Can J Diabetes 39 (2015) S127–S128
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: w w w. c a n a d i a n j o u r n a l o f d i a b e t e s . c o m
Editor’s Note
Current and Emerging Pharmacotherapies for Type 2 Diabetes This December supplement to the Canadian Journal of Diabetes is published to celebrate the occasion of the joint meeting of the World Diabetes Congress and the 17th annual Joint Professional Conference of the Canadian Diabetes Association and the Canadian Society of Endocrinology, which is being held in the beautiful city of Vancouver, British Columbia. The joint conference is an ideal forum for presentation of the latest advances in research and in the clinical management and prevention of diabetes and related conditions. Because our journal is widely distributed to delegates attending the joint conference, we would like to take advantage of this opportunity to update the congress’s participants, in this special supplement, on the current and emerging pharmacotherapies for optimal management of type 2 diabetes. The World Diabetes Congress meets every 3 years to bring together internationally renowned leaders in diabetes medicine to share the latest advances in research and in the clinical management and prevention of diabetes and related conditions. Regardless of the latest research and advances in clinical practice, we are facing an enormous public health issue—the alarming and relentless increase in the global prevalence of diabetes. It is unfortunate that more and more people globally are affected by diabetes. In 2013, more than 380 million people globally had diabetes. By 2035, the World Health Organization predicts that 592 million people globally will have diabetes, which is an alarming 70% increase (1). The dramatic rise in the prevalence of diabetes is fuelled mainly by the continuing global obesity epidemic. Type 2 diabetes is a chronic disease characterized by insulin resistance and progressive betacell failure. The overall goal in the treatment of people with diabetes is to restore, optimize and maintain their quality of life by keeping their blood sugar levels as close to normal as possible and within a target range that will prevent or delay the development of the serious small- and large-blood vessel complications of diabetes. The cornerstone of its management is nutrition therapy along with regular physical activity. The majority of people with type 2 diabetes are overweight or obese, so weight loss is recommended to achieve and maintain a healthy body weight. The Action for Health in Diabetes (Look AHEAD) trial demonstrated that intensive healthbehaviour modification for modest weight loss provided many benefits. They include improved glycemic control, reduction in the need, number and cost of medications required to manage and achieve blood glucose and blood pressure targets, improvements in mobility, minimization of sleep apnea and urinary incontinence and optimization of quality of life, as well as fewer hospitalizations and reductions in long-term healthcare costs (2). This special supplement features a number of reviews of and perspectives on practice concerning exercise and current and emerging therapies for type 2 diabetes. People with type 2 diabetes can derive significant health benefits from regular physical activity. Armstrong and Sigal review the importance of resistance training (strength training), the dose-response relationship of physical activity
and the emerging evidence concerning the role of sedentary behavior in people with type 2 diabetes and provide valuable information for healthcare practitioners so they prescribe appropriate physical activity counselling with their patients (3). Modest weight loss through health-behaviour modification can significantly prevent or delay the onset of type 2 diabetes in people at risk. Each kilogram of body weight loss is associated with a 16% relative reduction in diabetes risk (4), and a recent meta-analysis concluded that intentional weight loss of only ~5 kg is associated with a 15% reduction in all-cause mortality (5). Unfortunately, healthbehaviour modification alone seldom sustains weight loss adequate for achieving the desired health outcomes, especially in people with diabetes who already have greater difficulty losing weight. Pharmacotherapy is a realistic treatment option as an adjunct to diet and exercise. The U.S. Endocrine Society recently published clinical practice guidelines for pharmacotherapy for obesity and emphasized the importance of addressing weight management prior to treating the obesity-related comorbidities (6). The guidelines also alert physicians to be aware of drugs that are associated with weight gain and, whenever possible, choose drugs that are less likely to cause weight gain. This is particularly relevant when selecting glucose-lowering drugs for the glycemic management of patients with type 2 diabetes because many of these agents are associated with modest and sometimes fairly significant weight gain. With respect to antiobesity drugs, orlistat has been the only drug available for