Cardiovascular disease (ischaemic

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1 diabetes the CV Risk equivalent Earn 3 CPD Points online The heart: Where sugar and fat meet KEY MESSAGES Dr Zaheer Bayat Endocrinologist/Physician Mediclinic Sandton Johannesburg Type 2 diabetes mellitus is a medically incurable disease It is often inadequately controlled Cardiovascular problems will almost certainly kill your diabetic patient 1 Not all drugs are equally safe There needs to be a move away from drugs that harm There are gaps in our knowledge that we need to keep working towards addressing The path ahead is exciting indeed. Cardiovascular disease (ischaemic heart disease and stroke) ranks among the top 10 causes of death in all countries worldwide, regardless of whether they re developed or developing countries. Across the world, 33 people die every minute from cardiovascular disease and importantly 75% of diabetic patients will die from a fatal cardiovascular event 1. said Dr Zaheer Bayat. He was speaking at a CPD meeting hosted by the South African Academy of Family Practice on 12 July. The link between diabetes and cardiovascular disease is well established and diabetes is a huge and growing problem. In 2013 worldwide, for every one person with HIV, there were 11 with diabetes and that fails to take into account the hidden data, as many diabetics remain undiagnosed. Sub-Saharan Africa will see a 99% increase in diabetes over the next 20 years, he said. A worldwide epidemic of obesity is driving the rapidly increasing incidence of type 2 diabetes. 2,3 In the USA in 2010, one in three people was overweight ( arrowres.com/program-obesity.html) so this is a massive problem. The more obese someone is, the greater their likelihood of developing diabetes. Diabetes is not a mild disease. It is the leading cause of blindness, non-traumarelated amputations and end-stage renal disease. Diabetic retinopathy is the most frequent cause of new cases of blindness Table 1. Available therapies for Glycaemic control: Pharmacological control Class Biguanides Glitazones Alpha-glucosidase SGLT-2 (sodium glucose transporter) Inhibitor GLP-1 agonists (Glucagon- like peptide-1) DPP-4 inhibitors (Dipeptidyl peptidase-4) Pharmacological action Decrease hepatic glucose production and increase glucose uptake Increase insulin sensitivity and glucose uptake in skeletal muscle. Decrease lipolysis in adipose tissue and decrease hepatic glucose output Delay intestinal carbohydrate digestion and absorption. Inhibitors Increase urinary glucose excretion. Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying Prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release, delay gastric emptying This article was made possible by an unrestricted educational grant from MSD, which had no control over content. Sulphonylureas & Meglitinides Insulins Increase insulin secretion from pancreatic alpha cells Increase glucose uptake in skeletal muscle and reduce hepatic glucose production Source: Cheng Y, Fantus IG. Oral anti hyperglycaemic therapy for type 2 Diabetes.CAMJ2005; 172(2): NOVEMBER

2 Timeline of treatment options Figure 1. Timeline of treatment options as they have become available to physicians among adults aged years. 4 Diabetes is also the most common single cause of end-stage renal disease. 5 The cardiovascular consequences of diabetes are devastating with 75% of diabetic patients dying from Cardiovascular events. 6 Foot ulcers and amputations are also a major cause of morbidity, disability, emotional and physical costs for people with diabetes. 7 Obesity itself is not a mild condition either, and over and above its being a risk factor for diabetes and cardiovascular disease, it also has psychosocial, pulmonary, musculoskeletal and gastrointestinal implications. Darwin would be proud. The obese society we have become has proven evolution in a rapid way. People s calorie intake has increased dramatically over the last 20 years as portion sizes have grown. This includes an increased sugar intake, much of it hidden in soft drinks and fruit juices. According to NHANES data published in Circulation in 2009, the average person over the age of one year consumes 22 teaspoons of sugar per day. 8 Dr Bayat underscored the important role lifestyle modification can play in managing diabetes. The Diabetes Prevention Program proved that its impact is sustainable over time and that regardless of age, all diabetics benefit from lifestyle measures. However, it is an ongoing challenge to persuade patients to change their eating habits and do more exercise. Treatment of diabetes Turning to pharmacological treatments for diabetes, Dr Bayat noted that where once there was only insulin and then insulin and the sulphonylureas, there is now a plethora of treatment options, all acting in different ways and at different sites in the body to address the same problem (Table 1). Earn 3 CPD points at Click on Accredited Education Programmes/CPD Practical clinical challenges However, all antidiabetic agents come with challenges that involve both physician and patient, as well as the medications themselves (Figure 2). The challenge to the physician is that he needs to optimise the use of currently available therapies to ensure adequate glycaemic, blood pressure and lipid control in Figure 2. Challenges in daily practice: interaction between physician, patient and medication 2 NOVEMBER 2014

