Information intended for UK healthcare professionals only. 

This management algorithm was developed by a multidisciplinary expert panel: Javaid et al with the support of an educational grant from AstraZeneca. See end of algorithm for full disclaimer.

In this algorithm

 

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Algorithm on the management of patients with type 2 diabetes, cardiovascular disease, and heart failure

 Background

  • In recent years, international consensus reports and guidelines have taken into consideration the results of cardiovascular (CV) outcome trials demonstrating CV benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs)3–18
  • During the development of this algorithm, NICE also updated the treatment algorithm for managing patients in the guideline on management of type 2 diabetes mellitus in adults (NICE guideline 28) to take these CV outcome trials into account19
  • An expert group has developed a consensus treatment algorithm to help UK primary healthcare professionals manage patients with type 2 diabetes, cardiovascular disease (CVD), and heart failure (HF), incorporating the evidence for CV benefit with SGLT2 inhibitors and GLP-1 RAs
  • The algorithm includes two separate pathways for: 
    • patients with type 2 diabetes and atherosclerotic CVD or HF with preserved ejection fraction (HFpEF) but not HF with reduced ejection fraction (HFrEF)
    • patients with type 2 diabetes and symptomatic HFrEF, including patients with atherosclerotic CVD
  • Atherosclerotic CVD includes patients who have experienced a previous acute cardiovascular event for example, acute coronary syndrome, stroke, or transient ischaemic attack or patients with objective evidence of atherosclerotic CVD (for example, stable angina, previous percutaneous coronary intervention, or peripheral arterial disease)
  • HF should be confirmed by echocardiography or magnetic resonance imaging 
    • HFpEF is defined as left ventricular ejection fraction (LVEF) ≥50%
    • HFrEF is defined as LVEF <40%
    • patients with mid-range LVEF 40–49% should be treated as those with HFrEF.

Patients with type 2 diabetes and atherosclerotic CVD in the absence of HFrEF

  • The priority for treatment of patients with type 2 diabetes, atherosclerotic CVD, and HFpEF but not HFrEF is to treat the diabetes and manage cardiovascular risk: 
    • standard of care includes non-pharmacological and pharmacological interventions
  • Counsel patients on non-pharmacological lifestyle interventions (Box 1)

Box 1: Lifestyle changes

  • Smoking cessation
  • Exercise (exercise-based rehabilitation (for patients with HFrEF))
  • Salt reduction
  • Alcohol reduction
  • Weight reduction if overweight or central obesity
  • Healthy diet.

HFrEF=heart failure with reduced ejection fraction.

Pharmacological interventions

  • Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies
  • Metformin, as long as there are no contraindications
    • consider appropriate glycated haemoglobin (HbA1c) for long-term reduction of microvascular risk 
    • take into account the risk of hypoglycaemia
    • counsel patients on sick-day rules (Box 2)

Box 2: Sick-day rules

  • Patients should take medications as normal unless advised otherwise by an HCP20
  • Consider temporarily stopping the following medications during acute illnesses that can cause dehydration or acute decline in renal function:21–23
    • sulfonylureas—increased risk of hypoglycaemia
    • ACE inhibitors—increased risk of developing AKI due to reduced renal efferent vasoconstriction
    • diuretics—increased risk of developing AKI 
    • metformin—increased risk of developing lactic acidosis
    • ARBs—increased risk of developing AKI 
    • NSAIDs—increased risk of developing AKI due to reduced renal afferent vasodilation 
    • SGLT2 inhibitors—increased risk of developing euglycaemic DKA 
  • Once the person is feeling better and able to eat and drink for 24–48 hours, these medications should be restarted, providing there is no other clinical reason preventing this.23  

ACE=angiotensin-converting enzyme; AKI=acute kidney injury; ARB=angiotensin receptor blocker; DKA=diabetic ketoacidosis; HCP=healthcare professional; NSAID=non-steroidal anti-inflammatory drug; SGLT2=sodium-glucose co-transporter-2.