long-term weight management in many countries until recently. New agents have now been approved for weight management in the United States, the European Union and Canada. Two reviews in this issue are devoted to weight issues in diabetes; one is focused on the impact of glucose-lowering drugs on body weight (7), and a second provides an update of current and emerging pharmacotherapies for obesity management in patients with prediabetes and diabetes (8). With a better understanding of the pathophysiology of type 2 diabetes, the quest for novel strategies and therapeutic agents with novel mechanisms of action that target the defects of type 2 diabetes without causing adverse side effects has led to exciting advances in recent years. Researchers have focused on the importance of beta-cell preservation in inducing the remission and progression of type 2 diabetes. This topic is reviewed by Dr. Retnakaran, who also discusses novel strategies that could potentially modify the natural history of this disease. With respect to better and novel glucose-lowering drugs, sodium glucose cotransporter 2 (SGLT2) receptor inhibitors (gliflozins) are a new class of potent antihyperglycemic agents that lower blood glucose levels in an insulin-independent manner by increasing renal glucose excretion. SGLT2 inhibitors are the first class of oral glucoselowering drugs that lower body weight as well as blood pressure, and they may decrease albuminuria. The 2015 interim update on pharmacotherapy for type 2 diabetes published recently by the
1499-2671 © 2015 Published by Elsevier Inc. on behalf of Canadian Diabetes Association. http://dx.doi.org/10.1016/j.jcjd.2015.09.095
S128
Editor’s Note / Can J Diabetes 39 (2015) S127–S128
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee have specifically addressed SGLT2 inhibitors (9). The mode of action, efficacy and safety of SGLT2 inhibitors and how they fit into the management of type 2 diabetes are discussed in the review by Katz and Leiter (10). As diabetes progresses with declining beta-cell function, insulin therapy may become necessary in selected patients. Unfortunately, effective insulin therapy is limited by the adverse side effects of hypoglycemia and weight gain. Severe hypoglycemia caused by insulin and insulin secretagogues remain a serious threat that not only compromises the quality of life but has also been recognized to be associated with worse cardiovascular (CV) outcomes. This topic as well as strategies for avoiding and managing hypoglycemia are discussed by Dr. Paty (11). On the other hand, several new insulin preparations are now available, and the major benefits are the reduction of risk for hypoglycemia due to their flatter profile and the allowance of flexibility owing to their longer duration of action. In addition, biosimilar insulin analogues are also available as cheaper alternatives. Cheung and Senior provide a timely update of novel and emerging insulin preparations and delivery systems that optimize insulin therapy in people with type 2 diabetes (12). Although glycemic management is highly beneficial in delaying the onset of and reducing the risk for microvascular complications, its impact on CV disease has been questioned. The ACCORD, ADVANCE and VADT trials failed to demonstrate the benefits of glucose lowering in the reduction of CV disease. In addition, concerns were raised regarding the impact of some glucose-lowering drugs, notably the thiazolidinediones, on CV disease. This has led the U.S. Food and Drug Administration to issue a guidance on the CV safety of glucose-lowering drugs. All novel antidiabetic agents have to demonstrate CV safety in the pooled clinical trials prior to approval, and manufacturers are mandated to conduct postapproval CV safety trials. The CV safety of current and emerging glucoselowering drugs are reviewed by Dr. Fitchett (13). To date, 3 CV outcome trials concerning dipeptidyl-peptidase-4 (DPP4) inhibitors have been conducted, and all demonstrated CV safety when compared to placebo. More recently, the results of the first study of CV safety of SGLT2 inhibitors were released at the annual meeting of the European Association for the Study of Diabetes and were published simultaneously (14). Empagliflozin was associated with an impressive 38% and 35% relative risk reduction in deaths from CV causes and from any cause. The number needed to treat is 39, which means that 39 patients would need to be treated during a 3-year period to prevent 1 death. For the first time, we now have a glucoselowering drug that reduces CV outcomes and death. SGLT2 inhibitors as a class may become the game changers in glycemic management. Speaking of CV risk reduction, it remains critically important for patients with diabetes to achieve LDL-cholesterol at or below the guideline target of 2 mmol/L. Hoe and Hegele provide us with a
