution of Postprandial Glucose Increases as A1C Approaches Target 100 70% 60% 55% 49% 30% 80 Optional DISCUSSION POINTS: Though both fasting and postprandial glucose contribute to overall glycemic control (A1C), the relative contribution of postprandial glucose to overall glycemia increases as the A1C decreases toward the normal range. On the graph, the teal bars indicate that the contribution of postprandial glucose (relative to fasting glucose) to the A1C increased progressively (30% to 70%) from the highest (>10.2%) to the lowest (<7.3%) A1C quintile. It is important to note that in the commonly observed range of A1C (approximately 7% to 10%), postprandial glucose had an important contribution (40% to 50%) to the A1C. SLIDE BACKGROUND: This study analyzed the diurnal glycemic profiles of 290 patients with type 2 diabetes who exhibited different levels of glycemic control, as measured by A1C. The patients were treated with diet alone, or with a stable dose of metformin (1700 mg/day), glyburide (5 to 15 mg/day), or both for at least 3 months prior to the study. Plasma glucose concentrations were determined at fasting (8:00 AM) and during postprandial and post-absorptive periods (at 11:00 AM, 2:00 PM, and 5:00 PM). Based on these glucose measurements, the investigators calculated the relative contribution of fasting and postprandial glucose to overall glycemic control. 70% 60 % Contribution 51% 40 45% 40% 30% 20 >10.2 9.3-10.2 8.5-9.2 7.3-8.4 <7.3 A1C Range (%) N = 290; Percentages are approximations Adapted from Monnier L, et al. Diabetes Care 2003; 26:881-885

The Pathogenesis of Type 2 Diabetes An Imbalance of Beta-Cell Workload and Beta-Cell Response Not Required DISCUSSION POINTS: --In type 2 diabetes, the balance of beta-cell response and workload is disturbed as a result of reduced beta-cell capacity to secrete insulin and the increase in beta-cell workload. --Beta cells secrete less and less insulin in response to elevated glucose, and the first-phase insulin response progressively worsens. --Many factors that contribute to beta-cell workload are pathologically dysfunctional in type 2 diabetes. --The result of this imbalance between beta-cell workload and beta-cell response is hyperglycemia. SLIDE BACKGROUND: --Contributors to insulin resistance (in addition to obesity) include genetics, age, exercise/physical fitness, dietary nutrients, medications, and body fat distribution. Hyperglycemia 02-05-1219-A; EX 36570 ©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

Balancing Beta-Cell Response and Beta-Cell Workload Insulin Is Enhanced and Glucagon Is Suppressed Healthy Subjects (n = 14)  Beta-Cell Workload  Beta-Cell Workload  Beta-Cell Response Not Required DISCUSSION POINTS: --Insulin and glucagon are the counter regulatory hormones of the pancreas that help to control blood glucose. --This study looked at insulin secretion (beta-cell response) and glucagon secretion (alpha-cell response) after a large carbohydrate meal in healthy, normally glucose-tolerant individuals. -- Normal glucose homeostasis was maintained by: --Insulin secretion (beta-cell response), which initially increased and then declined as blood glucose declined --Decreased glucagon secretion (alpha-cell response) after the meal --This combination of actions reduced hepatic glucose output during the fed state, as carbohydrate is being absorbed from the GI tract, and euglycemia was maintained. SLIDE BACKGROUND: --The carbohydrate meal consisted of 140 g spaghetti, 256 g corn, 252 g rice, 2 medium-sized potatoes (244 g), all of which were boiled, and 2 slides of white bread (26 g). Together, they contained approximately 200 g of carbohydrate. Euglycemia Mean (SE) 02-05-1219-A; EX 36570 ©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

