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)

 [bib_ref] REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a..., Gerstein [/bib_ref] [bib_ref] DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes, Wiviott [/bib_ref] [bib_ref] Effect of dapagliflozin on heart failure and mortality in type 2 diabetes..., Kato [/bib_ref] [bib_ref] DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and..., Mcmurray [/bib_ref] 

## Changes to consensus recommendations
We previously recommended that, in the setting of type 2 diabetes, established CVD was a compelling indication for treatment with a GLP-1 receptor agonist or SGLT2 inhibitor. We now further suggest the following: General consideration c In appropriate high-risk individuals with established type 2 diabetes, the decision to treat with a GLP-1 receptor agonist or SGLT2 inhibitor to reduce MACE, hHF, CV death, or CKD progression should be considered independently of baseline HbA 1c or individualized HbA 1c target. c Providers should engage in shared decision making around initial combination therapy in new-onset cases of type 2 diabetes. GLP-1 receptor agonist recommendations c For patients with type 2 diabetes and established atherosclerotic CV disease (such as those with prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging or stress test, or revascularization of coronary, carotid, or peripheral arteries) where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists. c To reduce risk of MACE, GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established CVD with indicators of high risk, specifically, patients aged 55 years or older with coronary, carotid, or lower extremity artery stenosis .50%, left ventricular hypertrophy, eGFR ,60 mL min -1 [1.73 m] -2 , or albuminuria. SGLT2 inhibitor recommendations c For patients with or without established atherosclerotic CVD, but with HFrEF (EF ,45%) or CKD (eGFR 30 to #60 mL min -1 [1.73 m] -2 or UACR .30 mg/g, particularly UACR .300 mg/g), the level of evidence for benefit is greatest for SGLT2 inhibitors. c SGLT2 inhibitors are recommended in patients with type 2 diabetes and HF, particularly those with HFrEF, to reduce hHF, MACE, and CV death. c SGLT2 inhibitors are recommended to prevent the progression of CKD, hHF, MACE, and CV death in patients with type 2 diabetes with CKD. c Patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decision making around risks and benefits with comprehensive education on foot care and amputation prevention. The REWIND trial of the GLP-1 receptor agonist dulaglutide had no lower limit to HbA 1c for eligibility and demonstrated equivalent efficacy for reduction of MACE above and below the median HbA 1c of 55 mmol/mol (7.2%) [bib_ref] REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a..., Gerstein [/bib_ref]. None of the CVOTs of SGLT2 inhibitors with primary MACE end points have recruited patients with an HbA 1c ,48 mmol/mol (,6.5%), and there is little data to inform clinical decision making for patients with an HbA 1c ,53 mmol/mol (,7%) (9). However, the outcome benefits observed in the CVOTs do not appear restricted to patients with an elevated HbA 1c . That said, the DAPA-HF trial recruited patients with HFrEF with and without diabetes [bib_ref] DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and..., Mcmurray [/bib_ref].
The benefit for reduction of mortality rate and HF events with dapagliflozin was significant in both subgroups, suggesting that the effects of dapagliflozin on these end points is independent of HbA 1c [bib_ref] DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and..., Mcmurray [/bib_ref]. We now recommend that in appropriate high-risk individuals with established type 2 diabetes, the decision to treat with a GLP-1 receptor agonist or SGLT2 inhibitor to reduce MACE, hHF, cardiovascular death, or CKD progression should be considered independently of baseline HbA 1c or individualized HbA 1c target. That said, there are no specific analyses addressing HbA 1c ,48 mmol/ mol (,6.5%). We continue to recommend that substituting a drug with known CVD, CKD, and hHF benefit for one without known benefit in high-risk patients is reasonable when patients are at individualized glycemic targets.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial of the SGLT2 inhibitor canagliflozin was the first renal outcome trial of a diabetes medication (10) with a primary composite end point of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR of ,15 mL min -1 [1.73 m] -2 ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The trial recruited patients with type 2 diabetes and CKD on the maximally tolerated dose of ACE inhibitors or angiotensin receptor blockers with a urinary albumin-to-creatinine ratio (UACR) of 300-5,000 mg/g and an eGFR of 30 to ,90 mL min -1 [1.73 m] -2 . This trial demonstrated a clear benefit of canagliflozin (100 mg) on multiple renal end points, including progression to endstage kidney disease, and on cardiovascular mortality, MACE, and hHF. Furthermore, the CREDENCE results demonstrated that the benefits conferred by canagliflozin in terms of reducing MACE, hHF, cardiovascular mortality, and renal end points were similar regardless of baseline status for cardiovascular or CKD grade 2-3 [bib_ref] Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and..., Mahaffey [/bib_ref]. We now recommend that SGLT2 inhibitors should be used to prevent hHF, MACE, and CV death and the progression of CKD in patients with type 2 diabetes with CKD. The benefits are clearcut for those with UACR .300 mg/g and eGFR 30-90 mL min -1 [1.73 m] -2 and less well established for lesser grades of CKD based on secondary end point analyses of the CVOT.
A concern in the CANVAS Program was the increased risk of amputation with canagliflozin compared with placebo (7). In CREDENCE (10), although the risk of amputation was higher overall than in other SGLT2 inhibitor trials, no significant increase in risk was observed with canagliflozin 100 mg versus placebo (HR 1.11; 95% CI 0.79, 1.56). This may be due to the risk mitigation strategies employed: exclusion of patients with a history of a traumatic amputation within 12 months of screening, or an active foot ulcer, osteomyelitis, gangrene, or critical ischemia of the lower extremity within 6 months of screening; and interruption of therapy for emergence of any of the above with careful consideration of the individual risks and benefits prior to restarting canagliflozin after resolution of the event. We now recommend that patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decision making around risks and benefits with comprehensive education on foot care and amputation prevention.