state-of-the-art update on lipid management, with a focus on emerging therapies and, notably, inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9) to help manage patients who are at high CV risk and not achieving targets and those patients who have statinassociated myalgia or side effects (15). Evolocumab is the first such agent from this class of potent lipid-lowering drugs approved in Canada. Our readers will have the opportunity to familiarize themselves with PCSK9 inhibitors. This supplement promises to update our readers with the latest developments in the management of type 2 diabetes. The availability of novel strategies and drugs offer us fresh hope in tackling the tsunami of chronic diseases, which could potentially threaten to bankrupt our personal health and the healthcare system. David C.W. Lau, MD, PhD, FRCPC Editor-in-Chief, Canadian Journal of Diabetes, E-mail address: [email protected]
References 1. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137– 49. 2. Look AHEAD Research Group, Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the Look AHEAD Trial. Arch Intern Med 2010;170:1566–75. 3. Armstrong M, Sigal RJ. Exercise as medicine: Key concepts when discussing physical activity with people with type 2 diabetes. Can J Diabetes 2015;39:S129– 33. 4. Lau DCW, Teoh H. Benefits of modest weight loss on the management of type 2 diabetes mellitus. Can J Diabetes 2013;37:128–34. 5. Kritchevsky SB, Beavers KM, Miller ME, et al. Intentional weight loss and allcause mortality: A meta-analysis of randomized clinical trials. PLoS ONE 2015;10:e0121993. 6. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100:342–62. 7. Lau DCW, Teoh H. Impact of current and emerging glucose-lowering drugs on body weight in type 2 diabetes. Can J Diabetes 2015;39:S148–54. 8. Lau DCW, Teoh H. Current and emerging pharmacotherapies for weight management in prediabetes and diabetes. Can J Diabetes 2015;39:S134–41. 9. Harper W, Clement M, Goldenberg R, et al. Policies, guidelines and consensus statements: Pharmacologic management of type 2 diabetes: 2015 interim update. Can J Diabetes 2015;39:250–2. 10. Katz P, Leier LA. The role of the kidney and SGLT2 inhibitors in type 2 diabetes. Can J Diabetes 2015;39:S167–75. 11. Paty B. The role of hypoglycemia in cardiovascular outcomes in diabetes. Can J Diabetes 2015;39:S155–9. 12. Cheung KKT, Senior PA. Novel and emerging insulin preparations for type 2 diabetes. Can J Diabetes 2015;39:S160–6. 13. Fitchett DH. Cardiovascular safety of current and emerging glucose lowering therapies. Can J Diabetes 2015;39:S176–82. 14. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015. 15. Hoe E, Hegele RA. Lipid management in diabetes with focus on emerging therapies. Can J Diabetes 2015;39:S183–90.
Contents lists available at ScienceDirect
Canadian Journal of Diabetes journal homepage: w w w. c a n a d i a n j o u r n a l o f d i a b e t e s . c o m
Editor’s Note
Current and Emerging Pharmacotherapies for Type 2 Diabetes This December supplement to the Canadian Journal of Diabetes is published to celebrate the occasion of the joint meeting of the World Diabetes Congress and the 17th annual Joint Professional Conference of the Canadian Diabetes Association and the Canadian Society of Endocrinology, which is being held in the beautiful city of Vancouver, British Columbia. The joint conference is an ideal forum for presentation of the latest advances in research and in the clinical management and prevention of diabetes and related conditions. Because our journal is widely distributed to delegates attending the joint conference, we would like to take advantage of this opportunity to update the congress’s participants, in this special supplement, on the current and emerging pharmacotherapies for optimal management of type 2 diabetes. The World Diabetes Congress meets every 3 years to bring together internationally renowned leaders in diabetes medicine to share the latest advances in research and in the clinical management and prevention of diabetes and related conditions. Regardless of the latest research and advances in clinical practice, we are facing an enormous public health issue—the alarming and relentless increase in the global prevalence of diabetes. It is unfortunate that more and more people globally are affected by diabetes. In 2013, more than 380 million people globally had diabetes. By 2035, the World Health Organization predicts that 592 million people globally will have diabetes, which is an alarming 70% increase (1). The dramatic rise in the prevalence of diabetes is fuelled mainly by the continuing global obesity epidemic. Type 2 diabetes is a chronic disease characterized by insulin resistance and progressive betacell failure. The overall goal in the treatment of people with diabetes is to restore, optimize and maintain their quality of life by keeping their blood sugar levels as close to normal as possible and within a target range that will prevent or delay the development of the serious small- and large-blood vessel complications of diabetes. The cornerstone of its management is nutrition therapy along with regular physical activity. The majority of people with type 2 diabetes are overweight or obese, so weight loss is recommended to achieve and maintain a healthy body weight. The Action for