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2 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys This article is a CME/CE certified activity. To earn credit for this activity visit: CME/CE Released: 23/12/2011; Valid for credit through 10/26/2012 Target Audience This educational activity is intended for a Canadian audience of healthcare professionals and is not intended for U.S. healthcare professional audiences. This activity is intended for Canadian family physicians and primary-care practitioners, particularly those with an interest in the management of type 2 diabetes. Goal The goal of this activity is to improve the treatment of type 2 diabetes at the primary-care level in Canada by informing and updating family physicians and primary-care practitioners regarding treatment goals, available therapeutic options, and emerging therapies related to the novel perspective on the role of the kidneys in glucose handling. Learning Objectives Upon completion of this activity, participants should be able to: 1. Set glycemic targets for their patients with type 2 diabetes. 2. Compare the advantages, disadvantages and mechanisms of action of available antihyperglycemic agents. 3. Describe the pathophysiology of type 2 diabetes related to glucose imbalance. 4. Explain the role of renal sodium-glucose cotransporter 2 in glucose homeostasis, and the role for pharmacotherapy aimed at this transporter. Supporter Attribution This activity was developed to be distributed on Medscape Education. The content of this activity was developed by the members of the Steering Committee. This activity is published by STA HealthCare Communications Inc. as a professional service funded by Bristol-Myers Squibb Canada Co., and AstraZeneca Canada Inc. Accreditation Statements This program has been accredited by The College of Family Physicians of Canada for up to 1 Mainpro-M1 credits. For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity at chelseab@sta.ca For technical assistance, contact CME@medscape.net Pg.2

3 Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape Education encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing Edit Your Profile at the top of your Medscape homepage. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access Medscape Education users will need A computer with an Internet connection. Internet Explorer 6.x or higher, Firefox 2.x or higher, Safari 2.x or higher, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader. Authors and Disclosures Carl Fournier, MD, CCFP Associate Professor of Medicine University of Montreal Associate Member Notre-Dame Hospital (CHUM) Dr. Fournier has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca, BMS, sanofi-aventis, Novartis Served as a speaker or a member of a speakers bureau for: AstraZeneca, BMS, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, sanofi-aventis, Novartis Pg.3

4 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Ronald Goldenberg, MD, FRCPC, FACE Consultant Endocrinologist North York General Hospital & LMC Endocrinology Centres Dr. Goldenberg has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca, BI, BMS, Eli Lilly, GSK, Merck, Novo Nordisk, sanofi-aventis, Servier Served as a speaker or a member of a speakers bureau for: AstraZeneca, BI, BMS, Eli Lilly, GSK, Merck, Novo Nordisk, sanofi-aventis, Servier Received grants for clinical research from: AstraZeneca, BI, BMS, Eli Lilly, GSK, Merck, Novo Nordisk, sanofi-aventis, Servier Solomon Stern, MD Lead Physician Argus Medical Centre Family Health Organization Dr. Stern has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Purdue, Janssen, BMS, Pfizer, Astra Zeneca Served as a speaker or a member of a speakers bureau for: Purdue, Janssen, Valeant, Pfizer, Takeda, BMS, sanofi-aventis, Astra Zeneca,Merck Received grants for clinical research from: Astra Zeneca Jordan Weinstein, MD Division of Nephrology St. Michael s Hospital Assistant Professor of Medicine University of Toronto Dr. Weinstein has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Novartis, Abbott, Servier, Amgen, Merck, BMS, BI Served as a speaker or a member of a speakers bureau for: Novartis, Abbott, Servier, Amgen, Merck, BMS, BI Jean-François Yale, MD, CSPQ Professor of Endocrinology McGill Nutrition and Food Science Centre McGill University Health Centre Dr. Yale has disclosed the following relevant financial relationships: Served as an advisor or consultant for: sanofi-aventis, Merck, GSK, Eli Lilly, Bayer, Pfizer,Novo-Nordisk, Innodia, Lifescan, Roche, Novartis, BMS, Astra Zeneca, Boehringer-Ingelheim Served as a speaker or a member of a speakers bureau for: sanofi-aventis, Merck, GSK, Eli Lilly, Bayer, Pfizer, Novo-Nordisk, Roche, Abbott, BMS, Astra Zeneca, Medtronic, Boehringer-Ingelheim Received grants for clinical research from: NIH, CIHR, sanofi-aventis, Pfizer, NovoNordisk, Merck, Novartis Pg.4

