INSULIN AND INCRETIN THERAPIES: WHAT COMBINATIONS ARE RIGHT FOR YOUR PATIENT?

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1 INSULIN AND INCRETIN THERAPIES: WHAT COMBINATIONS ARE RIGHT FOR YOUR PATIENT? MARTHA M. BRINSKO, MSN, ANP-BC CHARLOTTE COMMUNITY HEALTH CLINIC CHARLOTTE, NC

2 Diagnosed and undiagnosed diabetes in the United States, all ages, 2012 Total: 29.1 million people or 9.3% of the population have diabetes. Diagnosed: 21.0 million people. Undiagnosed: 8.1 million people (27.8% of people with diabetes are undiagnosed).

3% of the population have diabetes. Diagnosed: 21.

3 AGE-ADJUSTED * PERCENTAGE OF PEOPLE AGED 20 YEARS OR OLDER WITH DIAGNOSED DIABETES, BY RACE/ETHNICITY, UNITED STATES, Non- Hispanic whites 7.6 Asian Americans 9.0 Hispanics 12.8 Non- Hispanic blacks 13.2 American Indians/ Alaska Natives 15.9 *Based on the 2000 U.S. standard population. Source: National Health Interview Survey and 2012 Indian Health Service s National Patient Information Reporting System.

8 Non- Hispanic blacks 13.2 American Indians/ Alaska Natives 15.9 *Based on the 2000 U.S.

5 NATURAL HISTORY OF TYPE 2 DIABETES Years from diagnosis Onset Diagnosis Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Pre-diabetes Microvascular complications Macrovascular complications Type 2 diabetes Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med. 2002;347:

Microvascular complications Macrovascular complications Type 2 diabetes Adapted from

6 PATHOPHYSIOLOGY OF TYPE 2 DIABETES Insulin resistance. Beta cell dysfunction.

7 PATHOPHYSIOLOGY OF TYPE 2 DIABETES INSULIN RESISTANCE Insulin Resistance starts very early in the course of the disease. Insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.

Insulin resistance alone will not produce diabetes.

8 PATHOPHYSIOLOGY OF TYPE 2 DIABETES BETA CELL DEFECT All type 2 patients have at least a relative defect in both beta-cell function and mass. Function: in the (UKPDS), newly diagnosed people with diabetes had, on average, only about 50% of normal beta-cell function.[diabetes. 1995;44: , Diab Res Clin Pract. 1998;40(suppl):S21-S25.] Mass: Autopsy studies comparing the volume of beta cells in nondiabetic individuals with that of people with diabetes found a 41% decrease in beta-cell mass among people with type 2 diabetes

Function: in the (UKPDS), newly diagnosed people with diabetes had, on average, only about 50% of normal beta-cell function.

9 BETA-CELL FUNCTION DECLINES AS DIABETES PROGRESSES Beta-cell function decline over time Beta-cell function (%) IGT Diagnosis Beta-cell decline exceeds 50% by time of diagnosis Insulin initiation Postprandial 25 Type 2 Diabetes Hyperglycemia Adapted from Lebovitz H. Diabetes Rev 1999;7: Roper Survey of the US Diabetes Market, courtesy of GfK Market Measures. Years from diagnosis This information is general diabetes information and not intended to suggest that NovoLog Mix 70/30 can help reduce micro- and macrovascular complications of diabetes.

H. Diabetes Rev 1999;7:139-153. 2004 Roper Survey of the US Diabetes Market, courtesy of GfK Market Measures.

10 What Does GLP-1 Do? Stimulates pancreatic beta cells (insulin secretagogue). Stimulates beta cells only in the presence of hyperglycemia (glucose-dependent secretagogue function) Inhibits alpha cell function (thereby reducing glucagon and hepatic glucose output) Stimulates beta cell neogenesis (thereby reversing the progressive decline in insulin secretory reserve) Delays gastric emptying (thereby reducing postprandial hyperglycaemia and promoting both satiety and weight loss) Stimulates hypothalamic satiety (thereby promoting weight loss)

(thereby reducing glucagon and hepatic glucose output) Stimulates beta cell neogenesis (thereby reversing the progressive decline in

11 What Is the Incretin Effect? Oral glucose is able to produce an endogenous insulin response that is twice as high than intravenous glucose, suggesting that intestinal factors promote and amplify the secretion of insulin, ie. the incretin effect. This incretin effect is deficient in subjects with obesity, pre-diabetes and overt diabetes.

than intravenous glucose, suggesting that intestinal factors promote and amplify the

