Issue 3 – At the Heart of Diabetes Management
Gearing up for New Ways of Potentially Reducing Cardiovascular Risk
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity for people living with diabetesi. In a series of presentations at LMC Diabetes & Endocrinology sites, LMC researchers and specialists reviewed the impact of Diabetes on CVD, as well as both the proven and potential interventions that reduce their impact.
Diabetes accelerates cardiovascular age due to the multiple CVD risk factors associated with this chronic conditionii. Dr. Ronnie Aronson pointed out that the onset of CVD is 15 years earlier for people with diabetes and that more than 60% of people living with type 2 diabetes will eventually die of CVD (see Figure 1). Therefore, prevention remains essential and in people with diabetes, cardiovascular (CV) risk factors should be treated aggressively. Cardiovascular disease in type 2 diabetes is a ticking bomb.
“Cardiovascular disease in type 2 diabetes is a ticking bomb.”
MANAGING CV RISK FACTORS IN YOUR TYPE 2 PATIENTS:
CASE STUDY: MR. CJ, 58 YEARS OLD, FIRST POST-MI FOLLOW-UP
- Mr. CJ is a 58-year-old man with a number of cardiovascular risk factors.
- He has recently suffered an acute ST-segment elevation myocardial infarction (STEMI)
- T2DM x 5 years
- Hypertension x 10 years
- Past smoker
- A1c – 7.8% & FBG- 8.8 mmol/L
- BMI- 31kg/m2
- A1c= 7.8%
- BP= 132/80 mmHg
- LDL-C= 1.9 mmol/L
- BMI= 31kg/m
- Activity level?
What to do to reduce the elevated residual risk?
- Better blood pressure control?
- Better glucose control?
- Better lipid control?
- Weight loss?
- Increased physical activity?
People living with type 2 diabetes have consider-ably worse short and long term outcomes after an acute coronary eventiii. Dr. Prakash Chandra reviewed the importance of addressing all risk factors in patients living with diabetes including maintaining a healthy weight, under-taking physical activity, smoking cessation, optimal glycemic control, optimal blood pressure control, healthy diet, and the need for vascular protective medications. The 2013 CDA Guidelines reiterate that there are a number of interventions designed to reduce CV risk and each of these interventions are an important component of optimal therapy. These interventions include both health behavior interventions and pharmacological therapies (anti-platelet agents, statins, angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs], glycemic and blood pressure control)iv.
Dr. Aronson also reviewed a 2006 Framingham publication which reported a population cohort, who had no history of stroke or CVD, at age 50. These patients were then followed for over two decades to develop an estimate of their lifetime risks of various endpoints, for both male and female participants. The cumulative lifetime risk of coronary heart disease (CHD) in both men and women was then looked at in the presence or absence of diabetes. In male participants without diabetes the rate of CHD was 30%, com-pared to 67% if the participant had diabetes. The impact of Diabetes on female participants was even more significant: when no diabetes was present, the CVD rate was 16%, in female participants living with diabetes, the rate was far higher at 57%v. Type 2 diabetes confers the highest lifetime risk for CHD of any risk factor studied and the clock starts ticking at age 50 (see Figure 2). Prevention remains essential since patients with type 2 diabetes have a high lifetime risk of dying of CAD.
MANAGING CV RISK FACTORS IN YOUR T2DM PATIENTS
The 2013 CDA Guidelines recommends an A1c target of ?7.0% for most patients living with diabetes which remains unchanged from the 2008 guidelines. One notable difference from the 2008 CDA Guidelines is the recommendation for select situations in which a higher target range could be considered instead (7.1-8.5%). A higher target could be used in situations such as limited life expectancy, patients with a high level of functional dependency, or established exten-sive CAD at high risk of ischemic eventsvi. As Dr. Chandra mentioned, there is no longer a single “fit all” approach and different A1c targets can be set after looking at the patient profile, vari-ous risk factors, side effects, and the specific end-points for each patient case. The CDA Guidelines do not recommend a second line of therapy for patients but does outline a number of factors which should be looked at when considering the next line of therapy. These factors include both patient-related factors such as hyperglycemia, hypoglycemia, weight, comorbidities, access to treatment, and preferences, as well as medica-tion-related factors including glucose lowering ability, hypoglycemia, effects on weight, contra-indications, and cost vii.
As highlighted by Dr. Aronson, only about 50% of patients in Canada are achieving a target A1c of 7.0% or less. There are many treatment options available for patients living with type 2 diabetes however the two biggest limitations to achieving optimal blood glucose control are risk of hypoglycemia and weight gain. It is also hard to treat adequately because it is a progressive disease and there are many pathophysiological abnormalities present in type 2 diabetes. Hyperglycemia is contributed to by a number of different mechanisms and the mechanisms involved will definitely vary from patient to patientviii.
Some of the abnormalities include decreased incretin effect, increased lipolysis, increased glucose reabsorption, decreased glucose update, neurotransmitter dysfunction, increased hepatic glucose production, increased glucagon secretionix, and decreased insulin secretion. Dr. Chandra reviewed some key messages surrounding CVD and type 2 diabetes including the fact that CVD is more prevalent in patients living with type 2 diabetes and the risk is increased in these patients due to a number of pathophysiologic changes.
