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)
Davies, Melanie J D’Alessio, David A Fradkin, Judith Kernan, Walter N Mathieu, Chantal Mingrone, Geltrude Rossing, Peter Tsapas, Apostolos Wexler, Deborah J Buse, John B
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, publishe
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American Diabetes Association
Among patients with type 2 diabetes who have established ASCVD, SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management (Figs. 2 and 3).

ASCVD is defined somewhat differently across trials, but all trials enrolled individuals with established CVD (e.g., myocardial infarction [MI], stroke, any revascularization procedure) while variably including related conditions compatible with clinically significant atherosclerosis (e.g., transient ischemic attack, hospitalized unstable angina, amputation, congestive heart failure New York Heart Association [NYHA] class II–III, >50% stenosis of any artery, symptomatic or asymptomatic coronary artery disease documented by imaging, CKD with estimated glomerular filtration rate [eGFR] <60 mL min−1 [1.73]−2). Most trials also included a “risk factor only” group with entry criteria based on age and usually the presence of two or more cardiac risk factors (46). Trials were designed to evaluate cardiovascular safety (i.e., statistical noninferiority compared with placebo), but several showed ASCVD outcome benefit (i.e., statistical superiority compared with placebo), including, in some cases, mortality.

Among GLP-1 receptor agonists, liraglutide, studied in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (n = 9,340), demonstrated an ARR of 1.9% with a hazard ratio (HR) of 0.87 (95% CI 0.78, 0.97; P = 0.01 for superiority) for the primary composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke (major adverse cardiac events [MACE]) compared with placebo over 3.8 years. Each component of the composite contributed to the benefit, and the HR for cardiovascular death was 0.78 (95% CI 0.66, 0.93; P = 0.007; ARR 1.7%). The LEADER trial also demonstrated an HR of 0.85 (95% CI, 0.74, 0.97; P = 0.02; ARR 1.4%) for all-cause mortality (47). In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) (n = 3,297), semaglutide compared with placebo demonstrated an ARR of 2.3% with HR 0.74 for MACE (95% CI 0.58, 0.95; P = 0.02 for superiority) over 2.1 years, but the reduction in events appeared to be driven by the rate of stroke rather than CVD death (48). The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) compared exenatide extended-release with placebo over 3.2 years in 14,752 participants with type 2 diabetes. While the medication was safe (noninferior), the HR for MACE in the entire trial was 0.91 (95% CI 0.83, 1.0; P = 0.06) not reaching the threshold for demonstrated superiority versus placebo; ARR was 0.8% (49). All-cause death was lower in the exenatide arm (ARR 1%, HR 0.86 [95% CI 0.77, 0.97]), but it was not considered to be statistically significant in the hierarchical testing procedure applied. Lixisenatide, a short-acting GLP-1 receptor agonist, did not demonstrate CVD benefit or harm in a trial of patients recruited within 180 days of an acute coronary syndrome admission (50). Taken together, it appears that among patients with established CVD, some GLP-1 receptor agonists may provide cardiovascular benefit, with the evidence of benefit strongest for liraglutide, favorable for semaglutide, and less certain for exenatide. There is no evidence of cardiovascular benefit with lixisenatide. Adverse effects for the class are discussed in the section “The Full Range of Therapeutic Options: Lifestyle Management, Medication, and Obesity Management.”

Among the SGLT2 inhibitors, empagliflozin compared with placebo was studied in the Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) in 7,020 participants with type 2 diabetes and CVD. With a median follow-up of 3.1 years, the ARR was 1.6% and the HR was 0.86 (95% CI 0.74, 0.99; P = 0.04 for superiority) for the primary composite end point of nonfatal MI, nonfatal stroke, and cardiovascular death. The ARR was 2.2% and the HR was 0.62 (95% CI 0.49, 0.77; P < 0.001) for cardiovascular death (51). The ARR was 2.6% and the HR was 0.68 (95% CI 0.57, 0.82; P < 0.001) for death from any cause. Canagliflozin compared with placebo was studied in the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (comprised of two similar trials, CANVAS and CANVAS-Renal; n = 10,142) in participants with type 2 diabetes, 66% of whom had a history of CVD. Participants were followed for a median of 3.6 years. In the combined analysis of the two trials, the primary composite end point of MI, stroke, or cardiovascular death was reduced with canagliflozin (26.9 vs. 31.5 participants per patient-year with placebo; HR 0.86 [95% CI 0.75, 0.97]; P = 0.02) for superiority in the pooled analysis, with consistent findings in the component studies. Though there was a trend toward benefit for cardiovascular death, the difference from placebo was not statistically significant in the CANVAS Program (52). For the SGLT2 inhibitors studied to date, it appears that among patients with established CVD, there is likely cardiovascular benefit, with the evidence of benefit modestly stronger for empagliflozin than canagliflozin. Adverse effects for the class are discussed in the section “The Full Range of Therapeutic Options: Lifestyle Management, Medication, and Obesity Management.”