Health in Diabetes (Look AHEAD) trial demonstrated that intensive healthbehaviour modification for modest weight loss provided many benefits. They include improved glycemic control, reduction in the need, number and cost of medications required to manage and achieve blood glucose and blood pressure targets, improvements in mobility, minimization of sleep apnea and urinary incontinence and optimization of quality of life, as well as fewer hospitalizations and reductions in long-term healthcare costs (2). This special supplement features a number of reviews of and perspectives on practice concerning exercise and current and emerging therapies for type 2 diabetes. People with type 2 diabetes can derive significant health benefits from regular physical activity. Armstrong and Sigal review the importance of resistance training (strength training), the dose-response relationship of physical activity
and the emerging evidence concerning the role of sedentary behavior in people with type 2 diabetes and provide valuable information for healthcare practitioners so they prescribe appropriate physical activity counselling with their patients (3). Modest weight loss through health-behaviour modification can significantly prevent or delay the onset of type 2 diabetes in people at risk. Each kilogram of body weight loss is associated with a 16% relative reduction in diabetes risk (4), and a recent meta-analysis concluded that intentional weight loss of only ~5 kg is associated with a 15% reduction in all-cause mortality (5). Unfortunately, healthbehaviour modification alone seldom sustains weight loss adequate for achieving the desired health outcomes, especially in people with diabetes who already have greater difficulty losing weight. Pharmacotherapy is a realistic treatment option as an adjunct to diet and exercise. The U.S. Endocrine Society recently published clinical practice guidelines for pharmacotherapy for obesity and emphasized the importance of addressing weight management prior to treating the obesity-related comorbidities (6). The guidelines also alert physicians to be aware of drugs that are associated with weight gain and, whenever possible, choose drugs that are less likely to cause weight gain. This is particularly relevant when selecting glucose-lowering drugs for the glycemic management of patients with type 2 diabetes because many of these agents are associated with modest and sometimes fairly significant weight gain. With respect to antiobesity drugs, orlistat has been the only drug available for long-term weight management in many countries until recently. New agents have now been approved for weight management in the United States, the European Union and Canada. Two reviews in this issue are devoted to weight issues in diabetes; one is focused on the impact of glucose-lowering drugs on body weight (7), and a second provides an update of current and emerging pharmacotherapies for obesity management in patients with prediabetes and diabetes (8). With a better understanding of the pathophysiology of type 2 diabetes, the quest for novel strategies and therapeutic agents with novel mechanisms of action that target the defects of type 2 diabetes without causing adverse side effects has led to exciting advances in recent years. Researchers have focused on the importance of beta-cell preservation in inducing the remission and progression of type 2 diabetes. This topic is reviewed by Dr. Retnakaran, who also discusses novel strategies that could potentially modify the natural history of this disease. With respect to better and novel glucose-lowering drugs, sodium glucose cotransporter 2 (SGLT2) receptor inhibitors (gliflozins) are a new class of potent antihyperglycemic agents that lower blood glucose levels in an insulin-independent manner by increasing renal glucose excretion. SGLT2 inhibitors are the first class of oral glucoselowering drugs that lower body weight as well as blood pressure, and they may decrease albuminuria. The 2015 interim update on pharmacotherapy for type 2 diabetes published recently by the
1499-2671 © 2015 Published by Elsevier Inc. on behalf of Canadian Diabetes Association. http://dx.doi.org/10.1016/j.jcjd.2015.09.095
S128
Editor’s Note / Can J Diabetes 39 (2015) S127–S128
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee have specifically addressed SGLT2 inhibitors (9). The mode of action, efficacy and safety of SGLT2 inhibitors and how they fit into the management of type 2 diabetes are discussed in the review by Katz and Leiter (10). As diabetes progresses with declining beta-cell function, insulin therapy may become necessary in selected patients. Unfortunately, effective insulin therapy is limited by the adverse side effects of hypoglycemia and weight gain. Severe hypoglycemia caused by insulin and insulin secretagogues remain a serious threat that not only compromises the quality of life but has also been recognized to be associated with worse cardiovascular (CV) outcomes. This topic as well as strategies for avoiding and managing hypoglycemia are discussed by Dr. Paty (11). On