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Practice Rapid Recommendations

SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline

BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n1091 (Published 11 May 2021) Cite this as: BMJ 2021;373:n1091

Visual summary of recommendation

Population No underlying cardiovascular or chronic kidney disease More than 3 cardiovascular risk factors Cardiovascular disease Chronic kidney disease Both Cardiovascular and chronic kidney disease These recommendations are relevant for all adults with type 2 diabetes but differ depending on risk factors: + Coronary artery disease on diagnostic testing or prior myocardial infarction Stroke Albuminuria >60 years old Male Current smoking Family history of cardiovascular or kidney disease Asian, African or Hispanic Dyslipidaemias Recommendation 2 Recommendation 3 Recommendation 4 Recommendation 1 Including Reduced high density lipoprotein (HDL) cholesterol (<1 mmol/L) eGFR <60 Cardiovascular risk factors Use individualised targets if available Uncontrolled hypertension (>140/90 mm Hg) Uncontrolled HbA 1c (>6.5%) Elevated total cholesterol (≥5.2 mmol/L) Adults with type 2 diabetes 3 or fewer cardiovascular risk factors Albumin excretion rate: ≥30mg/24 hoursAlbumin-to-creatinine ratio: ≥30mg/g (≥3mg/mmol) <60 mL/min/1.73 m 2 Estimated Glomerular Filtration Rate
Interventions compared Usual care SGLT-2 inhibitors GLP-1 receptor agonists Includes lifestyle interventions and a range of antidiabetic drugs typically focusing on glucose control, based on best current evidence and guidance Oral anti-diabetic agents given once daily in the morning. Available preparations include: Most available GLP-1 receptor agonist preparations are given via subcutaneous injection (twice daily, daily, or weekly), with the exception of semaglutide that is available in oral preparation Recommendation 5 Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin
Recommendation 1Patients with 3 or fewercardiovascular risk factors
Usual careSGLT-2 inhibitors or GLP-1receptor agonistsorWe suggest not using SGLT-2 inhibitors or GLP-1 receptor agonistsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Potential benefitsPotential harmsAll Cause MortalityEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists201718NodataNodataNodataNonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists302628NodataNodataNodataNonfatal strokeEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists303025NodataNodataNodataEnd stage kidney diseaseEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists212NodataNodataNodataHospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists535NodataNodataNodataDiabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists221NodataNodataNodataGenital infectionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists7321652NodataNodataNodataSevere gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists4444102NodataNodataNodataSee full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aidKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Individual considerations

Key practical issues Individual patients likely place different values on avoiding cardiovascular and renal outcomes, weighed against harms and practical issues from taking these medications. For patients with low risk of cardiovascular and renal disease, the weak recommendation reflects what the panel considered to be a fine balance between benefits, harms, and burdens of treatment options Values and preferences SGLT-2 inhibitors and GLP-1 receptor agonists are costly and may not be reimbursed by health care providers, leaving potentially prohibitive high out of pocket costs for patients. Costs vary between specific agents and GLP-1 receptor agonists are usually 2 to 3 times more expensive than SGLT-2 inhibitors Costs and reimbursement SGLT-2 inhibitors GLP-1 receptor agonists Usual care Tablets swallowed once daily. Some must be taken in the morning Most anti-diabetic medications are tablets except insulin, an injection Injection once or twice daily or once weekly Formulas that combine GLP-1 receptor agonists and insulin are available Also available as tablets, but these are not yet widely available Should not be taken while a person is unwell, especially if there is vomiting, diarrhoea, or the person isn’t eating and drinking much
Recommendation 2Patients with more than 3cardiovascular risk factors
Usual careSGLT-2 inhibitorsorWe suggest SGLT-2 inhibitors StrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Usual careGLP-1 receptor agonistsorWe suggest not using GLP-1 receptor agonistsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Potential benefitsPotential harmsAll Cause MortalityEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists706062NodataNodataNodataNonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists585154NodataNodataNodataNonfatal strokeEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists585949NodataNodataNodataEnd stage kidney diseaseEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists1078NodataNodataNodataHospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists302128NodataNodataNodataDiabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists221NodataNodataNodataGenital infectionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists7321652NodataNodataNodataSevere gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists4444102NodataNodataNodataSee full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aidKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Individual considerations