3 Table 2. Practical hints to improve Patient Compliance with long term medication Use Combinations of: Instruction and instructional materials Simplify the regimen (e.g., less frequent dosing, controlled release dosage forms) Counsel about the regimen Support group sessions Reminders (manual and computer) for medications and appointments Cue medications to daily events Reinforcement and rewards (e.g., explicitly acknowledging the patient s efforts to adhere) Introduce Self-monitoring with regular physician review and reinforcement Involve family members and significant others Source: Based on Haynes RB, McDonald HP and Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA 2002; 288(22): order to reduce the long-term complications of type 2 diabetes. 9 The physician also needs to ensure that he prescribes a combined therapy of oral antidiabetic agents with complementary modes of action to address the underlying pathology of type 2 diabetes. This means that, aside from sulphonylureas and metformin which target fasting hyperglycaemia and have limited effect on post prandial glycaemia, he should use newer agents to control post prandial glucose excursions also. 10 Helping patients follow their prescribed therapy is a key element of the primary care practitioner s role. Some very useful practical hints have been investigated and are summarised in Table Side-effects of progressive diabetic treatment As doctors we often fail to make it clear to patients that diabetes is progressive and that they will require more drugs as time goes by. The majority of diabetic treatments cause weight gain, which creates a vicious circle, given the role of overweight and obesity in diabetes. One also needs to take into account the risk of hypoglycaemia, which is one of the reasons why relatively few patients are treated to target, despite our knowing that better HbA 1c control is associated with fewer complications and reduced risk. (Figure 3) The UKPDS early study evaluated the consequences of 6 years intensification of therapy in type 2 diabetes with sulphonylureas (mainly glibenclamide) and insulin.while it showed that glycaemic control improved, both therapies were associated with increased hypoglcaemia and weight gain. In the case of insulin, weight gain over the period was in the region of 6-10 kg and sulphonylureas usage was associated with an average of 2-4 kg of weight gain. 12 This also occurred in the more recent ADOPT trial of commonly prescribed anti-diabetic , ,2 17, ,5 5,4 5 0 n/n= 1/8 Glipizide 21/66 Glibenclamide 38/198 Gliclazide 63/351 Glimepiride 36/669 Vildagliptin Post hoc descriptive analysis. Source: Al-Arouj M, et al. The effect of vildagliptin relative to sulphonylureas in muslim patients with type 2 diabetes fasting during Ramadan. Int J Clin Pract. 2013;67(10): Figure 3. Muslim patients during Ramadan with 1 hypoglycaemic events (%) 14 NOVEMBER

4 diabetes the CV RISK equivalent agents; in this real-world study, sulphonylurea treatment was associated with an average of 1.8kg weight gain over the 4 years of the study.13 In a recent study which evaluated the effect of vildagliptin compared to Sulphonylureas in Muslim patients with type 2 Diabetes as experienced during Ramadan, the reduction in hypoglycaemic events when using vildagliptin as compared to a variety of sulphonylureas is clearly of major benefit to patients.14 Treating to target approaches International guidance for type 2 diabetes targets an HbA1c of less than 7%, but only 50% of patients reach this target. Furthermore it is of concern that some 30% have HbA1c levels above 9%. Getting to target is vital as every 1% reduction in HbA1c to a level of 7%,results in a reduced risk of deaths from diabetes (21% reduction risk), heart attacks (reduced by 14%), microvascular complications (reduced by 37%) and peripheral vascular disorders (reduced by 43%).15 Diabetes and the heart With specific reference to diabetes and the heart, Dr Bayat observed that 75% of diabetics die from a fatal cardiovascular event, but they may experience atypical presentations. Diabetes causes accelerated atherosclerosis, though we re not sure exactly why.,. Hyperglycaemia is not good for the heart, but neither is hypoglycaemia. Reducing cardiovascular risk an holistic approach It is vital to address all aspects of cardiovascular risk in type 2 diabetes; hypertension, lipids and obesity. With regard to reducing the cardio-vascular impact of hyperglycaemia, there is a huge armamentarium of glucose-lowering drugs available to the physician. Therapy comes with side-effects and it s important to first do no harm. The withdrawal of rosiglitazone further Earn 3 CPD points at Click on Accredited Education Programmes/CPD 4 NOVEMBER 2014 Figure 4. Glycemic control algorithm17 to a 2007 study that showed its association with an increased risk of myocardial infarction and death from cardiovascular causes16 led to the FDA requiring cardiovascular outcome data for all new drugs, said Dr Bayat. Consequently, we have good safety data for the incretin therapies and we do also know that metformin does not contribute to atherosclerosis or cause hypoglycaemia.