  • Maximal tolerated dose of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
    • aim for blood pressure (BP) <130/80 mmHg (refer to NICE guideline 1361)
  • Lipid-lowering drugs 
    • aim for low-density lipoprotein cholesterol (LDL-C) ≤1.4 mmol/l
    • individualise targets for patient factors, including frailty and life expectancy 
    • refer to NICE clinical guideline 181
  • Consider antiplatelet therapy depending on bleeding risk and severity of atherosclerotic CVD (for example, stenosis >50%), unless the patient is on this pathway because they have HFpEF without atherosclerotic CVD
  • SGLT2 inhibitor with proven CV benefit
    • see Box 3 for recommendations for choice of SGLT2 inhibitor
    • if an SGLT2 inhibitor is not tolerated or contraindicated consider a GLP-1 RA (see Box 4 for recommendations for choice of GLP-1 RA)
    • consider combining SGLT2 inhibitor or GLP-1 RA if not at target HbA1c or the patient has other comorbidities
      • be aware that there is very little evidence for incremental CV benefit and there are cost implications
    • Box 5 provides considerations when using an SGLT2 inhibitor or GLP-1 RA in patients on existing type 2 diabetes therapy.
  • Only three SGLT2 inihibitors within the class have positive CV data (empagliflozin, canagliflozin, and dapagliflozin), there is greater uncertainty around the CV benefits associated with ertugliflozin19

Empagliflozin

  • 10 or 25 mg24
    • most robust data in this cohort, including CV mortality benefit (EMPA-REG OUTCOME study)12
    • for CV risk reduction as add on to standard of care, a dose of 10 mg once daily should be used in patients with eGFR <60 ml/min/1.73 m2; in patients with eGFR <30 ml/min/1.73 m2 empagliflozin is not recommended.24

Canagliflozin

  • CV data can be found in the CANVAS and CREDENCE studies13,14
  • 100 mg canagliflozin if eGFR >30 ml/min/1.73 m2; if eGFR <30 ml/min/1.73 m2 and ACR >300 mg/g continue 100 mg canagliflozin for patients already taking it, but should not be initiated.25

Dapagliflozin

  • CV data can be found in the DECLARE-TIMI 58 study15
  • 10 mg once daily; no dose adjustment is required based on renal function; in patients with eGFR <15 ml/min/1.73 m2 dapagliflozin is not recommended.26

ACR=albumin-to-creatinine ratio; CV=cardiovascular; CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; SGLT2=sodium-glucose co-transporter-2. 

 

Liraglutide 

  • Uptitrate to 1.8 mg injectable daily27
    • this higher dose has the majority of evidence for cardiovascular benefit (predominantly secondary prevention in LEADER)16
    • 1.8 mg dose is 50% more expensive than 1.2 mg dose.27

Semaglutide 

  • 0.5 mg or 1 mg injectable once weekly28
    • proven benefit in a predominantly secondary prevention population (SUSTAIN-6).17

Dulaglutide 

  • 1.5 mg injectable once weekly29
    • proven benefit in a mixed primary and secondary prevention population (REWIND).18

CVD=cardiovascular disease; GLP-1=glucagon-like peptide 1; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction.

 

Box 5: Considerations when using SGLT2 inhibitors or GLP-1 RAs in patients on pre-existing diabetes therapy

  • If on SU and at glycaemic target: 
    • eGFR <45 ml/min/1.73 m2, continue SU if prescribing an SGLT2 inhibitor; GLP-1 RAs can still lower blood glucose in patients with renal impairment—if adding a GLP-1 RA in patients with CKD stage 3B or higher monitor blood glucose and reduce dose of SU
    • eGFR >45 ml/min/1.73 m2, monitor blood glucose and halve dose of SU, and then stop if possible (due to increased risk of hypoglycaemia) when adding an SGLT2 inhibitor or GLP-1 RA
  • If on SU and evidence of hypoglycaemia, stop SU
  • If on a DPP-4 inhibitor, stop if at glycaemic target after adding in SGLT2 inhibitor or adding GLP-1 RA
  • If on pioglitazone, continue unless evidence of HF or other contraindications; consider lowest tolerated dose30
  • If on insulin, discuss with diabetes specialist team due to significant risk of hypoglycaemia or DKA.

CKD=chronic kidney disease; DKA=diabetic ketoacidosis; eGFR=estimated glomerular filtration rate; GLP-1 RA=glucagon-like peptide 1 receptor agonist; HF=heart failure; SGLT2=sodium-glucose co-transporter-2; SU=sulfonylurea.