As highlighted by Dr. Aronson, only about 50% of patients in Canada are achieving a target A1c of 7.0% or less.”
THECURRENTLANDSCAPE OFCV RISK:
BENEFIT WITHANTIHYPERGLYCEMIC THERAPIES
Which currently available classes of glucose-low-ering medications have been shown to definitively reduce the risk for CVD in patients with T2DM?
- Alpha-glucosidase inhibitor (Acarbose)
- Biguanides (Metformin)
- Dipeptidyl peptidase-4 (DPP-4) inhibitors
- Glucagon-like peptide 1 (GLP-1) receptor agonists
- Sulfonylureas (SUs)
- Thiazolidinedione (TZD; piolgitazone)
- None of the above
“To date, traditional T2DM agents have not been shown conclusively to reduce macrovascular events…”
The achievement of optimal glycemic control has been shown to prevent microvascular events however, there has been no evidence proving that glycemic con-trol definitively re-duces macrovascu-lar events as well. Dr. Robert Schloss-er summarized the current studies to date and pointed out that there is conflicting evi-dence as to whether glycemic control reduces the risk of CVD. Several randomized long-term stud-ies could not individually demonstrate evidence of cardiovascular benefit with traditional oral hypoglycemic agents aimed at intensively lower-ing A1C (UKPDSx, ACCORDxi, ADVANCExii, VADTxiii).
Alternatively, there is evidence of benefit when a meta-analysis of the individual studies was completed, as well as through the long-term fol-low up of the UKPDS studyxiv. To date, traditional T2DM agents have not been shown conclusively to reduce macrovascular events but the need is definitely there for agents which provide cardio-vascular benefit since CVD is more prevalent in this patient population.
Preliminary evidence suggests that DPP-4 in-hibitors and GLP-1 agonists may have direct CV benefits beyond glycemic control. Dr. Robert Schlosser pointed out that a growing number of studies are suggesting that incretin therapies may have pleiotropic effects on the vasculature and, therefore, may have the potential to influ-ence CV outcomes. These effects are shown on the kidney, heart, and vascular system. Dr. David Twum-Barima reviewed the suggested possible beneficial CV effects of incretin therapies includ-ing the reduction in blood glucose, reduction in atherosclerosis, reduction in inflammation, and the suggested improvement in endothelial function. The improvement in endothelial function could be related to the endothelial dependent vasodilatation & improved endothelial viability which reduces atherogenesis and in turn, could lead to a reduction in CV events. It has also been postulated that increased GLP-1 levels improve lipid levels and assist with reducing blood pres-sure which could both lead to reductions in CV eventsxv.
CV RISK REDUCTION WITH ANTIHYPER-GLYCEMIC TREATMENTS: HOPE FOR THE
Recent meta-analyses of trials have shown that DPP-4 inhibitors have a 31% significant risk re-duction of CV events in patients living with type 2 diabetes when compared with other antihy-perglycemic agents. When DPP-4 inhibitors were compared with placebo, there was a statistically significant relative reduction of 29% (see Figure 3)xvi. These results cannot be considered defini-tive and therefore, many prospective studies are underway which are investigating incretin thera-py on CV outcomes in type 2 diabetic patients.
Drs. Aronson, Chandra, Twum-Barima and Schlosser each, in turn, reviewed the ongoing CV outcome trials currently taking place. There are eight outcome trials looking at various incretin therapies and their impact on CV events using different primary endpoints and populations. For example, Saxagliptin (Onglyza) is currently being investigated in a large randomized, con-trolled trial —- SAVOR-TIMI 53. This study is expected to enroll about 16,500 patients living with type 2 diabetes and will likely be the first of the incretin outcome studies to be completed. Dr. Aronson reviewed the primary endpoint of the study which includes CV death, non-fatal MI, or non-fatal ischemic stroke.
These outcome trials may prove that incretin therapies have additional benefits beyond glu-cose control. Type 2 diabetes is a very serious, progressive condition and hopefully these newer agents could prove to be a new means for reduc-ing CV risk in this high risk patient population.
i Perk J, De Backer G, Gohlke H, et al. Eur Heart J 2012; 33(13):1635-701.
ii Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212.
iii Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1): S1-S201.
iv CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.
v Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006; 113(6):791-8.
vi CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.
vii CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.
viii Defronzo RA. Banting Lecture. Diabetes 2009; 58(4):773-95.
ix Defronzo RA. Banting Lecture. Diabetes 2009; 58(4):773-95.
x UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-53.
xi The ACCORD Study Group. N Engl J Med 2011; 364:818-28.
xii The ADVANCE Collaborative Group. N Engl J Med. 2008; 358:2560-72.
xiii Duckworth W, Abraira C, Moritz T, et al; N Engl J Med 2009; 360:129-39.
xiv Holman RR, Paul SK, Bethel MA, et al. N Engl J Med 2008; 359:1577-89.
xv Mannucci E, Dicembrini I. Curr Med Res Opin 2012; 28(5): 715-21.
xvi Lamanna C, et al. Presented at EASD 2011; Abstract 244
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