There has been extensive continuing research in the causes,

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1 FREE Category 1 Credit A CME HOME STUDY COURSE J U E U M B E R 1 4 ormalizing nsulin Secretion in Type 2 Diabetes Mellitus There has been extensive continuing research in the causes, complications and effective management of the group of diseases called Diabetes Mellitus. Diabetes mellitus is a common disorder, occurring in 5 to 10% of the population. Most of these patients are receiving care by primary care physicians but every health-care provider sees numerous diabetic individuals. The goal of this course is to provide you with concise and current information on the diagnosis and management of diabetes mellitus for use every day in your practice. The editors realize the value and scarcity of free time. We will attempt to make each issue short and practical. With diabetes mellitus, more than with any other chronic disorder, the patients play major roles in their self-care. Between visits, they must know what to do, how to do it, what to watch for and when to call for help. This makes education and self-management training an essential part of diabetes care. Many issues will include pages of essential information suitable for photocopying and distributing to your patients. We hope you will find this course interesting and valuable. By participating, you should end up with a loose-leaf Resource Manual which can be updated as needed. The editors welcome your comments and suggestions for future topics. Editors: William L. sley, M.D., Saint Luke s Lipid and Diabetes Research Center; Associate Professor of Medicine, University of Missouri- Kansas City School of Medicine David M. Klachko, M.D., Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cosmopolitan nternational Diabetes Center, University of Missouri-Columbia School of Medicine. Accreditation: The Office of Continuing Education, School of Medicine, University of Missouri-Columbia is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The Office of Continuing Education, School of Medicine, University of Missouri-Columbia takes responsibility for the content, quality, and scientific integrity of this CME activity. The Office of Continuing Medical Education, School of Medicine, University of Missouri-Columbia designates this educational activity for a maximum of 1.0 hour in category 1 credit towards the AMA Physician s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. This program is eligible for application for CME credits under Category 2-B of the American Osteopathic Association s CME Program. A record of these units will be maintained by the Office of Continuing Education, MU School of Medicine, filed by social security number. Designation of this activity for Category 1 AMA Credit is valid through June This CME activity was planned and produced in accordance with the ACCME Essentials on Enduring Materials. Disclosure: Current ACCME (Accreditation Council for Continuing Medical Education) rules state that participants in CME activities should be made aware of any affiliation or financial interest that faculty has with a commercial supporter of an educational activity. This does not suggest such relationships with industry are wrong or will lead to bias. ACCME s requirement is to intend to assure that such relationships are disclosed so you may decide for yourself. The following disclosure is provided: Dr. sley has no relationship to disclose. Dr. Klachko disclosed he serves as a consultant for Procter & Gamble, Aventis, Takeda, Lilly, Merck and Bristol Myers-Squibb. For CME credit, please record time spent on this course on registration form. A few weeks after we receive your registration form we will send you an explanation of each item on the test, highlighting any you have missed. Please review this carefully as it is part of the educational activity for which CME credit has been granted. An educational grant from ovartis Pharmaceuticals and support from the MU School of Medicine have made it possible to offer this course at no charge for CME credit.

2 ormalizing nsulin Secretion in Type 2 Diabetes Mellitus QUESTOS (Each question has one best answer) Please record your answers on the registration form. (1) The absence of an insulin secretory defect would OT result in diabetes mellitus despite the presence of insulin resistance in patients with a) obesity b) polycystic ovary disease c) hypertension d) all of the above (2) The most physiologic (rapid onset after eating) insulin secretagogue is a) metformin b) nateglinide c) pioglitazone d) glimepiride e) glipizide (3) Glyburide a) controls fasting glucose better than postprandial glucose b) is a major cause of hypoglycemia c) is shorter acting than glipizide d) all of the above e) a and b (4) ncreases in hemoglobin A1c are determined a) by fasting blood glucose b) by postprandial glucose c) by fasting glucose and postprandial glucose d) by the level of hepatic glucose production e) by the level of insulin resistance (5) The rationale behind short acting insulin secretagogues is a) better control of fasting blood sugar b) better control of hemoglobin A1c c) better control of postprandial blood sugar d) better control of cholesterol (6) Short acting insulin secretagogues given before meals may be useful (though not necessarily yet approved by the Food and Drug Administration) a) as monotherapy b) with metformin c) with a glitazone (thiazolidinedioine) d) with long acting insulin e) all of the above

