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diabetes – the CV Risk equiValent

Dr Zaheer BayatEndocrinologist/PhysicianMediclinic SandtonJohannesburg

•Type2diabetesmellitusisamedicallyincurabledisease• Itisofteninadequatelycontrolled•Cardiovascularproblemswillalmostcertainlykillyourdiabeticpatient1

•Notalldrugsareequallysafe•Thereneedstobeamoveawayfromdrugsthatharm•Therearegapsinourknowledgethatweneedtokeepworkingtowardsaddressing•Thepathaheadisexcitingindeed.

KEY MEssaGEs

The heart: Where sugar and fat meet

This article was made possible by an unrestricted educational grant from MSD, which had no control over content.

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 event1.” 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 car-diovascular 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 driv-ing the rapidly increasing incidence of type 2 diabetes.2,3 “In the USA in 2010, one in three people was overweight (http://www.arrowres.com/program-obesity.html) so this is a massive problem. The more obese some-one is, the greater their likelihood of devel-oping diabetes.”

Diabetes is not a mild disease. “It is the leading cause of blindness, non-trauma-related 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 Pharmacological action

Biguanides Decrease hepatic glucose production and increase glucose uptake

Glitazones Increase insulin sensitivity and glucose uptake in skeletal muscle.Decrease lipolysis in adipose tissue and decrease hepatic glucose output

Alpha-glucosidase Delay intestinal carbohydrate digestion and absorption.Inhibitors

SGLT-2 (sodium glucose transporter) Inhibitor

Increase urinary glucose excretion.

GLP-1 agonists (Glucagon- like peptide-1)

Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying

DPP-4 inhibitors (Dipeptidyl peptidase-4)

Prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release, delay gastric emptying

Sulphonylureas & Meglitinides

Increase insulin secretion from pancreatic alpha cells

Insulins 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): 213-226

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among adults aged 20-74 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, emo-tional 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 dis-ease, it also has psychosocial, pulmonary, musculoskeletal and gastrointestinal impli-cations. “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 man-aging diabetes. “The Diabetes Prevention Program proved that its impact is sustain-able over time and that regardless of age, all diabetics benefit from lifestyle meas-ures. 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).

Practical clinical challenges However, all antidiabetic agents come with challenges that involve both physi-cian and patient, as well as the medications themselves (Figure 2).

The challenge to the phy-sician 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

Figure 1. Timeline of treatment options as they have become available to physicians

Timeline of treatment options

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diabetes – the CV Risk equiValent

order to reduce the long-term complica-tions 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 met-formin which target fasting hyperglycaemia and have limited effect on post prandial gly-caemia, he should use newer agents to con-trol 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 2.11

Side-effects of progressive diabetic treatmentAs 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 treat-ments 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 hypogly-caemia, which is one of the reasons why relatively few patients are treated to target, despite our knowing that better HbA1c con-trol 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

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): 2880-2883.

Figure 3. Muslim patients during Ramadan with ≤1 hypoglycaemic events (%)14

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):957-963.

35

30

25

20

15

10

5

038/198

VildagliptinGlimepirideGliclaziden/N=

Post hoc descriptive analysis.

36/669

5,4

63/351

17,919,2

21/66

Glibenclamide

31,8

1/8

Glipizide

12,5

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diabetes – the CV Risk equiValent

agents; in this real-world study, sulpho-nylurea 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 approachesInternational guidance for type 2 diabe-tes 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% reduc-tion 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 diabet-ics die from a fatal cardiovascular event, but they may experience atypical presentations.

“Diabetes causes accelerated atheroscle-rosis, though we’re not sure exactly why.,. Hyperglycaemia is not good for the heart, but neither is hypoglycaemia.”

Reducing cardiovascular risk – an holistic approachIt is vital to address all aspects of cardio-vascular risk in type 2 diabetes; hyperten-sion, lipids and obesity.

With regard to reducing the cardio-vas-cular 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

to a 2007 study that showed its associa-tion with an increased risk of myocardial infarction and death from cardiovascular causes16 led to the FDA requiring cardio-vascular 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.

Figure 4. Glycemic control algorithm17

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diabetes – the CV Risk equiValent

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).

ConclusionTreatment should be individualised for each patient to ensure HbA1c lowering with improved control, reduced hypoglycaemia, no weight gain and enhanced beta-cell func-tion. Wrapping up, Dr Bayat underlined that diabetes is an incurable condition, often inad-equately 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.

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, medi-cal practitioners are referred to the product insert docu-mentation as approved by relevant control authorities.

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for combination therapy in the treatment of type 2 diabetes. Diabetologia 2003; 46 Suppl 1: M44-50.

11. Haynes RB, McDonald HP and Garg AX. Helping patients follow prescribed treatment: clinical applications. JAMA 2002; 288(22): 2880-2883.

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13. 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): 1737-1743.

14. 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): 957-63. doi: 10.1111/ijcp.12243.

15. 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): 405-12.

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