While the evidence of an ASCVD outcomes benefit for GLP-1 receptor agonists and SGLT2 inhibitors has been demonstrated for people with established ASCVD, the evidence of benefit beyond glucose lowering has not been demonstrated in those without ASCVD. Indeed, in subgroup analyses of these trials, lower-risk individuals have not been observed to have an ASCVD benefit. While this may be due to the short time frame of the studies and the low event rate in those without ASCVD, the finding is consistent across the reported trials. Overall, CVOTs of dipeptidyl peptidase 4 (DPP-4) inhibitors have demonstrated safety, i.e., noninferiority relative to placebo, for the primary MACE end point, but not cardiovascular benefit.

The available evidence for cardiovascular event reduction in patients with type 2 diabetes and clinical CVD is derived from trials in which the participants were not meeting glycemic targets (HbA1c ≥53 mmol/mol [≥7%] at baseline). Furthermore, most (∼70% across trials) participants were treated with metformin at baseline. Thus, we recommend that patients with clinical CVD not meeting individualized glycemic targets while treated with metformin (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1 receptor agonist with proven benefit for cardiovascular risk reduction added to their treatment program. There are no clinical trial data that support prescribing an SGLT2 inhibitor or GLP-1 receptor agonist with the intent of reducing cardiovascular risk in patients with an HbA1c <53 mmol/mol (<7%). Limited data suggest that there is no heterogeneity in the cardiovascular benefits of SGLT2 inhibitors or GLP-1 receptor agonists as a function of background glucose-lowering therapy. Thus, background glucose-lowering therapy in patients with clinical CVD arguably is not pertinent in clinical decision making. However, dose adjustment or discontinuation of background medications may be required to avoid hypoglycemia when adding a new agent to a regimen containing insulin, sulfonylurea, or glinide therapy, particularly in patients at or near glycemic goals. Full efforts to achieve glycemic and blood pressure targets and to adhere to lipid, antiplatelet, antithrombotic, and tobacco cessation guidelines (7) should continue after an SGLT2 inhibitor or GLP-1 receptor agonist is added, as such efforts were integral to all studies that have demonstrated cardiovascular benefit of these agents.

Patients who are unable to maintain glycemic targets on basal insulin in combination with oral medications can have treatment intensified with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin (Figs. 7 and 8).

It has become common practice to approach insulin use in people with type 2 diabetes by following the established paradigms developed for those with type 1 diabetes. This includes multiple daily injections with doses of insulin analogs before meals that are adjusted based on ambient blood glucose and meal constituents. While this is reasonable for people with type 2 diabetes who are lean, insulinopenic, and sensitive to exogenous insulin, it ignores the substantial differences in pathophysiology between most people with type 2 diabetes and type 1 diabetes. Most people with type 2 diabetes are obese and insulin resistant, requiring much larger doses of insulin and experiencing lower rates of hypoglycemia than those with type 1 diabetes. In patients with type 2 diabetes, weight gain is a particularly problematic side effect of insulin use. Recent evidence supports the effectiveness of combinations of insulin with glucose-lowering medications that do not increase body weight. For example, SGLT2 inhibitors can be added to insulin regimens to lower blood glucose levels without increasing insulin doses, weight gain, or hypoglycemia (219–221). In a meta-analysis that studied the combination of either SGLT2 inhibitors or DPP-4 inhibitors with insulin, the SGLT2 inhibitor–insulin combination was associated with a greater reduction in HbA1c, an advantage in terms of body weight and no increase in the rates of hypoglycemia (222,223). Depending on baseline HbA1c, glycemic profile, and individual response, the insulin dose may need to be reduced to prevent hypoglycemia when adding an SGLT2 inhibitor.

