Cardiovascular Risk in Type 2 Diabetes – Reflecting on the ADVANCE Study

The world is facing an unprecedented increase in type 2 diabetes. Most disability and premature mortality experienced by patients with diabetes is related to vascular disease and, in particular, macrovascular disease (such as coronary heart disease and stroke) and microvascular disease (such as retinopathy, nephropathy and neuropathy). Indeed, around 1.9 million cardiovascular deaths worldwide are attributable to high blood glucose levels and diabetes, as well as to their associated dangerous companions of high blood pressure and abnormal lipid levels. The global economic costs of diabetes, including foregone economic growth and increasing healthcare expenditure, are substantial and are anticipated to grow. Therefore, strategies to reduce disease burden have continued to focus on reducing cardiovascular risk. Recently, a number of large-scale clinical trials have evaluated approaches for managing cardiovascular risk in patients with type 2 diabetes. Among them the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial has reported the effects of blood pressure lowering and intensive glucose control on major vascular events in patients with established type 2 diabetes. In this article we summarise the findings of the ADVANCE trial and discuss its relevance to the management of cardiovascular risk in patients with type 2 diabetes worldwide.

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Reducing cardiovascular risk in diabetes: insights from the ADVANCE study

Italian Journal of Medicine ◽

10.4081/itjm.2008.2.30 ◽

2013 ◽

pp. 30-34

Author(s):

Giuliano Pinna

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Vascular Disease ◽

Fixed Combination ◽

Microvascular Complications ◽

Current Therapy ◽

Vascular Events ◽

Advance Study ◽

Routine Administration

BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes. That’s why guidelines recommend intensive lowering of blood pressure in those patients. The ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) study has been recently introduced. It assessed the effects of such an approach on vascular disease using a fixed combination of the ACE-inhibitor perindopril, and the diuretic indapamide, in a population of patients with type 2 diabetes and a broad range of blood pressure values. METHODS After a 6-week active run-in period, 11,140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. Primary end-points: major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease. The macrovascular and microvascular composites were analysed jointly and separately. RESULTS To the end of the follow-up a meaningful reduction of the deaths has been obtained, both for cardiovascular causes and for macro and microvascular events, examined in together (in the total) (separately significance has not turned out). The best result has been obtained in the reduction of the renal events. DISCUSSION AND CONCLUSIONS The authors conclude that routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes and with a good controlled blood pressure, was well tolerated and reduced the risks of major vascular events, including death, but it remains the doubt if these results have been obtained because of the better pressure control or are specific of this preconstructed association.

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The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial

10.2337/figshare.14485251.v1 ◽

2021 ◽

Author(s):

Tu N Nguyen ◽

Katie Harris ◽

Mark Woodward ◽

John Chalmers ◽

Mark Cooper ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Glucose Control ◽

Severe Hypoglycaemia ◽

Intensive Glucose Control ◽

Vascular Events ◽

Significant Difference ◽

Secondary Outcomes ◽

The Impact

Objective. To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), amongst participants with type-2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Research Design and Methods. Cox proportional-hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI>0.21) status. The primary outcomes were macrovascular events and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycaemia, and discontinuation of BP treatment due to hypotension/dizziness. Results. There were 11140 participants (mean age 65.8, 42.5% female, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: HRs for combined major macro- and micro-vascular events 1.03, 95%CI 0.90-1.19 in the frail vs 0.84, 95%CI 0.74-0.94 non-frail (p=0.02). A similar trend was observed with BP intervention. <a>Severe hypoglycaemia rates (per 1000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in non-frail</a> (p<0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. Conclusions. It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose lowering and BP lowering treatments.

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The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial

10.2337/figshare.14485251 ◽

2021 ◽

Author(s):

Tu N Nguyen ◽

Katie Harris ◽

Mark Woodward ◽

John Chalmers ◽

Mark Cooper ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Glucose Control ◽

Severe Hypoglycaemia ◽

Intensive Glucose Control ◽

Vascular Events ◽

Significant Difference ◽

Secondary Outcomes ◽

The Impact

Objective. To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), amongst participants with type-2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Research Design and Methods. Cox proportional-hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI>0.21) status. The primary outcomes were macrovascular events and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycaemia, and discontinuation of BP treatment due to hypotension/dizziness. Results. There were 11140 participants (mean age 65.8, 42.5% female, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: HRs for combined major macro- and micro-vascular events 1.03, 95%CI 0.90-1.19 in the frail vs 0.84, 95%CI 0.74-0.94 non-frail (p=0.02). A similar trend was observed with BP intervention. <a>Severe hypoglycaemia rates (per 1000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in non-frail</a> (p<0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. Conclusions. It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose lowering and BP lowering treatments.