Based on the studies published thus far, we believe that for patients with type 2 diabetes and established atherosclerotic CVD (such as those with prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging or stress test, or revascularization of coronary, carotid, or peripheral arteries) where MACE is the gravest threat, that the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists.
The Peptide Innovation for Early Diabetes Treatment 6 (PIONEER 6) cardiovascular safety trial of oral semaglutide, a GLP-1 receptor agonist, involved 3,183 patients with type 2 diabetes followed for only a median of 16 months, but it provided adequate demonstration of cardiovascular safety (HR 0.79; 95% CI 0.57, 1.11) and a strong signal for reduction of CV mortality rate (HR 0.49; 95% CI 0.27, 0.92) [bib_ref] PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type..., Husain [/bib_ref]. This formulation of semaglutide has been approved for marketing in the U.S. and a decision in the European Union is expected soon.
For patients with or without established atherosclerotic CVD, but with HFrEF or CKD (eGFR 30 to 60 mL min -1 [1.73 m] -2 or UACR >30 mg/g, particularly UACR >300 mg/g), the level of evidence for benefit is greatest for SGLT2 inhibitors. For patients with type 2 diabetes at low cardiovascular risk and without CKD, there have been no studies to examine the cardiovascular or renal benefit of GLP-1 receptor agonists or SGLT2 inhibitors.
Some meta-analyses [bib_ref] GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes:..., Giugliano [/bib_ref] [bib_ref] Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with..., Kristensen [/bib_ref] suggest the presence of heterogeneity in estimates for MACE and CV death with GLP-1 receptor agonists, although this is mostly due to the results of a single trial with lixisenatide. Likewise, there is some heterogeneity in the estimate for CV death with SGLT2 inhibitors. Whether differences in point estimates of benefits and harms are the result of differences in the effects of the medications, the design and conduct of the trials, or chance effects is uncertain. Attention to patient-specific factors and preferences, product labeling, meta-analyses, and the primary research reports should drive individualized clinical decision making with regard to prescribing particular medications within a class. For many patients, treatment with a GLP-1 receptor agonist or SGLT2 inhibitor in some health care settings involves considerable direct cost to them, and the impact of this on their overall well-being needs to be factored into decision making.
The Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) trial randomized adults at high cardiovascular risk to receive the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin or to receive the sulfonylurea glimepiride to evaluate a primary MACE end point. No between-group difference in the primary end point was demonstrated (HR 0.98; 95% CI 0.84, 1.14). At trial end, for linagliptin as compared with glimepiride, there was a 1.5-kg weight loss benefit, no difference in HbA 1c or introduction of glucose-lowering medications postbaseline, and substantial benefits in terms of reductions in hypoglycemia, though serious hypoglycemic events were rare with glimepiride (0.45/100 patient-years) [bib_ref] Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients..., Rosenstock [/bib_ref]. Paired with other DPP-4 inhibitor CVOTs, including Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) [bib_ref] CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in..., Rosenstock [/bib_ref] , which demonstrated the CV safety of linagliptin, this is a reassuring safety signal for glimepiride, an inexpensive and effective sulfonylurea. It is unclear whether these findings extend to other sulfonylureas.
Whereas we previously stated that there was limited evidence for initial combination therapy, the Vildagliptin Efficacy in Combination with Metformin for Early Treatment of Type 2 Diabetes (VERIFY) trial provides additional information. The initial combination of the DPP-4 inhibitor vildagliptin and metformin was shown to provide for a lower rate of secondary failure of glycemic control to HbA 1c $53 mmol/mol ($7%) versus metformin alone or the sequential addition of metformin and vildagliptin [bib_ref] Glycaemic durability of an early combination therapy with vildagliptin and metformin versus..., Matthews [/bib_ref]. We now suggest that providers should engage in shared decision making around initial combination therapy in new-onset cases of type 2 diabetes.
There are several major questions regarding the optimal application of new diabetes drugs. One obvious question arising from recent trial results is whether combined use of GLP-1 receptor agonists and SGLT2 inhibitors provides additional benefit for the prevention of MACE, CV death, hHF, and CKD progression. Three trials have demonstrated the HbA 1c -lowering and weight-reduction efficacy of the combination [bib_ref] Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2..., Zinman [/bib_ref] [bib_ref] Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled..., Ludvik [/bib_ref] [bib_ref] Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone..., Frias [/bib_ref] , but none addresses the impact of the combination of the two on cardiorenal end points. A second question that arises from the recent secondary analyses of SGLT2 inhibitor studies is whether there are subsets of patients who benefit disproportionately, or very little, from treatment with the newer diabetes drugs. The emerging evidence that SGLT2 inhibitors may be particularly useful in preventing adverse outcomes in patients with diabetes with HFrEF raises the possibility of more targeted use of these agents. Finally, the mechanism(s) of action by which GLP-1 receptor agonists and SGLT2 inhibitors confer cardiorenal benefit in diabetes are not understood. Research in this area will be very useful in optimizing the now clear potential of drugs for diabetes to mitigate the cardiovascular and renal complications of the disease.
Modifications to the main figures of the prior publication are suggested as shown in [fig_ref] Figure 2 -: Choosing glucose-lowering medication in those with indicators of high-risk or established atherosclerotic... [/fig_ref] 
[fig] Figure 2 -: Choosing glucose-lowering medication in those with indicators of high-risk or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF). RA, receptor agonist; SU, sulfonylureas; TZD, thiazolidinediones. Adapted from Davies et al. (1).  American Diabetes Association and European Association for the Study of Diabetes, 2018. [/fig]