Key practical issues Individual patients likely place different values on avoiding cardiovascular and renal outcomes, weighed against harms and practical issues from taking these medications. For patients with three or more risk factors for cardiovascular disease, the weak recommendation reflects what the panel considered to be a fine balance between benefits, harms, and burdens of treatmentoptions Values and preferences SGLT-2 inhibitors and GLP-1 receptor agonists are costly and may not be reimbursed by health care providers, leaving potentially prohibitive high out of pocket costs for patients. Costs vary between specific agents and GLP-1 receptor agonists are usually 2 to 3 times more expensive than SGLT-2 inhibitors Costs and reimbursement SGLT-2 inhibitors GLP-1 receptor agonists Usual care Tablets swallowed once daily. Some must be taken in the morning Most anti-diabetic medications are tablets except insulin, an injection Injection once or twice daily or once weekly Formulas that combine GLP-1 receptor agonists and insulin are available Also available as tablets, but these are not yet widely available Should not be taken while a person is unwell, especially if there is vomiting, diarrhoea, or the person isn’t eating and drinking much
Recommendation 3Patients with establishedcardiovascular or renal disease
Usual careSGLT-2 inhibitors or GLP-1receptor agonistsorWe suggest SGLT-2 inhibitors or GLP-1 receptor agonistsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile - patients with cardiovascular disease

Potential benefitsPotential harmsAll Cause MortalityEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists120104107NodataNodataNodataNonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists10895100NodataNodataNodataNonfatal strokeEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists10810992NodataNodataNodataEnd stage kidney diseaseEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists201416NodataNodataNodataHospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists805776NodataNodataNodataDiabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists221NodataNodataNodataGenital infectionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists7321652NodataNodataNodataSevere gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists4444102NodataNodataNodataSee full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aidKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Evidence profile - patients with renal disease

Potential benefitsPotential harmsAll Cause MortalityEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists170148153NodataNodataNodataNonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists120106111NodataNodataNodataNonfatal strokeEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists120121103NodataNodataNodataEnd stage kidney diseaseEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists926773NodataNodataNodataHospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists1057699NodataNodataNodataDiabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists221NodataNodataNodataGenital infectionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists7321652NodataNodataNodataSevere gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists4444102NodataNodataNodataSee full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aidKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Individual considerations

Key practical issues Individual patients likely place different values on avoiding cardiovascular and renal outcomes, weighed against harms and practical issues from taking these medications. For patients with established cardiovascular or renal disease, the weak recommendation reflects what the panel considered to be a fine balance between benefits, harms, and burdens of treatment options Values and preferences SGLT-2 inhibitors and GLP-1 receptor agonists are costly and may not be reimbursed by health care providers, leaving potentially prohibitive high out of pocket costs for patients. Costs vary between specific agents and GLP-1 receptor agonists are usually 2 to 3 times more expensive than SGLT-2 inhibitors Costs and reimbursement SGLT-2 inhibitors GLP-1 receptor agonists Usual care Tablets swallowed once daily. Some must be taken in the morning Most anti-diabetic medications are tablets except insulin, an injection Injection once or twice daily or once weekly Formulas that combine GLP-1 receptor agonists and insulin are available Also available as tablets, but these are not yet widely available Should not be taken while a person is unwell, especially if there is vomiting, diarrhoea, or the person isn’t eating and drinking much
Recommendation 4Patients with establishedcardiovascular and renal disease
Usual careSGLT-2 inhibitorsorWe recommend SGLT-2 inhibitorsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone
Usual careGLP-1 receptor agonistsorWe suggest GLP-1 receptor agonists as an alternativeStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile

Potential benefitsPotential harmsAll Cause MortalityEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists265235241NodataNodataNodataNonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists190169177NodataNodataNodataNonfatal strokeEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists190192165NodataNodataNodataEnd stage kidney diseaseEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists148110119NodataNodataNodataHospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists235177224NodataNodataNodataDiabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists221NodataNodataNodataGenital infectionEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists7321652NodataNodataNodataSevere gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsUsual careSGLT-2inhibitorsGLP-1receptoragonists4444102NodataNodataNodataSee full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aidKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Individual considerations

Key practical issues Individual patients likely place different values on avoiding cardiovascular and renal outcomes, weighed against harms and practical issues from taking these medications. For the patients at highest risk the panel considered treatment with SGLT2-inhibitors to represent a clear benefit, resulting in a strong recommendation for such treatment Values and preferences SGLT-2 inhibitors and GLP-1 receptor agonists are costly and may not be reimbursed by health care providers, leaving potentially prohibitive high out of pocket costs for patients. Costs vary between specific agents and GLP-1 receptor agonists are usually 2 to 3 times more expensive than SGLT-2 inhibitors Costs and reimbursement SGLT-2 inhibitors GLP-1 receptor agonists Usual care Tablets swallowed once daily. Some must be taken in the morning Most anti-diabetic medications are tablets except insulin, an injection Injection once or twice daily or once weekly Formulas that combine GLP-1 receptor agonists and insulin are available Also available as tablets, but these are not yet widely available Should not be taken while a person is unwell, especially if there is vomiting, diarrhoea, or the person isn’t eating and drinking much
Recommendation 5Patients committed to further reducing their riskfor cardivascular and renal disease outcomes
SGLT-2 inhibitorsGLP-1 receptor agonistsorWe suggest SGLT-2 inhibitors rather than GLP-1 receptor agonistsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyone

Evidence profile - Patients with 3 or fewer cardiovascular risk factors

Potential benefitsPotential harmsAll Cause Mortality*Events per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists1718Nonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists2628Nonfatal strokeEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists3025End stage kidney diseaseEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists12Hospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists35Diabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21Genital infectionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21652Severe gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists44102See full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aid* Mortality values for SGLT-2 inhibitors in this recommendation are different from the other recommendations, because we present direct comparisons with GLP-1 inhibitors. The evidence profiles for the other recommendations present a comparison with standard careKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Evidence profile - Patients with more than 3 cardiovascular risk factors

Potential benefitsPotential harmsAll Cause Mortality*Events per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists5962Nonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists5154Nonfatal strokeEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists5949End stage kidney diseaseEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists78Hospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists2128Diabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21Genital infectionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21652Severe gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists44102See full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aid* Mortality values for SGLT-2 inhibitors in this recommendation are different from the other recommendations, because we present direct comparisons with GLP-1 inhibitors. The evidence profiles for the other recommendations present a comparison with standard careKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Evidence profile - Patients with cardiovascular disease

Potential benefitsPotential harmsAll Cause Mortality*Events per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists102107Nonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists95100Nonfatal strokeEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists10992End stage kidney diseaseEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists1416Hospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists5776Diabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21Genital infectionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21652Severe gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists44102See full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aid* Mortality values for SGLT-2 inhibitors in this recommendation are different from the other recommendations, because we present direct comparisons with GLP-1 inhibitors. The evidence profiles for the other recommendations present a comparison with standard careKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Evidence profile - Patients with renal disease

Potential benefitsPotential harmsAll Cause Mortality*Events per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists146153Nonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists106111Nonfatal strokeEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists121103End stage kidney diseaseEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists6773Hospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists7699Diabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21Genital infectionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21652Severe gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists44102See full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aid* Mortality values for SGLT-2 inhibitors in this recommendation are different from the other recommendations, because we present direct comparisons with GLP-1 inhibitors. The evidence profiles for the other recommendations present a comparison with standard careKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Evidence profile - Patients with cardiovascular and renal disease