 

Patients with type 2 diabetes and symptomatic HF, including atherosclerotic CVD 

  • The priority for treatment of patients with type 2 diabetes and HFrEF is to manage the HF:
    • standard of care includes non-pharmacological and pharmacological interventions
  • Counsel patients on non-pharmacological lifestyle interventions (Box 1).

Pharmacological interventions

  • Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies
  • Maximal tolerated doses of ACE inhibitor, ARB, or sacubitril/valsartan
  • Maximal tolerated doses of licensed β-blocker (bisoprolol, carvedilol, metoprolol, or nebivolol)
  • Mineralocorticoid receptor antagonist (MRA) (for example, spironolactone 25 mg or eplerenone 25–50 mg), if appropriate 
  • Loop diuretic, as required for symptomatic relief
  • Dapagliflozin or empagliflozin 
    • dapagliflozin if New York Heart Association (NYHA) class remains ≥2 irrespective of eGFR (caution if eGFR <25 ml/min/1.73 m2 due to lack of experience in this population, not recommended in patients with eGFR <15 ml/min/1.73 m2)26
    • empagliflozin if NYHA remains 2 or more (in patients with or without type 2 diabetes empagliflozin is not recommended if eGFR <20 ml/min/1.73 m2)
      • dose of loop diuretic may need to be adjusted after adding dapagliflozin or empagliflozin
  • Box 6 provides considerations when using dapagliflozin or empagliflozin in patients on pre-existing diabetes therapy.

Box 6: Considerations when using dapagliflozin or empagliflozin in patients on pre-existing diabetes therapy

  • Most patients with HFrEF will be elderly and frail, so have a low threshold for de-escalation of glycaemic therapy 
  • If on SU and at glycaemic target: 
    • eGFR <45 ml/min/1.73 m2, continue SU
    • eGFR >45 ml/min/1.73 m2, monitor blood glucose, halve dose of SU, and then stop if possible (due to increased risk of hypoglycaemia) when adding dapagliflozin
  • If on SU and evidence of hypoglycaemia, stop SU
  • If on DPP-4 inhibitor, stop DPP-4 inhibitor if at glycaemic target or if specifically on saxagliptin or alogliptin (because of worsening HF signal)31
  • If on pioglitazone, stop pioglitazone30
  • If on insulin, discuss with diabetes specialist team due to significant risk of hypoglycaemia or DKA.

DKA=diabetic ketoacidosis; DPP-4=dipeptidyl peptidase-4; eGFR=estimated glomerular function; HF=heart failure; SU=sulfonylurea.

Consider device therapy

  • Implantable cardioverter defibrillator (ICD) in patients with LVEF ≤35%
  • Cardiac resynchronisation therapy (CRT) in patients with LVEF ≤35% and QRS >130 ms. 