The combination of basal insulin and a GLP-1 receptor agonist has high efficacy, with recent evidence from clinical trials demonstrating the benefits of this combination to lower HbA1c and limit weight gain and hypoglycemia compared with intensified insulin regimens (224,225). Most data come from studies in which a GLP-1 receptor agonist is added to basal insulin. However, there is evidence that insulin added to a GLP-1 receptor agonist can also effectively lower HbA1c, although some weight gain results (215). Fixed-ratio combinations of insulin and GLP-1 receptor agonists are available and can decrease the number of injections compared with administering the medications separately (226–228).

A final approach to glycemic management when basal insulin plus oral medications is insufficient to achieve HbA1c targets is intensified insulin regimens (Figs. 7 and 8). DSMES focused on insulin therapy is particularly helpful when intensified insulin therapy is considered. Referral to a diabetes specialist team should be considered in cases where the provider is uncomfortable or unfamiliar with intensification, poor outcomes continue despite intensification, or patients have other issues that complicate intensification. Intensified insulin regimens include 1) one or more daily injections of rapid- or short-acting insulin before meals (prandial insulin) or 2) switching to one to three daily administrations of a fixed combination of short- and long-acting insulin (premixed or biphasic insulins) (229,230). When adding prandial insulin, giving one injection with the largest meal of the day is a simple and safe approach (231). Over time, if glycemic targets are not met with one dose of prandial insulin daily, additional prandial injections can be added to other meals (232). Results of meta-analyses suggest a modestly greater reduction in HbA1c with basal-prandial regimens compared with biphasic insulin regimens, but at the expense of greater weight gain (233–235). While still commonly used, we do not generally advocate premixed insulin regimens, particularly those administered three times daily, for routine use when intensifying insulin regimens (Fig. 7).

Continuous insulin infusion using insulin pumps may have a role in a small minority of people with type 2 diabetes (236).

Acknowledgments. The authors would like to acknowledge Mindy Saraco (Associate Director, Scientific & Medical Communication), Gedeon Topacio (Finance & Project Manager, Research & Scientific Programs), and Erika Berg (Director, Scientific & Medical Affairs) from the American Diabetes Association as well as Mary Hata (Executive Assistant) and Petra Niemann (Executive Assistant) from EASD for their help with the development of the consensus report and related meetings/presentations. The authors would like to also acknowledge Mike Bonar (Creative Director) and Charlie Franklin (Design Assistant) from the Leicester Diabetes Centre, Leicester, U.K., who provided considerable support in drafting and amending the figures. The authors also acknowledge Francesco Zaccardi (PhD, Clinical Research Fellow, University of Leicester, Leicester, U.K.) and David Kloecker (Medical Student, University of Leicester) who assisted with extracting PubMed articles and identifying relevant records by title and abstract; Francesco Zaccardi helped to define the initial search strategy and prepare the Excel file. The authors acknowledge the invited peer reviewers who provided comments on an earlier draft of this report: Amanda Adler (Addenbroke’s Hospital, Cambridge, U.K.), Kåre I. Birkeland (University of Oslo, Oslo, Norway), James J. Chamberlain (St. Mark’s Hospital, Salt Lake City, UT), Jill P. Crandall (Albert Einstein College of Medicine, New York City, NY), Ian H. de Boer (University of Washington, Seattle, WA), Stefano Del Prato (University of Pisa, Pisa, Italy), George Dimitriadis (Athens University, Athens, Greece), Sean Dinneen (National University of Ireland, Galway, Ireland), Vivian A. Fonseca (Tulane University, New Orleans, LA), Simon R. Heller (University of Sheffield, Sheffield, U.K.), Richard I.G. Holt (University of Southampton, Southampton, U.K.), Silvio E. Inzucchi (Yale University, New Haven, CT), Eric L. Johnson (University of North Dakota, Grand Forks, ND), Joshua J. Neumiller (Washington State University, Spokane, WA), Kamlesh Khunti (University of Leicester, Leicester, U.K.), Harald H. Klein (Ruhr University of Bochum, Bochum, U.K.), Line Kleinebreil (Hôpital national de Saint Maurice, Saint-Maurice, France), José Manuel Fernández-Real (Universitat de Girona, Girona, Spain), Sally M. Marshall (Newcastle University, Newcastle upon Tyne, U.K.), Manel Mata-Cases (Institut Universitari d’Investigació en Atenció Primària Jordi Gol [IDIAP Jordi Gol], Barcelona, Spain), David R. Matthews (University of Oxford, Oxford, U.K.), David M. Nathan (Massachusetts General Hospital, Boston, MA), Michael A. Nauck (Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University, Bochum, Germany), Frank Nobels (OLV-Hospital, Aalst, Belgium), Richard E. Pratley (Florida Hospital Diabetes Institute, Orlando, FL), Maria Jose Redondo (Baylor College of Medicine, Houston, TX), Michael R. Rickels (University of Pennsylvania, Philadelphia, PA), Matthew C. Riddle (Oregon Health & Science University, Portland, OR), Julio Rosenstock (Diabetes and Endocrine Center, Dallas, TX), Giorgio Sesti (Magna Graecia University of Catanzaro, Catanzaro, Italy), Neil Skolnik (Abington Family Medicine, Jenkintown, PA), Krzysztof Strojek (Silesian Medical University, Zabrze, Poland), Jennifer Trujillo (University of Colorado, Denver, CO), Guillermo E. Umpierrez (Emory University, Atlanta, GA), and Jennifer Wyckoff (University of Michigan, Ann Arbor, MI).

