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Job Code: PC-GB-103191                         Date of preparation: March 2021



This promotional module has been initiated, funded and reviewed by Boehringer Ingelheim. The content of this industry-supported learning activity has been generated by Practice Nurse.

INTRODUCTION

The goals of treatment for type 2 diabetes are to prevent or delay complications and maintain quality of life.1 According to international guidelines, this requires control not only of blood glucose levels, but also cardiovascular risk factor management.1

This module looks at the increased risk of cardiovascular disease (CVD) associated with type 2 diabetes, and the role of pharmacotherapy in managing the condition in line with current guidelines.

LEARNING OBJECTIVES

On completion of this module, you will have a better understanding of:

  • The association between type 2 diabetes and cardiovascular complications
  • Evidence from the cardiovascular outcomes trials of agents used in the management of type 2 diabetes
  • Latest guidance for the pharmacological management of type 2 diabetes
  • The importance of a patient-centred approach to management

This module is one of a series of five. Others in the series are:

This resource is provided at an intermediate level. Read the article and answer the self-assessment questions, and reflect on what you have learned.

Complete the resource to obtain a certificate to include in your revalidation portfolio. You should record the time spent on this resource in your CPD log.

Cardiovascular considerations in patients with type 2 diabetes

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in people with type 2 diabetes.1 Diabetes is a substantial independent risk factor for ASCVD, and this risk may be compounded by the presence of additional risk factors including hypertension, dyslipidaemia, obesity, physical inactivity, chronic kidney disease (CKD), and smoking.1

ASCVD risk management is an essential part of diabetes management.1

TYPE 2 DIABETES AND CARDIOVASCULAR COMPLICATIONS

Every week in the UK, diabetes leads to more than 680 strokes, 530 heart attacks and almost 2,000 cases of heart failure.2 Compared with people without diabetes, people with type 2 diabetes are nearly 2.5 times more likely to have a myocardial infarction (MI), more than 2.5 times more likely to develop heart failure, and twice as likely to have a stroke.2

Myocardial infarction (MI)

Diabetes is a major risk factor for the development of coronary artery disease. As well as the higher incidence of MI in patients with diabetes than without, after an MI patients with diabetes have higher rates of morbidity, mortality and further MI than people without diabetes.3

Heart failure (HF)

In the UK, approximately 920,000 people have a diagnosis of heart failure (HF).4 Prevalence of HF, particularly HF with preserved ejection fraction, is higher in patients with diabetes (16-31%) than in the general population (4-6%).3 While some of the difference may be explained by conventional cardiovascular risk factors, diabetes may independently alter cardiac structure and function.3

Stroke

Diabetes is a strong independent predictor of stroke and cerebrovascular disease.5 Patients with type 2 diabetes have a greatly increased risk – of between 150% and 400% – of stroke compared with the general population.5 They are also at increased risk of a further stroke, stroke-related dementia, and stroke-related mortality.5

A meta-analysis that included almost 700,000 people’s individual records of diabetes, fasting blood glucose concentration and other risk factors, without initial vascular disease, revealed that patients with diabetes (compared with those without diabetes) were more than twice as likely to have an ischaemic stroke, and more than one-and-a-half times more likely to have a haemorrhagic stroke.6 The risks did not change noticeably after adjustment for lipid, inflammatory or renal markers, and at population level, diabetes was estimated to account for 11% of vascular deaths.6

EVIDENCE FROM CARDIOVASCULAR OUTCOME TRIALS

Since 2013, following cardiovascular safety concerns about rosiglitazone, both the European Medicines Agency (EMA) and the US Food and Drugs Administration (FDA) have required cardiovascular outcomes trials (CVOTs) for all new glucose-lowering drugs (Figure 1).

Data from the CVOTs have shown evidence of cardiovascular safety for DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors, and for specific agents, of cardiovascular and renal benefits, defined as reductions in major adverse cardiovascular events (MACE), and major adverse renal events (MARE), respectively.

This list is not exhaustive but among the key CVOTs of diabetic agents in adult patients with type 2 diabetes are:

  • PIONEER 6 – demonstrated cardiovascular safety through non-inferiority of 3-point MACE (composite of nonfatal MI, nonfatal stroke and cardiovascular death) of oral semaglutide vs placebo7
  • EMPA-REG OUTCOME – reported a significant reduction in 3-point MACE with empagliflozin vs placebo8
  • CANVAS – significant reduction in 3-point MACE with canagliflozin vs placebo9
  • DECLARE-TIMI – demonstrated non-inferiority of dapagliflozin to placebo for MACE. Reduction in MACE was not demonstrated, but was demonstrated for the composite of cardiovascular death and hospitalisation for heart failure, drive by the reduction in hospitalisation for heart failure.10
  • VERTIS-CV – confirmed the cardiovascular safety profile of ertugliflozin and non-inferiority for MACE compared with placebo11
  • LEADER – found significant reductions in  3-point MACE, and also all cause mortality for the GLP-1 receptor agonist liraglutide vs placebo12
  • EXCEL – found exenatide (once weekly) to be non inferior to placebo for cardiovascular safety. Exanatide did not reach the threshold for superiority in MACE vs placebo13
  • REWIND – showed improvements in 3-point MACE with dulaglutide vs placebo. The effects were consistent with patients with pre-existing history of CVD or without CVD14
  • SUSTAIN 6 – demonstrated significant reduction in primary composit of 3-point MACE with semaglutide vs placebo15

CVOTs have also confirmed the cardiovascular safety profile of the DPP-4 inhibitors:

  • SAVOR-TIMI 53 – saxagliptin vs placebo16
  • EXAMINE – alogliptin vs placebo17
  • TECOS – sitagliptin vs placebo18
  • CARMELINA – linagliptin vs placebo19
  • CAROLINA – linagliptin vs glimepiride20

The long term safety profile of linagliptin was investigated in a CVOT programme that included >13,000 adult patients with type 2 diabetes.19,20 CARMELINA (n=6,979) assessed the cardiovascular (3P-MACE*) and renal safety profile of linagliptin 5mg once daily (n= 3494) vs placebo (n=3485) added to usual care, and was the first CVOT to specifically assess the renal safety profile of a DPP-4 inhibitor (as a secondary endpoint).19

*3P-MACE: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke

CAROLINA (n=6,033) is the only CVOT for a DPP-4 inhibitor (linagliptin 5mg once daily, n=3023) to include an active comparator, glimepiride (1-4mg once daily, n=3010).20 Together they demonstrated the safety profile of linagliptin 5mg once daily in a broad range of adult patients with type 2 diabetes, including those on metformin, insulin and who are treatment-naïve, and with kidney disease, cardiovascular disease or both.19,20

GUIDELINE RECOMMENDATIONS

National (NICE, SIGN) and international (European Society for Cardiology-European Association for the Study of Diabetes [ESC-EASD] and American Diabetes Association-EASD [ADA-EASD]) guidelines have been updated – or are in the process of being updated – to reflect these data, and the presence of cardiovascular disease or indicators of high risk are now a primary consideration when choosing treatment after metformin.21-24

International guidelines now recommend either SGLT2 inhibitors or GLP-1 receptor agonists after metformin in people with type 2 diabetes and a history of ASCVD. The ESC-EASD and ADA-EASD guidelines now recommend either an SGLT2 inhibitor or GLP-1 receptor agonist in people with type 2 diabetes at high or very high risk of cardiovascular disease, irrespective of whether they are treatment naïve or already on metformin.22-24

In patients with cardiovascular and renal comorbidities, who are on metformin, SGLT2 inhibitors and GLP-1 receptor agonists should be considered ‘independently of baseline HbA1c or individualised HbA1c target’.22

However, there are currently restrictions on the use of GLP-1 receptor agonists in patients who do not meet current NICE criteria (NICE currently stipulates a body mass index [BMI] threshold of 35 kg/m2 prior to receiving GLP-1 RA therapy), and the majority of SGLT2 inhibitors cannot be prescribed in patients with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73m2.25,26

In the management of type 2 diabetes, the choice of drug after metformin is becoming increasingly complex: the prescriber needs to consider cardiovascular risk, renal function and other factors such as hypoglycaemia risk, weight, patient co-morbidities including frailty, and patient adherence to treatment.1

It is worth remembering that DPP-4 inhibitors are recommended for a wide range of patients with type 2 diabetes at various stages of disease, and have been shown to lower blood glucose without increasing the risk of hypoglycaemia or causing weight gain.

In the self-assessment that follows, hypothetical case scenarios based on fictitious patients are presented. Please refer to the relevant Summary of Product Characteristics before prescribing any of the medications mentioned. 

Please note that neither Practice Nurse nor Boehringer Ingelheim have any control over the content of the external websites listed in the references below. 

References

1. Davies MJ, D’Alessio D, Fradkin J. Management of hyperglycemia in T2DM, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-2701

2. Diabetes UK. Us, diabetes and a lot of facts and stats. https://www.diabetes.org.uk/professionals/position-statements-reports/statistics [Accessed March 2021]

3. Leon BN, Maddox TM. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015;6(13):1246-1258

4. NICE NG106. Chronic heart failure in adults: diagnosis and management; 2018. Available at: https://www.nice.org.uk/guidance/ng106 [Accessed March 2021]

5. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008;26(2):77-82

6. Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375(9733):2215-2222

7. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcome in patients with type 2 diabetes. N Engl J Med 2019;381:841-51

8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N England J Med 2015;373:2117-28

9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N England J Med 2017;377:644-57

10. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57

11. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425-35

12. Marso SP, Daniels GH, Brown-Frandsen, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322

13. Holman R, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39

14. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30

15. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44

16. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317

17. White B, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-1335

18. Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-242

19. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high vardiovascular and renal risk. The CARMELINA randomized clinical trial. JAMA 2019;321:69-79

20. Rosenstock J, Kahn SE, Zinman B, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes. JAMA 2019;322(12):1155-66

21. SIGN 154. Pharmacological management of glycaemic control in people with type 2 diabetes; 2017. https://www.sign.ac.uk/media/1090/sign154.pdf [Accessed March 2021]

22. Buse JB, Wexler DJ, Tsapas A. 2019 Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2020;43(2):487-493

23. Consentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255-323

24. Neuen BL, Jardine MJ, Perkovic V. Sodium-glucose cotransporter 2 inhibition: which patient with chronic kidney disease should be treated in the future? Nephrol Dial Transplant 2020;35:i48-i55

25. NICE. 2019 surveillance of diabetes (NICE guidelines NG17,NG18, NG19 and NG28). https://www.nice.org.uk/guidance/ng28/resources/2019-surveillance-of-diabetes-nice-guidelines-ng17-ng18-ng19-and-ng28-6837997933/chapter/Surveillance-decision?tab=evidence [Accessed March 2021]

26. Lewis R. Diabetic kidney disease: diagnosis and management in primary care. Practice Nurse 2020;50(7):23-27

27. NICE CG182. Chronic kidney disease in adults: assessment and management; 2014 (updated 2015). https://www.nice.org.uk/guidance/cg182 [Accessed March 2021]


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