Useful resources

References

  1. NICE. Hypertension in adults: diagnosis and management. NICE Guideline 136. NICE, 2019 (last updated March 2022). Available at: www.nice.org.uk/ng136  
  2. NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. Clinical Guideline 181. NICE, 2014 (last updated September 2016). Available at: www.nice.org.uk/cg181  
  3. Davies M, D’Alessio D, Fradkin J et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61 (12): 2461–2498. 
  4. Buse J, Wexler D, Tsapas A et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020; 63 (2): 221–228. 
  5. Cosentino F, Grant P, 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 (2): 255–323. 
  6. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes–2021. Diabetes Care 2021; 44 (Suppl 1, part 9): S111–S124. 
  7. British Cardiovascular Society. Guide for non-diabetes specialist physicians and primary care teams for cardiovascular risk optimisation in patients with type 2 diabetes and atherosclerotic cardiovascular disease. BCS, 2020. Available at: www.britishcardiovascularsociety.org/resources/bcs-videos-and-webcasts/careme  
  8. Heerspink H, Stefánsson B, Correa-Rotter R et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383 (15): 1436–1446. 
  9. NICE. Dapagliflozin for treating chronic heart failure with reduced ejection fraction. NICE Technology Appraisal Guidance 679. NICE, 2021. Available at: www.nice.org.uk/ta679
  10. NICE. Empagliflozin for treating chronic heart failure with reduced ejection fraction. NICE Technology Appraisal Guidance 773. NICE, 2022. Available at: www.nice.org.uk/ta773
  11. Packer M, Anker S, Butler J et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383 (15): 1413–1424.
  12. Zinman B, Wanner C, Lachin J et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22): 2117–2128.
  13. Neal B, Perkovic V, Mahaffey K et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377 (7): 644–657. 
  14. Perkovic V, Jardine M, Neal B et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380 (24): 2295–2306.
  15. Wiviott S, Raz I, Bonaca M et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380 (4): 347–357.
  16. Marso S, Daniels G, Brown-Franderson K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375 (4): 311–322.
  17. Marso S, Bain S, Consoli A et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375 (19): 1834–1844.
  18. Gerstein H, Colhoun H, Dagenais G et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394 (10193): 121–130.
  19. NICE. Type 2 diabetes in adults: management. NICE Guideline 28. NICE, 2015 (last updated March 2022). Available at: www.nice.org.uk/ng28  
  20. International Diabetes Foundation. How to manage diabetes during an illness: “sick day rules”. Available at: www.idf.org/component/attachments/?task=download&id=2155:IDFE-Sick-day-management  
  21. Canadian Diabetes Association. Sick-day medication list. Can J Diabetes 2018; 42: S316.
  22. Think Kidneys. “Sick day” guidance in patients at risk of acute kidney injury: a position statement from the Think Kidneys Board. Think Kidneys, 2018. Available at: www.thinkkidneys.nhs.uk/aki/wp-content/uploads/sites/2/2018/01/Think-Kidneys-Sick-Day-Guidance-2018.pdf  
  23. Down S. How to advise on sick day rules. Diabetes Prim Care 2020; 22: 47–48. 
  24. Boehringer Ingelheim Limited. Jardiance 10 mg film-coated tablets. Available at: www.medicines.org.uk  
  25. Napp Pharmaceuticals Limited. Invokana 100 mg film-coated tablets. Available at: www.medicines.org.uk
  26. AstraZeneca UK Limited. Forxiga 5 mg film-coated tablets. Available at: www.medicines.org.uk
  27. Novo Nordisk Limited. Victoza 6 mg/ml solution for injection in pre-filled pen. Available at: www.medicines.org.uk
  28. Novo Nordisk Limited. Ozempic 0.5 mg solution for injection in pre-filled pen. Available at: www.medicines.org.uk
  29. Eli Lilly and Company Limited. Trulicity 0.75 mg 1.5 mg 3 mg 4.5 mg solution for injection in pre-filled pen. Available at: www.medicines.org.uk
  30. Sandoz Limited. Pioglitazone 30 mg tablets. Available at: www.medicines.org.uk
  31. US Food and Drug Administration. FDA announced that a safety review has found type 2 diabetes medicines containing saxagliptin and alogliptin may increase the risk of heart failure. www.fda.gov/drugs/fda-drug-safety-podcasts/fda-announced-safety-review-has-found-type-2-diabetes-medicines-containing-saxagliptin-and (accessed 22 April 2022).

About this management algorithm

Disclaimer:Guidelines identified a need for clinical guidance in a specific area and approached AstraZeneca for an educational grant to support the development of a management algorithm. The grant included honoraria for the contributors. This algorithm was developed by Guidelines, and the Chair and members of the working group were chosen and convened by Guidelines. The content is independent of and not influenced by AstraZeneca, who checked the final document for technical accuracy only. The views and opinions of the contributors are not necessarily those of AstraZeneca, or of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

Group members: Yassir Javaid (Chair, GPwSI Cardiology, Cardiovascular and Diabetes Clinical Lead Northamptonshire CCG), Manmeet Anand (Diabetes Specialist Pharmacist BLMK CCG), Ravi Assomull (Consultant Cardiologist, London North West Healthcare NHS Trust), Patrick Holmes (GP Partner/GPwSI Diabetes and Diabetes Network Lead (primary care) for the North East of England), Janaka Karalliedde (Clinical Reader in Diabetes and Cardiovascular Disease, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London; Consultant Diabetologist, Guy’s and St Thomas’ Hospital London).

Conflicts of interest: The group members have received an honorarium to develop this algorithm. Some of the group members have also received consultancy fees from other pharmaceutical companies, which may include AstraZeneca, for activities other than the development of this algorithm.

Date of preparation: April 2022