Potential benefitsPotential harmsAll Cause Mortality*Events per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists232241Nonfatal myocardial infarctionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists169177Nonfatal strokeEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists192165End stage kidney diseaseEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists110119Hospitalisation for heart failureEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists177224Diabetic ketoacidosisEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21Genital infectionEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists21652Severe gastrointestinal eventsEvents per 1000 peopleWithin 5 yearsSGLT-2inhibitorsGLP-1receptoragonists44102See full detailsMultiple comparisondata for all outcomescan be furtherexplored in theMATCH-IT decision aid* Mortality values for SGLT-2 inhibitors in this recommendation are different from the other recommendations, because we present direct comparisons with GLP-1 inhibitors. The evidence profiles for the other recommendations present a comparison with standard careKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effect

Individual considerations

Key practical issues Individual patients likely place different values on avoiding cardiovascular and renal outcomes, weighed against harms and practical issues from taking these medications. For patients with low risk of cardiovascular and renal disease, the weak recommendation reflects what the panel considered to be a fine balance between benefits, harms, and burdens of treatment options Values and preferences SGLT-2 inhibitors and GLP-1 receptor agonists are costly and may not be reimbursed by health care providers, leaving potentially prohibitive high out of pocket costs for patients. Costs vary between specific agents and GLP-1 receptor agonists are usually 2 to 3 times more expensive than SGLT-2 inhibitors Costs and reimbursement SGLT-2 inhibitors GLP-1 receptor agonists Tablets swallowed once daily. Some must be taken in the morning Injection once or twice daily or once weekly Formulas that combine GLP-1 receptor agonists and insulin are available Also available as tablets, but these are not yet widely available Should not be taken while a person is unwell, especially if there is vomiting, diarrhoea, or the person isn’t eating and drinking much

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  1. Sheyu Li, endocrinologist, clinical chair12,
  2. Per Olav Vandvik, methodologist, internist34,
  3. Lyubov Lytvyn, methodologist5,
  4. Gordon H Guyatt, methodologist, internist56,
  5. Suetonia C Palmer, nephrologist7,
  6. René Rodriguez-Gutierrez, endocrinologist8910,
  7. Farid Foroutan, methodologist11,
  8. Thomas Agoritsas, methodologist, internist12,
  9. Reed A C Siemieniuk, methodologist, internist56,
  10. Michael Walsh, nephrologist, methodologist56,
  11. Lawrie Frere, general practitioner13,
  12. David J Tunnicliffe, research fellow1415,
  13. Evi V Nagler, nephrologist16,
  14. Veena Manja, cardiologist17,
  15. Bjørn Olav Åsvold, endocrinologist1819,
  16. Vivekanand Jha, nephrologist2022,
  17. Mieke Vermandere, general practitioner23,
  18. Karim Gariani, internist12,
  19. Qian Zhao, general practitioner24,
  20. Yan Ren, endocrinologist1,
  21. Emma Jane Cartwright, UK patient editor25,
  22. Patrick Gee, patient partner26,
  23. Alan Wickes, patient partner27,
  24. Linda Ferns, patient partner27,
  25. Robin Wright, patient partner27,
  26. Ling Li, methodologist2,
  27. Qiukui Hao, geriatrician, methods chair528,
  28. Reem A Mustafa, nephrologist, methodologist, clinical chair529
  1. 1Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
  2. 2Chinese Evidence-based Medicine Center, Cochrane China Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, China
  3. 3University of Oslo, Oslo, Norway
  4. 4MAGIC Evidence Ecosystem Foundation
  5. 5Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
  6. 6Department of Medicine, McMaster University, Hamilton, ON, Canada
  7. 7Department of Medicine, University of Otago, Christchurch, New Zealand
  8. 8Plataforma INVEST Medicina UANL – KER Unit (KER Unit México), Subdirección de Investigación, Universidad Autónoma de Nuevo León, Monterrey, 64460, México
  9. 9Knowledge and Evaluation Research Unit in Endocrinology, Mayo Clinic, Rochester, MN, 55905, USA
  10. 10Endocrinology Division, Department of Internal Medicine, University Hospital “Dr. José E. González,” Universidad Autónoma de Nuevo León, Monterrey, 64460, México
  11. 11Ted Rogers Center for Heart Research, Canada
  12. 12Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Geneva, Switzerland
  13. 13Newbridge Surgery, Bath, UK
  14. 14Sydney School of Public Health, The University of Sydney, Sydney, Australia
  15. 15Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia
  16. 16Renal Division, Ghent University Hospital, Belgium
  17. 17University of California Davis, USA
  18. 18Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
  19. 19K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
  20. 20The George Institute for Global Health, UNSW, India
  21. 21School of Public Health, Imperial College, London, UK
  22. 22Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India
  23. 23Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
  24. 24International Medical Center / Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
  25. 25London, UK
  26. 26Founder & CEHD, iAdvocate, Inc., Virginia, Patient partner
  27. 27Patient partner
  28. 28The Center of Gerontology and Geriatrics/National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  29. 29Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas, Kansas City, USA
  1. Correspondence to: R A Mustafa rmustafa{at}kumc.edu, Q Hao haoqiukui{at}gmail.com