5 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Welcome to this educational program, entitled Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys. This program s faculty included perspectives from the fields of endocrinology, nephrology, and family medicine. This slide lists the Scientific Committee members who formed the faculty in developing this program s content. Pg.5

6 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys This program was designed to meet the educational needs identified in a survey of Canadian primary-care physicians. Areas covered include therapeutic targets in type 2 diabetes, comparisons of available antihyperglycemic agents, the pathophysiology of type 2 diabetes related to glucose imbalance, and the role of renal sodium-glucose cotransporter 2 (SGCT 2) and its inhibition. Charles represents a typical patient profile seen in Canadian primary-care practice. He is 51 years old and was diagnosed with type 2 diabetes two years ago. He works as a computer programmer, and reports that he takes short walks twice per week and saw a dietitian six months ago. Charles body mass index has been measured at 33 kg/m2, his waist circumference, at 103 cm, and his blood pressure, at 132/76 mmhg. Laboratory findings include an A1C of 8.1%, a fasting glucose of 8.3 mmol/l, a post-prandial glucose of 10.4 mmol/l, and normal lipid levels. Charles current treatment consists of lifestyle counselling, statin and ACE-inhibitor therapy, and metformin at a dose of 1 g twice daily. Pg.6

7 Type 2 diabetes is associated with several important chronic complications. These include the well-known diabetic retinopathy, nephropathy and neuropathy, but also the sometimes underappreciated cardiovascular and cerebrovascular risks associated with diabetes. Together, the risks of these complications highlight the importance of adequately controlling type 2 diabetes and treating to target therapeutic levels for important markers such as glycemia, lipids, blood pressure, and body weight. The Canadian Diabetes Association (CDA) has set recommended targets for glycemic control as part of its clinical practice guidelines. Shown here are the recommended targets for each of these markers in patients with type 2 diabetes. The CDA Clinical Practice Guidelines authors acknowledge that treatment goals and strategies must be tailored for individual patients, with consideration given to individual risk factors such as age, prognosis, level of glycemic control, duration of diabetes, presence of complications or comorbidities, and risk of hypoglycemia. Pg.7

8 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Despite the known risks associated with poor glycemic control and the availability of evidence-based clinical practice guidelines, many patients with type 2 diabetes in Canada are not adequately treated to achieve A1C targets. The DICE (Diabetes in Canada Evaluation) study was a national chart audit conducted from 2002 to 2003, in which 243 primarycare physicians provided information about a total of 2,473 eligible patients with type 2 diabetes. The investigators found that 49% of patients were not at their A1C target. Physicians plans to achieve glycemic targets in patients whose A1C was 7% are shown on the right-hand side of this slide. Lifestyle reinforcement was planned for 79% of patients, and more aggressive therapy for only 56% of patients. Pg.8

9 Three years later, this situation of suboptimal treatment in type 2 diabetes did not appear to have improved. In the DRIVE (Diabetes Registry to Improve Vascular Events) study conducted between 2005 and 2006, 3,002 outpatients with type 2 diabetes were enrolled in 229 primary healthcare settings across Canada, with the aim of evaluating vascular protection treatment patterns and attainment of the 2003 CDA-recommended targets in ambulatory patients with type 2 diabetes. Optimal A1C levels were achieved in 53% of patients. Of those who did not attain A1C targets, 3% were not taking glucose-lowering pharmacotherapy and 27% were receiving monotherapy. Charles is not currently achieving his glycemic targets, and is in need of intensified therapy. Pg.9

10 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys In addition, Charles is overweight, and this should be considered in selecting a treatment regimen for him. In patients like Charles, increasing the dose of metformin might seem like a rational first step towards trying to achieve glycemic targets. However, it is important to consider this agent s dose-effect curve before making such a treatment adjustment. The gastrointestinal side effects associated with metformin therapy are dose-related, and their prevalence increases considerably beyond the dose of 1,000 mg per day (which is about half the drug s maximal dose). As well, metformin exerts most of its antihyperglycemic effect at half its maximal dose. Based on this understanding, for patients already receiving half the maximal dose of metformin (1,000 mg/day) but still in need of enhanced glucose control, it may be more effective and better tolerated to add a second antihyperglycemic agent rather than to increase the dose of metformin. Pg.10