Balancing Beta-Cell Response and Beta-Cell Workload Insulin Is Enhanced and Glucagon Is Suppressed The Pathogenesis of Type 2 Diabetes Beta-Cell Workload Outpaces Beta-Cell Response Healthy Subjects (n = 14) Type 2 Diabetes (n = 12)  Beta-Cell Workload  Beta-Cell Workload  Beta-Cell Workload  Beta-Cell Response  Beta-Cell Workload  Beta-Cell Response Not Required DISCUSSION POINTS: --Insulin and glucagon are the counter regulatory hormones of the pancreas that help to control blood glucose. --This study looked at insulin secretion (beta-cell response) and glucagon secretion (alpha-cell response) after a large carbohydrate meal in healthy, normally glucose-tolerant individuals. -- Normal glucose homeostasis was maintained by: --Insulin secretion (beta-cell response), which initially increased and then declined as blood glucose declined --Decreased glucagon secretion (alpha-cell response) after the meal --This combination of actions reduced hepatic glucose output during the fed state, as carbohydrate is being absorbed from the GI tract, and euglycemia was maintained. SLIDE BACKGROUND: --The carbohydrate meal consisted of 140 g spaghetti, 256 g corn, 252 g rice, 2 medium-sized potatoes (244 g), all of which were boiled, and 2 slides of white bread (26 g). Together, they contained approximately 200 g of carbohydrate. Hyperglycemia Euglycemia Euglycemia Mean (SE) 02-05-1219-A; EX 36570 ©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

Medication used for DM II Glucophage (Metformin) Action is on the liver to decrease extra glucose Sulfonylureas or Secretagogs (Amaryl, Glucotrol) Causes the pancreas to produce more insulin SGLT2 (Invokana,Jardiance) Off load Glucose from Kidney Sensitizer (Actos and Avandia) Makes all of the cells of the body sensitive to insulin Incretin Family GLP1- mimics hormone naturally found in the body DPP4 inhibitors (Januvia, Tradjenta, Onglyza) prevent incretin breakdown.

Metformin/GLucophage Biguanide Dosed 500mg -2000mg QD Prevents the conversion of glycogen to glucose in the liver First Line Treatment for Diabetes Limitations Side effects GI and renal function/clearance Rarely Metabolic Acidosis since not metabolized in the liver

Sulfonylureas Glipizide 2nd Generation (Glucotrol) 2.5m-10mg Glyburide 2nd Generation (Micronase) Glimiperide 3rd Generation Pancreatic Specific (Amaryl) 2mg, 4mg and 8mg only in US By Blocking potassium channels the opening of voltage dependent gates causing calcium influx and insulin degranulation and release. Also may inhibit glucagon and potentiate insulin action at peripheral tissue

Meglitinides Starlix –nateglinide 60-120mg daily Prandin-repeglinide .5mg,1mg and 2mg once daily Secretagog like but less affinity with the ATP channels and thus a greater disassociation with the receptor when may lessen the rapid out flow of pro-insulin

Atypical Orals Precose- Acarbose alpha glucosidase inhibitor 25-100mg TID prior to meals Bromocriptine-Parlodel dopamine agonist 1.6mg-4.8mg daily Welchol-Colesevelam bile acid sequestrant doses 6 tablets daily or one packet daily

GLp -Incretins Byetta (Exenatide) BID dosing 5mcg and 10mcg Victoza (Liraglutide) QD Dosing .6mcg-1.8mcg Bydureon(Exenatide LAR) Q weekly Dosing 2mg Tanzium (Albiglutide) Q weekly Dosing 30mg and 50mg Trulicity (Dulaglutide) Q weekly Dosing .75mg and 1.5mg

DISCUSSION POINTS: The increasing plasma glucose resulting from ingestion of 50 g oral glucose (white line in left-side graph) results in an increase of C-peptide (a measure of insulin secretion) (white line in right-side graph). An isoglycemic intravenous glucose infusion designed to mimic the plasma glucose excursion achieved by the oral glucose load was later administered to the same study patients (orange line in left-side graph). The resulting beta-cell response, measured as C-peptide, is shown on the right-side graph. Despite the same plasma glucose profiles, there are significant differences in the beta-cell response, as measured by C-peptide. This difference prompted study into the role of incretins – factors secreted from the intestinal tract, upon the ingestion of food, that enhance the secretion of insulin – that would account for the greater insulin response to oral glucose. This incretin effect suggested that incretins, and not merely the direct actions of plasma glucose, affect the insulin secretory response. SLIDE BACKGROUND: Young, healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic intravenous glucose infusion. Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in CNS-mediated release of insulin. An early prandial phase, mediated by gut-derived incretin hormones (e.g., GLP-1 and GIP), occurs after food intake but before the ingested nutrients appear in the circulation (or reach the intestinal L cells that secrete GLP-1). Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted. Therefore, C-peptide serves as a marker for insulin secretion.