3 ORMALZG SUL SECRETO TYPE 2 DABETES MELLTUS Please detach and mail entire registration form to address listed below. ame Degree Social Security umber (Required for credit) Specialty Office ame and Address (f incorrect on mailing label) City County State ZP Office Phone ( ) - Office FAX ( ) - nternet Address Answers (circle): (Each question has one best answer) 1: a b c d 2: a b c d e 3: a b c d e 4: a b c d e 5: a b c d 6: a b c d e For CME credit, indicate the exact number of minutes spent on this home study course: Comments and suggestions for topics: How useful was this activity? _ Would you be interested in accessing this course through the World Wide Web? yes no Mail to: CME - Diabetes University of Missouri-Columbia 2401 Lemone ndustrial Blvd., DC Columbia, MO (573) or FAX to [573]882=5666

4 ORMALZG SUL SECRETO TYPE 2 DABETES MELLTUS LEARG OBJECTVES Participants will be able to: identify the insulin secretory defect in patients with type 2 summarize the pathophysiologic significance of the insulin secretory defect in type 2 name the treatment modalities and their relative time courses for reversing the insulin secretory defect in type 2 Type 2 diabetes mellitus is a complex pathophysiologic disorder characterized in general by loss of normal insulin sensitivity (insulin resistance) in muscle, fat, and liver, and relative insulin deficiency. While much emphasis has been placed in recent years on insulin resistance, it is important to remember that most patients have both defects and will ultimately require therapy targeting both processes. n fact, insulin resistance alone (as in states such as obesity, polycystic ovary disease, and hypertension) does not cause diabetes unless the patient has a concomitant insulin secretory defect. nsulin levels may actually be elevated early in the course of type 2 diabetes mellitus, but are still inadequate compared to the level of glycemia in the diabetic patient. Furthermore, the timing of insulin release is disordered, with loss of hyperacute insulin release (at least to intravenous glucose) and delayed release of insulin after oral ingestion of carbohydrate. nsulin levels peak about one hour after eating in normals, but approximately two hours postprandially in patients with type 2 There are two reasons why there is renewed interest in insulin secretagogues as therapy for type 2 diabetes mellitus: 1) the recognition that impaired insulin secretion is a necessary condition for the development of type 2 diabetes mellitus and that therapies aimed only at insulin resistance may be unsuccessful or successful only for a limited amount of time; and 2) the realization that postprandial sugar excursions are a far greater contributor to hemoglobin A1c (HbA1c) abnormalities than previously thought. Also, postprandial hyperglycemia occurs earlier in the course of diabetes mellitus than fasting hyperglycemia, and is a better marker than fasting glucose of cardiovascular risk. However, it has not yet been shown that better control of postprandial glucose excursions will necessarily result in lower rates of macrovascular disease. This lesson will focus on drugs targeting the insulin secretory defect, particularly newer drugs that produce more physiologic release of endogenous insulin. Sulfonylureas Sulfonylureas, a drug class available for >40 years, increase insulin secretion in normals and patients with type 2 These drugs have no effect in patients with type 1 diabetes mellitus since the pancreatic beta cells are destroyed in the development of this disease. First generation sulfonylureas, with the exception of tolbutamide, are generally long acting and produce a delayed release of insulin after ingestion, often independent of glucose stimulation, a very unphysiologic insulin release paradigm. Second and third generation agents have tended to be shorter acting, and in some cases, more physiologic in stimulating insulin release based on glycemia. However, these drugs still cause delayed insulin release after eating, resulting in incoordination of the glycemic-insulin response. The shortest acting of these later drugs (glipizide) tends to produce more rapid insulin release after meals (though still very delayed compared to normal physiology) with less insulin release overnight, resulting in better prandial glucose control, but less regulation of nocturnal hepatic glucose production and thus higher morning blood sugars. The longer acting of these drugs (glyburide) produces less rapid insulin release after eating, but more insulin secretion over night, resulting in better control of the fasting blood glucose in the morning. The Food and Drug Administration has also saddled sulfonylureas with the bold type warning from the University Group Diabetes Program (UGDP) from thirty years ago when tolbutamide treatment was associated with increased cardiovascular mortality. However, there are multiple valid criticisms of this study, and the more recently completed United Kingdom Prospective Diabetes Study (UKPDS) exonerated sulfonylureas from causing excess cardiovascular risk. ewer Drugs ewer agents have been developed to try to produce more physiologic insulin release by the pancreas after eating. While not perfect, these agents represent a step forward in this process and may be advantageous in certain patients, particularly those at greater risk for hypoglycemia. Repaglinide (Prandin, ovo-ordisk) is a meglitinide (not chemically related to sulfonylureas). t binds to the same or similar receptors in the pancreatic beta cell as sulfonylureas, but its onset of action and dissipation are much more rapid, resulting in more physiologic insulin release than sulfonylureas. Early studies at repaglinide doses up to 4 mg preprandially reduced fasting glucose ~30 mg/dl and postprandial glucose ~50 mg/dl. A more recent 24 week study of repaglinide 1mg/d and 4 mg/d showed mean HbA1c reductions of 2.1% in drug naïve patients, and 1.7% in previously treated patients. Greater efficacy and increased risk for hypoglycemia was shown in drug naïve patients and patients with better glycemic control (HbA1c<8%) at baseline. Weight gain in patients not O R M A L Z G S U L S E C R E T O 1