11 Type 2 diabetes is a multifaceted disease involving several pathophysiologic abnormalities. Each of the main classes of antihyperglycemic agents has a mechanism or mechanisms aimed at achieving glucose control in the face of the pathophysiologic defects of type 2 diabetes. Alpha-glucosidase inhibitors, such as acarbose, work by delaying the digestion and absorption of intestinal carbohydrates. Pg.11

12 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Biguanides, such as metformin, work by reducing hepatic glucose production and increasing peripheral glucose uptake. Sulfonylureas and rapid-acting secretagogues, such as glipizide and glimepiride, work by stimulating insulin secretion by pancreatic beta-cells. Pg.12

13 Thiazolidenidiones, such as rosiglitazone and pioglitazone, work by reducing insulin resistance in target tissues. GLP-1R agonists, such as exenatide and liraglutide, work by increasing GLP-1 action, stimulating insulin secretion, suppressing glucagon release, decreasing appetite and delaying gastric emptying. Pg.13

14 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys DPP-4 inhibitors, such as linagliptin, saxagliptin and sitagliptin, work by prolonging GLP-1 action, stimulating insulin secretion, and suppressing glucagon release. The CDA guidelines recommend the use of metformin as the first-line agent because of its glucose-lowering efficacy, the absence of weight gain and hypoglycemia associated with its use, as well as the reduction in mortality seen in the UKPDS (United Kingdom Prospective Diabetes Study) trial. The second agent to use is left to the judgment of the physician, as the other agents have strengths and weaknesses as shown on this slide. Pg.14

15 Several agents are available within each antihyperglycemic class, and any one could be chosen after metformin depending on the individual characteristics of the patient. Additionally, a new class of antihyperglycemic agents is being developed to target the kidney: the sodium-glucose cotransporter 2, or SGLT2, inhibitors. This class of oral antihyperglycemic agent will prevent glucose re-absorption in the kidneys, resulting in urinary glucose loss. The following slides provide a more detailed description of SGLT2 and of the role for SGLT2 inhibition in type 2 diabetes. Pg.15

16 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys The major role of the kidney in human physiology is to maintain intravascular volume and an acid-based electrolyte balance. Each day, approximately 180 litres of plasma pass through the kidney s glomerular filtration system, wherein minerals such as sodium, potassium, and chloride are absorbed and returned to the bloodstream rather than excreted in the urine. Glucose is also filtered in this manner in order to retain energy essential for physiologic functioning between meals. With a daily glomerular filtration rate of 180 litres of plasma, approximately 162 grams of glucose must be reabsorbed each day to maintain a plasma glucose concentration of 5.6 mmol/l. As shown here, reabsorption of glucose occurs mainly in the proximal tubule and is mediated by two different transport proteins, SGLT1 and SGLT2. SGLT2 is responsible for the majority of glucose reabsorption, which occurs in the S1 segment of the convoluted tubule. The remaining glucose is taken up by SGLT1, whose receptors are found in the S3 segment of the descending or straight section of the tubule. In individuals without diabetes, all filtered glucose is reabsorbed. Glucosuria results when the maximal reabsorptive capacity of the kidney is exceeded. In patients with type 2 diabetes, a chronic state of hyperglycemia upregulates SGLT2 expression, increasing the maximal capacity of glucose reabsorption, and returns the excess glucose to the bloodstream. Pg.16

17 This slide shows the basic mechanism of SGLT2 function in glucose reabsorption. On the luminal side of the early proximal tubule S1 segment, absorption of sodium across the cell membrane creates an energy gradient that in turn allows glucose to be absorbed. On the other side of the cell, sodium is reabsorbed through an ATPase-mediated sodium-potassium pump into the bloodstream in order to maintain intravascular volume. This exchange alters the concentration gradient within the cell so that glucose is reabsorbed into the bloodstream via the GLUT2 transporter. The GLUT2 transporter is present in red blood cells, the brain, and other tissues and thus is not a candidate for pharmacologic intervention. In contrast, SGLT2 is specific to the proximal tubule, so pharmacologic inhibition will affect glucose reabsorption in the kidney, but not in other tissues. Pg.17