DISCUSSION POINTS: The additional insulin response observed with oral vs. IV glucose administration (i.e., the incretin effect) is reduced in subjects with type 2 diabetes compared to healthy subjects. SLIDE BACKGROUND: Insulin responses to a 50 g oral glucose load and intravenous glucose infusion designed to mimic glucose concentration profiles after a 50 g oral glucose load were measured in patients with type 2 diabetes (N = 14) and healthy controls (N = 8). The contribution of incretin factors to total insulin responses (with 100% = response to oral load) was 73% in control subjects and 36% in subjects with type 2 diabetes (P0.05). The greater beta-cell response observed in subjects with type 2 diabetes during intravenous glucose administration is due to the higher glucose stimulus in subjects with diabetes.

DISCUSSION POINTS: The observation of the “incretin effect” started the search for “incretins” – factors secreted from the intestines that enhance the secretion of insulin in response to the ingestion of food. Glucose-dependent insulin secretion means enhanced insulin secretion is dependent on elevated blood glucose concentrations, and that when blood glucose concentrations return toward normal, enhanced insulin secretion subsides – hence, the glucose-dependent property. One of the incretins, glucagon-like peptide-1 (GLP-1) is of special interest, as besides enhancing glucose-dependent insulin secretion (beta-cell response), GLP-1 has other glucoregulatory effects that decrease beta-cell workload. Upon ingestion of food, GLP-1 is secreted into the circulation by the L cells of the small intestine. This occurs in advance of food directly stimulating the L cells, suggesting that a neural and/or hormonal communication pathway triggers the release of GLP-1 to prepare the body in advance of the absorption of carbohydrates from the meal. The similarity of GLP-1’s full name with glucagon is only because their amino acid chains are products of the same gene – not because they have similar sites of secretion, actions, or sites of action. NOTE: Speakers can highlight the differences that are included on the slide itself.

DISCUSSION POINTS: Upon food ingestion, GLP-1 is secreted into the circulation from L cells of small intestine. GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion. GLP-1 decreases beta-cell workload and hence the demand for insulin secretion by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake By decreasing beta-cell workload and improving beta-cell response, GLP-1 is an important regulator of glucose homeostasis. SLIDE BACKGROUND: Effect on Beta Cell: Drucker DJ. Diabetes. 1998; 47:159-169 Effect on Alpha Cell: Larsson H, et al. Acta Physiol Scand. 1997; 160:413-422 Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997; 160:413-422 Effects on Stomach: Nauck MA, et al. Diabetologia. 1996; 39:1546-1553 Effects on CNS: Flint A, et al. J Clin Invest. 1998; 101:515-520

New Approaches: Incretins for Improved Glucose Control Two Approaches to Prolonging Incretin Activity DPP-4 Inhibitors Incretin Mimetics Modest HbA1c reduction Weight neutral Oral administration Almost no GI side effects Very low rate of hypoglycemia Multiple targets (Preservation of GLP1 activity and GIP activity) Significant HbA1c reduction Weight loss Injection Higher rate in GI side effects Low rate of hypoglycemia Single target (GLP-1)

DPP-4 Inhibitors Dipeptidyl peptidase-4 inhibitor Sitagliptin – Januvia Typical Dose 100mg daily with or without food Secondary doses of 50mg GFR 30-50 and 25mg for GFR<30 Saxtagliptin- Onglyza Dosing 2.5mg and 5mg if GFR <50 then 2.5mg Linagliptin-Tradjenta 5mg single dosing irrespective of GFR

SGLT2 (Glucouretics) Invokana-(canagliflozin) 150mg GFR>45 300mg GFR>60 Farxiga-(Dapagliflozin) 5mg or 10mg GFR>60 Jardiance-(empagliflozin) 10mg or 25mg GFR>45 Lower the renal glucose threshold by inhibiting SGLT2 receptors in the Kidney causing renal glucose excretion up to 120 grams of glucose

SGLT2 Blockade

When to cross over to insulin. No more non-insulin medication to add. Rising post-meal blood sugars Increasing hemoglobin A1C (this occurs later) Very high blood sugars either early on in the disease or later in the advanced disease. A large percentage of diabetics will require Insulin within 10-15 years after diagnosis. SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1   REFERENCE 1. Lantus prescribing information.