5 previously treated was 3.3%. Repaglinide is also approved for usage with metformin. The package insert includes the warning from the UGDP previously mentioned. Repaglinide dosing starts with 0.5 mg with meals in patients with HbA1c<8%, and 1-2 mg with meals in patients with HbA1c>_8%. The maximum dose is 4 mg before meals. The dose can be titrated to the 2-hour postprandial glucose (< mg/dl) or the preprandial glucose ( mg/ dl). The drug is unlikely to be efficacious in patients unresponsive to a sulfonylurea. ateglinide (Starlix, ovartis) is a derivative of the amino acid phenylalanine. ts cellular action is similar to sulfonylureas, but its binding to the pancreatic beta cell is on the order of seconds rather than minutes. nsulin release is the most rapid of any of the currently available oral diabetes drugs and is dependent on ambient glucose concentrations. n a 24 week study of nateglinide compared to placebo (most patients naïve to drug therapy, with mean HbA1c~8%), active drug treatment (nateglinide 120 mg before meals) resulted in a mild but statistically significant drop in fasting plasma glucose compared to placebo (14 mg/dl) with a decrease in HbA1c of 0.7% and 1.6 kg weight gain compared to placebo. Hypoglycemia was uncommon. Results from a similar study using nateglinide and metformin are given in the table. Drug naïve patients generally responded better than previously treated subjects. ateglinide is usually dosed as 120-mg tablets 1 to 30 minutes before the meal. f a meal is skipped, a pill is omitted. o special dosing is necessary in patients with renal impairment or mild hepatic insufficiency. Sixty-mg tablets are available and may be used in patients who are near to target glycemia prior to the advent of therapy. The drug is approved for monotherapy as well as in conjunction with metformin. Patients unresponsive to other insulin secretagogues are unlikely to respond to nateglinide. While it is tempting to speculate that the ideal insulin secretagogue would be a combination of a short acting agent to normalize fasting glycemia and a longer acting agent to control the fasting glucose, limited studies suggest that this approach is not any more useful than either type of drug alone. This approach is currently not recommended. Utility of Short-Acting nsulin Secretagogues The obvious first use for these newer agents is in patients who are at increased risk for hypoglycemia, specifically elderly patients, and patients with renal and hepatic impairment. They do not control HbA1c better than older agents, but control of post-prandial glycemia (and presumed better control of post-prandial lipemia via more physiologic insulinemia) offers promise for reduced cardiovascular complications. However, until formally studied in a major clinical end-point trial, this potential benefit must be viewed as theoretical. To utilize these agents most effectively, the practitioner must change the usual self-blood glucose-monitoring paradigm. Targeting postprandial glucose measurements (presumably ~2hr after eating) would be in order. While repaglinide offers more dosage flexibility for titration, nateglinide offers more physiologic insulin release. Presumably both agents may hold promise for use with all insulin sensitizers as well as basal insulin regimens (nocturnal PH or ultralente and twice daily ultralente). time (hr) Figure. Relative insulin secretion in normals (solid line) and patients with type 2 diabetes mellitus treated with rapid acting insulin secretagogues (line with long dashes), short acting sulfonylureas (line with short dashes), and long acting sulfonylureas (dotted line). Arrows depict meals. from placebo nateglinide metformin combination HbA1c (%) fasting glucose (mg/dl) weight (kg) Table. Twenty-four week study of nateglinide 120 mg ac versus metformin 500 mg tid versus the combination in 665 patients with type 2 diabetes mellitus with baseline HbA1c~8.3% References 1. Prandin package insert. ovo ordisk Pharmaceuticals, nc. Princeton, ew Jersey, Starlix package insert. ovartis Pharmaceuticals Corporation. East Hanover, ew Jersey, For more information on Diabetes, call the American Diabetes Association at DABETES or the MO Diabetes Control Program at