18 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Observations about familial renal glucosuria lend support to the viability of inhibiting SGLT2 as an approach to managing glucose in type 2 diabetes. The condition is characterized by variable glucosuria (about g/day) but normal plasma glucose concentration. Of note, familial renal glucosuria is considered a benign condition, and is not associated with any known long-term health complications. As this benign glucosuria is due to SGLT2 mutations, it is considered unlikely that selective pharmacologic inhibition of SGLT2 would have important adverse effects aside from induction of glucosuria. Still, it should be noted that these observations about familial renal glucosuria do not replace the need for randomized controlled trials examining the safety of pharmacotherapy-induced SGLT2 inhibition. Pg.18

19 Inhibition of the SGLT2 protein channel is a rational approach to therapy for type 2 diabetes for the reasons listed on this slide. First, SGLT2 inhibitors reduce glucose reabsorption in the renal proximal tubule, resulting in glucosuria. This decreases plasma glucose levels and reverses glucotoxicity. This approach to therapy is simple and nonspecific, and thereby would complement the action of all other antidiabetic agents, including insulin. As a result, even refractory type 2 diabetes will respond. The next portion of this program discusses SGLT2 inhibition, a novel antihyperglycemic class being developed for the management of type 2 diabetes. Pg.19

20 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Multiple organs and tissues play a role in the body s handling of glucose. To date, both research and development for type 2 diabetes are focused primarily on insulin-dependant pathways; however, a new approach that acts independently in insulindependant mechanisms, involving the kidney, may help address the multiple challenges of type 2 diabetes. Research has established the renal sodium glucose co-transporter 2, or SGLT2, located in the nephron, as an important insulin-independent mechanism in glucose balance. Normally, 180 grams of glucose are filtered through the glomerulus each day, and virtually all of it is absorbed back into circulation in the renal proximal tubule. SGLT2, which is located in the S1 segment of the renal proximal tubule, is responsible for up to 90% of total renal glucose reabsorption. In the presence of hyperglycemia in type 2 diabetes, SGLT2 continues to reabsorb glucose and its associated calories from the kidney into the blood stream. SGLT2 inhibition is a novel insulin-independent approach that may help address the many challenges of type 2 diabetes. The mechanism of action of SGLT2 inhibition is to block the re-absorption of glucose in the S1 segment of the renal proximal tube. This leads to the direct excretion of glucose and its associated calories. This insulin-independent mechanism is important because insulin-dependant mechanisms progressively decline in patients with type 2 diabetes. Urinary glucose excretion via SGLT2 inhibition is now being studied as an important insulin-independent mechanism. Pg.20

21 This graph shows dose-dependent increases in urinary glucose excretion with dapagliflozin in 64 healthy volunteers. The long-term safety of SGLT2 inhibition has not yet been studied. However, short-term studies have shown that this treatment is associated with reduced A1C, body weight and blood pressure, and minimally increased urine volume. These studies have also found SGLT2 inhibition to be associated with no excessive losses of fluid, sodium or potassium, and few instances of hypoglycemia. Increased rates of urinary tract infections and vaginitis have been observed. It is also noteworthy that familial renal glycosuria a condition in which glucose is excreted in the urine despite normal or low blood glucose levels causes no apparent symptoms or serious effects. Pg.21

22 Novel Perspectives on Type 2 Diabetes: Traditional and Emerging Therapies and the Potential Role of the Kidneys Given the observations made to date regarding the effects of SGLT2 inhibition, this slide illustrates the potential clinical use of this class of medications. In summary, SGLT2 inhibition is associated with increased glucosuria, which in turn has been shown to lead to reduced A1C with rare or negligible risk of hypoglycemia, as well as reduced body weight and blood pressure. A large number of SGLT2 inhibitors are under investigation. At the time of publication, it should be noted that, among the SGLT2 inhibitors currently or previously in development, only dapagliflozin has phase 3 clinical data available in the published, peer-reviewed literature. Pg.22

23 In conclusion, the inadequate control of type 2 diabetes is associated with a number of important health consequences. Existing therapies for type 2 diabetes have distinct mechanisms of action and each present specific advantages and disadvantages. The kidneys play a role in glucose handling and present a novel target for interventions aimed at glucose imbalance in type 2 diabetes. SGLT2 inhibition produces glucosuria, and the clinical efficacy and safety of this approach is undergoing further study. Pg.23