DON’T BE AFRAID OF INSULIN It’s natural!

Modification of Oral when transitioning to Insulin No need for secretagogs (Sulfonylureas) personal opinion May continue sensitizers but may increase risk of edema Metformin may always be continued as long as appropriate (pts still have livers) GLP1 should always be considered if possible (Fortified with Insulin in Europe) SGLT2 (Kidney dependent) able to be added at any time to insulin SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1   REFERENCE 1. Lantus prescribing information.

Strive for Ideal: Insulin Regimen Discussion points The ideal insulin regimen should strive to match normal insulin secretion patterns. The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin.

Types of Insulin Commonly Used Once-a-day long-acting Lantus U100/U300 or Levemir or BID NPH 75/25 mix insulin, Novolog 70/30, or Humalog 50/50 Short-acting at meal time Bolus (Humalog, Novolog, Apidra, or Inhaled Affrezza) Complete transition to insulin using long-acting/short-acting with multiple injections termed Basal/Bolus Continuous Insulin Infusion using Pumps SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1   REFERENCE 1. Lantus prescribing information.

BasaL only; advantages and disadvantages Yeas Ideal for needle scared patients Less brain cell usage to administer Nays Frequently relied upon for too long Difficult to titrate Fasting Glucose is limiting factor Not quite physiologic, after all it is a basal No meal time or post prandial coverage

Premixed Insulin Preparations 75/25 mix /70/30 Mix 70%-75% 12 hour long acting and 25%-30% rapid meal time insulin. Better total day coverage and can be given initially once daily or increased to two times daily. A more physiologic (better fit) than older 70/30 with Regular. Don’t be stuck in the time warp of the past. Humalog 50/50 50% long 50% rapid Dosed QD-TID Basal/Bolus in a Pen “High Mix” SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1   REFERENCE 1. Lantus prescribing information.

Dosing Low Premix QD initiation begin with Dinner 15-20 units Monitor Pre meals or 2 hour post prandial for titration AM fasting elevation will also indicate need for increase dinner dose and PM pre Dinner Blood sugar to increase Breakfast Dose Augment with rapid with Lunch if Gaps in insulin coverage or transition to 50/50 or Basal/Bolus

Scope of Premix Insulin Advantages More physiologic in addressing meal time as well as basal Can start as once daily and work up from there Titration is possible Augmenting with rapid acting at lunch Disadvantages Fixed Dosing More awareness needed due to rapid acting Lunch time can be uncovered in patients who need more comprehensive insulin coverage

Intensive insulin management

Basal Bolus More Advanced Insulin Plan Once-a-day long-acting (Lantus, or Levamir BID could replace) Short-acting insulin Calculate using CBG levels: start at 1 unit per 50 blood sugar greater than 100 (glucose correction factor) Grams of carbohydrate: begin with 1 unit per 15 gram of carb. (insulin to carbohydrate ratio) Testing is the key to being successful Get assistance from your local CDE’s they are invaluable SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1   REFERENCE 1. Lantus prescribing information.

Basal-Bolus Insulin Regimen: MDI Discussion points The ideal insulin regimen should strive to match normal insulin secretion patterns. The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin. The basal bolus regimen involves up to 7 blood sugar measurements a day, and 3-4 injections a day, with adjustments necessary to match meal and activity levels. The use of a rapid acting insulin like Humalog for the bolus injections closely mimics the normal postprandial secretion of insulin.

Parting thoughts The treatment of diabetes is changing rapidly, with new information and insights yearly. Its a struggle for even the most enthusiastic of providers to stay current on treatment options. Remember this is a team approach, your education and input is critical for effective treatment.