Abstract

Clinical question What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes?

Current practice Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications’ glucose-lowering potential.

Recommendations The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes

• Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists.

• More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists.

• Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists.

• Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists.

• For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists.

How this guideline was created An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel applied an individual patient perspective.

The evidence A linked systematic review and network meta-analysis (764 randomised trials included 421 346 participants) of benefits and harms found that SGLT-2 inhibitors and GLP-1 receptor agonists generally reduce overall death, and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure (moderate to high certainty evidence). These medications exert different effects on stroke, hospitalisations for heart failure, and key adverse events in different subgroups. Absolute effects of benefit varied widely based on patients’ individual risk (for example, from five fewer deaths in the lowest risk to 48 fewer deaths in the highest risk, for 1000 patients treated over five years). A prognosis review identified 14 eligible risk prediction models, one of which (RECODe) informed most baseline risk estimates in evidence summaries to underpin the risk-stratified recommendations. Concerning patients’ values and preferences, the recommendations were supported by evidence from a systematic review of published literature, a patient focus group study, a practical issues summary, and a guideline panel survey.

Understanding the recommendation We stratified the recommendations by the levels of risk for CVD and CKD and systematically considered the balance of benefits, harms, other considerations, and practical issues for each risk group. The strong recommendation for SGLT-2 inhibitors in patients with CVD and CKD reflects what the panel considered to be a clear benefit. For all other adults with type 2 diabetes, the weak recommendations reflect what the panel considered to be a finer balance between benefits, harms, and burdens of treatment options. Clinicians using the guideline can identify their patient’s individual risk for cardiovascular and kidney outcomes using credible risk calculators such as RECODe. Interactive evidence summaries and decision aids may support well informed treatment choices, including shared decision making.

Footnotes

  • This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (https://magicevidence.org/) and The BMJ. A summary is offered here and the full version including decision aids is on the MAGICapp (https://app.magicapp.org/), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances and their values and preferences and may want to use consultation decision aids in MAGICapp to facilitate shared decision making with patients. We encourage adaptation and contextualisation of our recommendations to local or other contexts. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article.

  • Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a detailed description of all disclosures is reported in appendix 1 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. Three authors of the systematic review were on the guideline panel (Li L, Suetonia P, Farid F).

  • Funding: This guideline was funded by the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (grant number ZYGD18022).

  • Transparency: R A Mustafa and Q Hao affirm that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned and registered have been explained.

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