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Abstract #414 Ambulatory Blood Pressure Monitoring and Correlation with Cardiovascular Risk Markers in Type 2 Diabetes In Association with The Prevalence of Non-Dippers

Endocrine Practice ◽

10.1016/s1530-891x(20)47175-7 ◽

2018 ◽

Vol 24 ◽

pp. 103

Author(s):

Rohit Kapoor ◽

Shivam Kapoor ◽

Rishabh Kapoor

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Risk ◽

Ambulatory Blood Pressure Monitoring ◽

Ambulatory Blood Pressure ◽

Blood Pressure Monitoring ◽

Risk Markers ◽

Pressure Monitoring

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Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus compared to all middle-aged and elderly hypertensive study patients with high cardiovascular risk

Blood Pressure ◽

10.1080/08037051.2020.1856642 ◽

2021 ◽

pp. 1-8

Author(s):

Eirik Olsen ◽

Björn Holzhauer ◽

Stevo Julius ◽

Sverre E. Kjeldsen ◽

Anne Cecilie K. Larstorp ◽

...

Keyword(s):

Diabetes Mellitus ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cardiovascular Risk ◽

Middle Aged ◽

High Cardiovascular Risk ◽

Blood Pressure Targets ◽

Elderly Hypertensive

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HT3 COST-EFFECTIVENESS OF BLOOD PRESSURE LOWERING WITH A FIXED COMBINATION OF PERINDOPRIL AND INDAPAMIDE IN TYPE 2 DIABETES MELLITUS: A TRIAL-BASED ANALYSIS USING THE ADVANCE STUDY

Value in Health ◽

10.1016/s1098-3015(11)73064-9 ◽

2010 ◽

Vol 13 (7) ◽

pp. A504

Author(s):

PM Clarke ◽

P Glasziou ◽

J Alexander ◽

J Chalmers ◽

A Patel

Keyword(s):

Diabetes Mellitus ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cost Effectiveness ◽

Fixed Combination ◽

Blood Pressure Lowering ◽

Advance Study ◽

Pressure Lowering

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Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study

European Heart Journal ◽

10.1093/eurheartj/ehp055 ◽

2009 ◽

Vol 30 (9) ◽

pp. 1128-1135 ◽

Cited By ~ 116

Author(s):

X. Du ◽

T. Ninomiya ◽

B. de Galan ◽

E. Abadir ◽

J. Chalmers ◽

...

Keyword(s):

Atrial Fibrillation ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Events ◽

Blood Pressure Lowering ◽

Advance Study ◽

Routine Blood ◽

Pressure Lowering

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Intensive risk factor management and cardiovascular autonomic neuropathy in type 2 diabetes: the ACCORD Trial

10.2337/figshare.13020338.v1 ◽

2020 ◽

Author(s):

Yaling Tang ◽

Hetal Shah ◽

Carlos Roberto Bueno Junior ◽

Xiuqin Sun ◽

Joanna Mitri ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Risk ◽

Autonomic Neuropathy ◽

Pressure Control ◽

Cardiovascular Autonomic Neuropathy ◽

Risk Factor Management ◽

Traditional Risk Factors ◽

Intensive Blood Pressure

Objectives: The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in persons with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Research Design and Methods: CAN was defined as heart rate variability indices below the 5th percentile of the normal distribution. Of 10,250 ACCORD participants, 71% (n=7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models. Results: As compared to standard intervention, intensive glucose treatment reduced CAN risk by 16% (OR=0.84, 95%CI 0.75–0.94, p=0.003) – an effect driven by individuals without cardiovascular disease (CVD) at baseline (OR= 0.73, 95%CI 0.63–0.85, p<0.0001) rather than those with CVD (OR=1.10, 95%CI 0.91–1.34, p=0.34) (p for interaction=0.001). Intensive blood pressure intervention decreased CAN risk by 25% (OR=0.75, 95% CI 0.63–0.89, p=0.001), especially in patients ≥65 years old (OR=0.66, 95% CI 0.49–0.88, p=0.005) (p for interaction =0.05). Fenofibrate did not have a significant effect on CAN (OR=0.91, 95%CI 0.78–1.07, p=0.26). Conclusions: These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive blood pressure control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention.

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