BP regulation appears central to CV benefit seen with improved glycemic control

Blood Sugar Regulation for Cardiovascular Health Promotion and Disease Prevention

Literature - Schwarz PEH, Timpel P, Harst L, et al. - J Am Coll Cardiol 2018;72:1829–44

Introduction and methods

Hyperglycemia is a modifiable risk factor for the development of CV disease (CVD), and pre-diabetes is a major risk factor for progression to type 2 diabetes (T2DM), which is associated with elevated CV risk. The effective reduction of hyperglycemia decreases CVD risk, mainly through the reduction of non-fatal events [1-3].

It would be useful to know which interventions provide the most benefit. While conventional glucose-lowering agents have not shown significant macrovascular benefits, newer agents did show reductions in hard CVD endpoints [4-6]. It is important to understand the mechanisms tackled by the individual approaches to regulate blood glucose, including lifestyle interventions, in order to guide individual- or population-based prevention.

The primary objective of this umbrella review is to investigate which of the following interventions are most helpful in lowering blood glucose-related CV risk, which may inform therapeutic decisions by better consideration of blood glucose regulation pathways involved:

  • Pharmacological interventions
  • Evidence-based individual-level interventions
  • Evidence-based population-level interventions

Moreover, studies related to competencies and standardized health promotion care pathways were identified and analyzed. For this purpose, 44 systematic reviews of randomized clinical trials or meta-analyses reporting glucose-related outcomes, published in 2016 and 2017, of good to very good quality, were included for data extraction and analysis. For quality assessment of the identified reviews, a modified version of Oxman and Guyatt’s OQAQ was used [7], and studies with an OQAQ score <14 were rejected.

Main results

Pharmacological interventions:

  • Out of 769 identified references, 685 were excluded, and the remaining eligible studies had a median OQAQ score of 17 (IQR: 15-18).
  • Intensive glucose-lowering, mainly with insulin or sulfonylureas, yielded improved microvascular, but not macrovascular outcomes in landmark trials (UKPDS, ADVANCE, VADT).
  • Dipeptidylpeptidase-4 (DPP-4) inhibition, which increase the bioavailability of glucagon-like peptide-1 (GLP-1), was not associated with improved CV outcomes.
  • GLP-1 receptor agonists (GLP-1 RAs) reduce hyperglycemia through the same pathway, but did show improved CV outcomes. GLP-1RAs have various effects beyond glucose-lowering, including lowering body weight, systolic blood pressure (BP), triglycerides and LDL-c and they may positively affect inflammatory markers and subclinical atherosclerosis. Different effects are seen with different GLP-1RAs.
  • Sodium-glucose cotransporter 2 (SGLT2) inhibition, in addition to reducing blood glucose, also lowers systolic and diastolic BP. SGLT2 inhibitors are associated with a reduction in all-cause and CV mortality and major CV events, which may be the consequence of the metabolic effects of SGLT2 inhibitors, including weight loss, BP reduction, natriuresis, and improved renal function.
  • Multifactorial interventions combining intensive glucose-lowering with BP- and lipid-lowering therapies have been shown to reduce CV mortality and improve CV outcomes. Intensive BP lowering in already well-controlled patients may induce harm.

Evidence-based individual-level interventions for supporting behavior change to regulate glycemia

  • Out of a total of 861 papers, 24 met the eligibility criteria, and had a median QQAQ score of 16 (IQR: 14-18).
  • Individual lifestyle interventions targeting physical activity and/or diet were effective in reducing blood glucose for up to 54 months, reducing diabetes incidence in people at risk of developing T2DM for up to 72 months and in reducing body weight for up to 52 months of follow-up. Considerable variation in outcomes was observed between studies.
  • A reduction in effects on both blood glucose and weight was seen over time, in 6 systematic reviews that monitored patients for up to 60 months of follow-up.

Evidence-based population-level interventions for supporting behavior change to regulate glycemia

  • Out of a total of 85 papers identified, 82 were excluded, leaving 3 articles with a OQAQ score of ≥17.
  • The included studies did not focus on unique intervention strategies, and did not assess hard health outcomes. There are limited data on the effectiveness of population-based interventions for improving glucose outcomes, and no evidence was found solely for T2DM.

Competencies and standardized health promotion care pathways

  • 12 systematic reviews and meta-analyses were identified that related to health care worker involvement and task shifting toward non-doctor health practitioners, and 3 other studies focused on integrated care. The methodological quality of the included reviews was generally good (median OQAQ score: 16; IQR: 14-18).
  • The chronic care model used in primary care was evaluated as highly effective in reducing mortality and HbA1c, but standardized European diabetes care approaches showed only small improvements in clinical outcomes.
  • Integrated care in general was associated with improvement in patient outcomes, health care utilization and costs.
  • Pharmacist interventions were especially effective when pharmacists performed a clinical decision-making process as part of a multidisciplinary health are team.

Recommendations based on the findings of this umbrella review are summarized in two tables in the article.


This review of recent high-quality systematic reviews and meta-analyses demonstrates that intensive glucose lowering can reduce both microvascular and macrovascular morbidities and CV mortality.. The results with patients treated with insulin and sulfonylureas suggest that glucose lowering in itself does not reduce CV events. Pharmacological interventions improving glycemic control and multifactorial approaches can reduce CV outcomes, and BP regulation seems to be a key pathway mediating this effect. Nonpharmaceutical interventions can also efficiently reduce blood glucose, as well as BP and dyslipidemia. Multidisciplinary teams are effective in delivering multicomponent interventions in community-based settings.


1. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383–93.

2. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–72.

3. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288–98.

4. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–59.

5. Chou CY, Chang YT, Yang JL, et al. Effect of long-term incretin-based therapies on ischemic heart diseases in patients with type 2 diabetes mellitus: a network meta-analysis. Sci Rep 2017;7: 15795.

6. Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2016;4:411–9.

7. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991;44:1271–8.

Find this article online at J Am Coll Cardiol

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free