5 He therefore feels that there needs to be a patient-centric approach to treating the diabetic. In at-risk patients there should be a move away from the medication which are not as safe as they were once thought to be. But further to that, what treatments should be chosen? The ADA currently recommends metformin as preferred initial therapy if tolerated and not contraindicated. Thereafter consider insulin (with or without other agents). Alternatively add a second oral agent, GLP-1 receptor agonist or insulin. 16 The AACE glycaemic control algorithm suggests a hierarchy of usage in both monotherapy and dual therapy approaches (Figure 4). Conclusion Treatment should be individualised for each patient to ensure HbA 1c lowering with improved control, reduced hypoglycaemia, no weight gain and enhanced beta-cell function. Wrapping up, Dr Bayat underlined that diabetes is an incurable condition, often inadequately controlled and that its associated cardiovascular complications are a major concern and should always be taken into account, as not all drugs are equally safe. However, the path ahead is exciting indeed and we need to continue fixing the gaps in our current knowledge by doing trials in the best interests of our patients, he concluded. References: 1. Gray RP, Yudkin JS. Cardiovascular disease in diabetes mellitus, in Textbook of Diabetes, Eds. JC Pickup and G. Williams, 2nd edition, Blackwell Science Ltd. Oxford Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 1995; 122(7): Chan JM, Rimm EB, Colditz GA, et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994; 17(19): Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, et al. Diabetic Retinopathy. Diabetes Care 2003; 26 (suppl 1): S99-S Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, et al. Diabetic nephropathy. Diabetes Care 2003; 26 (suppl 1): S94-S Kannel WB, D Agostino RB, Wilson PW, Belanger AJ, Gagnon DR. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J 1990; 120(3): Mayfield JA, Reiber GE, Sanders LJ, Janisse D, et al. Preventive foot care in people with diabetes. Diabetes Care 2003; 26 (suppl 1) S78-S Johnson RK, Appell LJ, Brands M, American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism and the Council on Epideamiology and Prevention. et al. Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation 2009; 120(11): Blonde L. Current challenges in diabetes management. Clin cornerstone 2005; 7 Suppl 3: S Van Gaal LF, De Leeuw IH. Rationale and options for combination therapy in the treatment of type 2 diabetes. Diabetologia 2003; 46 Suppl 1: M Haynes RB, McDonald HP and Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA 2002; 288(22): UK prospective diabetes study 16. Overview of 6 years therapy of type 2 diabetes: a progressive disease. UKPDS group. Diabetes 1995; 44(11): Viberti G, Kahn SE, Greene DA, et al. A diabetes outcome progressive trial (ADOPT): an international multicentre study of the comparative efficacy of rosiglitazone, glyburide and metformin in recently diagnosed type 2 diabetes. Diabetes Care 2002; 25(10): Al-Arouj M, Hassoun AA, Medlej R, Pathan MF, et al. The effect of vildagliptin relative to sulphonylureas in Muslim patients with type 2 diabetes fasting during Ramadan: the VIRTUE study. Int J Clin Pract 2013; 67(10): doi: /ijcp Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321(7258): American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2014; 37: Suppl Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, et al. AACE comprehensive diabetes management algorithm Endocrine Practice 2013; 19(2): CPD How to earn CPD points: Visit click on Accredited Educational Programmes/CPD, click on registration, then answer the relevant questionnaire. Your CPD certificate will be ed to you within a week. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com NOVEMBER