Funding. This activity was funded by the American Diabetes Association and the European Association for the Study of Diabetes.

Duality of Interest. M.J.D. reports personal fees and grants from Boehringer Ingelheim, Janssen, Novo Nordisk, and Sanofi and personal fees from AstraZeneca, Eli Lilly, Gilead Sciences Ltd., Intarcia/Servier, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, and Takeda Pharmaceuticals International Inc. D.A.D’A. reports personal fees from Eli Lilly, Merck, Novo Nordisk, and Intarcia and grants from Merck and Ligand during the conduct of the study; personal fees from Eli Lilly, Merck, Novo Nordisk, and Intarcia and grants from Merck and Ligand outside the submitted work. J.F. has nothing to disclose. J.F.’s input into this consensus report is from her own perspective and the report does not reflect the view of the National Institutes of Health, Department of Health and Human Services, or the U.S. Government. W.N.K. has nothing to disclose. C.M. reports grants and personal fees from Novo Nordisk, grants and personal fees from Sanofi, grants and personal fees from Merck Sharp & Dohme, grants and personal fees from Eli Lilly and Company, grants and personal fees from Novartis, personal fees from Bristol-Myers Squibb, personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Hanmi Pharmaceuticals, grants and personal fees from Roche Diagnostics, grants and personal fees from Medtronic, grants and personal fees from Intrexon, grants and personal fees from Abbott, and personal fees from UCB, outside the submitted work. G.M. reports grants and personal fees from Novo Nordisk, personal fees from Johnson & Johnson, and personal fees from Fractyl Inc., during the conduct of the study. P.R. reports grants and nonfinancial and other support from Novo Nordisk, grants and other support from AstraZeneca, other support from Bayer, other support from Boehringer Ingelheim, other support from Merck Sharp & Dohme, and other support from Eli Lilly, during the conduct of the study. A.T. reports nonfinancial support from the European Association for the Study of Diabetes during the conduct of the study; grants and other support from Boehringer Ingelheim, grants and other support from Novo Nordisk, other support from Novartis, grants and other support from Sanofi, grants and other support from AstraZeneca, grants from GSK, and grants and other support from European Foundation for the Study of Diabetes, outside the submitted work. D.J.W. has nothing to disclose. J.B.B. has provided consultation to Adocia, AstraZeneca, Eli Lilly, GI Dynamics, Intarcia, MannKind, NovaTarg, Novo Nordisk, Senseonics, and vTv Therapeutics with fees paid to the University of North Carolina. He has received grant support from AstraZeneca, Johnson & Johnson, Novo Nordisk, Sanofi, and vTv Therapeutics. He is a consultant to Neurimmune AG. He holds stock options in Mellitus Health, PhaseBio, and Stability Health. He is supported by a grant from the National Institutes of Health (UL1TR002489). No other potential conflicts of interest relevant to this article were reported.

Author Contributions. All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

Data Availability. The details of the search strategy, the results, and the classification for the included articles are available at https://dx.doi.org/10.17632/h5rcnxpk8w.1.