12 GLP-1: EFFECTS IN HUMANS After food ingestion Stimulates glucosedependent insulin secretion Suppresses glucagon secretion Slows gastric emptying GLP-1 is secreted from L-cells of the jejunum and ileum Leads to a reduction of food intake Improves insulin sensitivity That in turn Long-term effects in animal models: Increase of β-cell mass and improved β-cell function Drucker. Curr Pharm Des Drucker. Mol Endocrinol. 2003

a reduction of food intake Improves insulin sensitivity That in turn Long-term effects in animal models:

13 WHAT IS INCRETIN THERAPY? Ø Postprandial plasma levels of GLP-1 are depressed in Type 2 diabetes, indicating an impaired GLP-1 response to nutrient ingestion. The effort to identify effective forms of GLP-1 administration is challenged by its extremely short half-life (the enzyme DPP-4 degrades GLP-1 rapidly following its release from gut cells) Ø Much research has focused on compounds with molecular structures and incretin activity that are similar to GLP-1, but which have longer half-lives because they are not degraded by DPP-4 or are resistant to DPP-4. These compounds include exenatide and liraglutide, which are injectable treatments. Ø Another approach is to identify compounds that inhibit the activity of DPP-4, thus prolonging the half-life of naturally occurring GLP-1. Two oral agents that act as DPP-4 inhibitors are sitagliptin and vildagliptin REFERENCES Drucker DJ. Cell Metab. 2006;3: Drucker DJ. Curr Pharm Des. 2001;7: Gallwitz B. Eur Endocr Dis. June 2006:43-46.

research has focused on compounds with molecular structures and incretin activity that are similar to GLP-1, but which have longer half-lives because they are not degraded by DPP-4 or are resistant

14 GLP-1 ENHANCEMENT GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildagliptin Oral agents Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1:

15 HOW ABOUT INSULIN? ü Insulin is the most physiologic treatment option available AND the and the form of therapy most familiar to clinicians ü In patients who do not achieve adequate glycemic control with lifestyle modification and metformin, basal insulin is one option recommended as a component of duel or triple therapy ü There are five recommended combinations of insulin therapy ü Insulin is NOT recommended in combination with sulfonylureas ü When combined with a GLP-1 angonist, the dose of insulin should be reduced to lower the risk of hypoglycemia

do not achieve adequate glycemic control with lifestyle modification and metformin, basal insulin is one option recommended as a component

16 INSULIN TYPES Rapid Acting Onset <15 min Peak hr Duration Lispro (Humalog) Aspar3 5 hrt (Novolog) Glulisine (Apidra) Short Acting Onset hr Peak 2 4 hr Duration 4 8 hr Regular Intermediate Acting Onset 2 4 hr Peak 4 10 hr Duration Hr NPH

Glulisine (Apidra) Short Acting Onset 0.

17 INSULIN TYPES Long Acting Onset 4 6 hr Peak none* Duration 24 hr Glargine (Lantus) Detemir (Levimir) Combinations 70/30 Humulin or Novolin Novolg Mix 70/30 Humalog Mix 75/25

18 INSULIN REGIMENS 1. Basal insulin only 2. Prandial insulin only 3. Basal bolus regimen 4. A stepwise regimen with basal insulin and 1, 2, or 3 prandial injections before larger meals 5. Premixed insulin regimen dosed before the 1 st and 3 rd meal of the day

A stepwise regimen with basal insulin and 1, 2, or 3 prandial

19 INSULIN REGIMENS injections breakfast lunch dinner bedtime Intermediate/long acting Short acting Short acting Short acting injections breakfast lunch dinner Biphasic insulin Biphasic insulin bedtime

21 LIFESTYLE CHANGES Maintain a healthy body weight Target BMI is 25 a target 10% of body weight loss at a time is an achievable goal Make healthy food choices calorie restricted, low carbohydrate, high protein diet Exercise regularly at least 150 minutes per week of moderate exercise

23 REFERENCES Centers for Disease Control and Prevention. Diabetes Report Card Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2012 Lifestyle Changes to Manage Type 2 Diabetes Am Fam Physician Jan 1;79(1):42. National Diabetes Statistics Report, 2014http:// diabetes/pubs/statsreport14.htm Increased Priority for Regimens Involving Incretin-Based and Insulin Therapy Journal of Family Practice. Dec :12 S5-10. Incretion therapy 2011: hype or reality? South Afr J Anaesth Analg 2011;17(1)

INSULIN INTENSIFICATION: Taking Care to the Next Level

INSULIN INTENSIFICATION: Taking Care to the Next Level By J. Robin Conway M.D., Diabetes Clinic, Smiths Falls, ON www.diabetesclinic.ca Type 2 Diabetes is an increasing problem in our society, due largely