the other hand, several new insulin preparations are now available, and the major benefits are the reduction of risk for hypoglycemia due to their flatter profile and the allowance of flexibility owing to their longer duration of action. In addition, biosimilar insulin analogues are also available as cheaper alternatives. Cheung and Senior provide a timely update of novel and emerging insulin preparations and delivery systems that optimize insulin therapy in people with type 2 diabetes (12). Although glycemic management is highly beneficial in delaying the onset of and reducing the risk for microvascular complications, its impact on CV disease has been questioned. The ACCORD, ADVANCE and VADT trials failed to demonstrate the benefits of glucose lowering in the reduction of CV disease. In addition, concerns were raised regarding the impact of some glucose-lowering drugs, notably the thiazolidinediones, on CV disease. This has led the U.S. Food and Drug Administration to issue a guidance on the CV safety of glucose-lowering drugs. All novel antidiabetic agents have to demonstrate CV safety in the pooled clinical trials prior to approval, and manufacturers are mandated to conduct postapproval CV safety trials. The CV safety of current and emerging glucoselowering drugs are reviewed by Dr. Fitchett (13). To date, 3 CV outcome trials concerning dipeptidyl-peptidase-4 (DPP4) inhibitors have been conducted, and all demonstrated CV safety when compared to placebo. More recently, the results of the first study of CV safety of SGLT2 inhibitors were released at the annual meeting of the European Association for the Study of Diabetes and were published simultaneously (14). Empagliflozin was associated with an impressive 38% and 35% relative risk reduction in deaths from CV causes and from any cause. The number needed to treat is 39, which means that 39 patients would need to be treated during a 3-year period to prevent 1 death. For the first time, we now have a glucoselowering drug that reduces CV outcomes and death. SGLT2 inhibitors as a class may become the game changers in glycemic management. Speaking of CV risk reduction, it remains critically important for patients with diabetes to achieve LDL-cholesterol at or below the guideline target of 2 mmol/L. Hoe and Hegele provide us with a
state-of-the-art update on lipid management, with a focus on emerging therapies and, notably, inhibitors of proprotein convertase subtilisin kexin 9 (PCSK9) to help manage patients who are at high CV risk and not achieving targets and those patients who have statinassociated myalgia or side effects (15). Evolocumab is the first such agent from this class of potent lipid-lowering drugs approved in Canada. Our readers will have the opportunity to familiarize themselves with PCSK9 inhibitors. This supplement promises to update our readers with the latest developments in the management of type 2 diabetes. The availability of novel strategies and drugs offer us fresh hope in tackling the tsunami of chronic diseases, which could potentially threaten to bankrupt our personal health and the healthcare system. David C.W. Lau, MD, PhD, FRCPC Editor-in-Chief, Canadian Journal of Diabetes, E-mail address: [email protected]
References 1. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137– 49. 2. Look AHEAD Research Group, Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the Look AHEAD Trial. Arch Intern Med 2010;170:1566–75. 3. Armstrong M, Sigal RJ. Exercise as medicine: Key concepts when discussing physical activity with people with type 2 diabetes. Can J Diabetes 2015;39:S129– 33. 4. Lau DCW, Teoh H. Benefits of modest weight loss on the management of type 2 diabetes mellitus. Can J Diabetes 2013;37:128–34. 5. Kritchevsky SB, Beavers KM, Miller ME, et al. Intentional weight loss and allcause mortality: A meta-analysis of randomized clinical trials. PLoS ONE 2015;10:e0121993. 6. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015;100:342–62. 7. Lau DCW, Teoh H. Impact of current and emerging glucose-lowering drugs on body weight in type 2 diabetes. Can J Diabetes 2015;39:S148–54. 8. Lau DCW, Teoh H. Current and emerging pharmacotherapies for weight management in prediabetes and diabetes. Can J Diabetes 2015;39:S134–41. 9. Harper W, Clement M, Goldenberg R, et al. Policies, guidelines and consensus statements: Pharmacologic management of type 2 diabetes: 2015 interim update. Can J Diabetes 2015;39:250–2. 10. Katz P, Leier LA. The role of the kidney and SGLT2 inhibitors in type 2 diabetes. Can J Diabetes 2015;39:S167–75. 11. Paty B. The role of hypoglycemia in cardiovascular outcomes in diabetes. Can J Diabetes 2015;39:S155–9. 12. Cheung KKT, Senior PA. Novel and emerging insulin preparations for type 2 diabetes. Can J Diabetes 2015;39:S160–6. 13. Fitchett DH. Cardiovascular safety of current and emerging glucose lowering therapies. Can J Diabetes 2015;39:S176–82. 14. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015. 15. Hoe E, Hegele RA. Lipid management in diabetes with focus on emerging therapies. Can J Diabetes 2015;39:S183–90.
