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Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

Published:January 09, 2021DOI:https://doi.org/10.1016/j.amjmed.2020.12.012
      Pharmacologic therapy of type 2 diabetes mellitus has evolved dramatically in the past 3-5 years. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are two new classes of medications that have revolutionized our approach to glycemic, cardiovascular, and renal management of these patients.
      Yet, utilization of these drugs in clinical practice is extremely limited compared with other medications. Why? What are the obstacles preventing wider use of GLP-1 receptor agonists and SGLT-2i by primary care providers, cardiologists, nephrologists, and even endocrinologists?
      The reasons for this are complex. Since the discovery of insulin in 1921 that saved countless lives of patients with diabetes, an almost 100-year history of diabetes management is replete with incremental improvements that significantly minimized the prevalence of acute and chronic complications of diabetes and extended life expectancy of this population.
      Although therapy of type 1 diabetes has remained fully dependent upon insulin, over the years, the pharmacologic treatment paradigms of type 2 diabetes have evolved from insulin therapy (until the 1950s) to the introduction of sulfonylurea preparations followed by biguanides, thiazolidinediones, dipeptidyl peptidase inhibitors, GLP-1 receptor agonists, and SGLT-2i, in addition to better insulins.
      • White Jr, JR
      A brief history of the development of diabetes medications.
      ,
      • Doyle-Delgado K
      • Chamberlain JJ
      • Shubrook JH
      • Skolnik N
      • Trujillo J
      Pharmacologic approaches to glycemic treatment of type 2 diabetes: synopsis of the 2020 American Diabetes Association's Standards of Medical Care in Diabetes clinical guideline.
      As these therapeutic improvements were firmly incorporated into daily practice, it became apparent that the diabetes-related damage to the cardiovascular system emerged as the number 1 cause of morbidity and mortality in patients with diabetes, especially type 2 diabetes.
      • Haffner SM
      • Lehto S
      • Rönnemaa T
      • Pyörälä K
      • Laakso M
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      Although lifestyle changes and medications significantly improved life expectancy of patients with diabetes, the residual mortality still results in a lower life-expectancy than those without the disease.
      Life expectancy of patients with diabetes is shortened by risk of stroke, myocardial infarction, and heart failure. Women with diabetes lose their protection against the cardiovascular complications of diabetes. Overall, patients with diabetes are twice as likely to have cardiovascular disease as their age-matched counterparts without diabetes.
      • Leon BM
      • Maddox TM
      Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research.
      Furthermore, this population continues to be the leading group to develop end-stage renal disease.

      USRDS. Annual data report. Available at: https://www.usrds.org/annual-data-report. Accessed November 29, 2020.

      In 2008 the US Food and Drug Administration issued a guidance for industry to require pre-approval and post-approval demonstration of cardiovascular safety of all new medications developed for glycemic management of type 2 diabetes. The goal was to prevent medications that lowered blood glucose but had adverse cardiovascular effects. As a result, the industry conducted large clinical trials designed to assess the cardiovascular influence of new diabetes medications. The clinical trials with 2 new classes of medications—GLP-1 receptor agonists and SGLT-2i—demonstrated their positive cardiovascular and renoprotective influence (reviewed by Marx et al

      Marx N, Davies M, Grant PJ, et al. Positioning the novel therapeutics in diabetes care: time to integrate the recommendations. Lancet Diabetes Endocrinol, in press.

      ).
      The last 5 years saw incredible growth in clinical evidence of beneficial cardiovascular and renal effects of these 2 new classes of drugs. Cardiovascular outcome trials with GLP-1 receptor agonists in type 2 diabetes, such as LEADER, HARMONY, REWIND, EXSCEL, SUSTAIN-6, ELIXA, and PIONEER 6, have demonstrated either highly significant or close to significant reduction in overall mortality, 3-point major adverse cardiovascular events (MACE), nonfatal stroke, and myocardial infarction. At the same time, cardiovascular outcome trials with SGLT-2i, such as EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, CREDENCE, and VERTIS-CV, demonstrated either highly significant or close to significant reduction in 3-point MACE, heart failure hospitalization, and cardiovascular mortality.

      Marx N, Davies M, Grant PJ, et al. Positioning the novel therapeutics in diabetes care: time to integrate the recommendations. Lancet Diabetes Endocrinol, in press.

      Similarly, reduction in renal events have been noted with both classes of agents, and with canagliflozin, this was shown as a primary renal composite endpoint in the trial CREDENCE.
      • McKee A
      • Al-Khazaali A
      • Albert SG
      Glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter inhibitors for treatment of T2DM.
      Despite newly emerged evidence of cardiovascular and renal benefits of these drugs, in real life the number of patients receiving these potentially life-saving medications remain low, between 1% and 5%.
      • Dave CV
      • Schneeweiss S
      • Wexler DJ
      • Brill G
      • Patorno E
      Trends in clinical characteristics and prescribing preferences for SGLT2 inhibitors and GLP-1 receptor agonists, 2013-201.
      ,
      • Vaduganathan M
      • Patel RB
      • Singh A
      • et al.
      Prescription of glucagon-like peptide-1 receptor agonists by cardiologists.
      There are several reasons for such a low utilization of these drugs. First is inadequate recognition that they may and should be used for cardiovascular benefits regardless of glycemic control (Figure). These medications reduce glycosylated hemoglobin on average by 0.8-1.0%, whereas their cardiovascular benefits are lifesaving in many cases.
      • Dave CV
      • Schneeweiss S
      • Wexler DJ
      • Brill G
      • Patorno E
      Trends in clinical characteristics and prescribing preferences for SGLT2 inhibitors and GLP-1 receptor agonists, 2013-201.
      Figure
      FigureDual indications of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) for glycemic control and cardiovascular benefits. Cardiovascular benefits are proven for patients with type 2 diabetes regardless of the degree of their glycemic control. ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; HF = heart failure.
      As shown in the Figure, both classes of medications can be used for attaining glycemic goals, and for cardiovascular and renal benefits in appropriately selected patients regardless of glycemic control. Both classes of drugs have additional benefits in terms of weight management, and in fact, higher doses of GLP-1 receptor agonist liraglutide are approved for weight reduction.
      • Mehta A
      • Marso SP
      • Neeland IJ
      Liraglutide for weight management: a critical review of the evidence.
      In patients with type 2 diabetes and without cardiovascular disease or renal disease who are inadequately controlled with lifestyle interventions with or without metformin, either a GLP-1 receptor agonist or an SGLT-2i can be started or added to the therapy. Both classes of medications are effective and can be added consecutively if a third medication is needed. Glucagon-like peptide-1 receptor agonists can also be added to basal insulin therapy before meal-time insulin is considered.
      • Maiorino MI
      • Chiodini P
      • Bellastella G
      • Capuano A
      • Esposito K
      • Giugliano D
      Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.
      Furthermore, dual combination products containing basal insulin and GLP-1 receptor agonists are now available: glargine plus lixisenatide and degludec plus liraglutide.
      The strategy for use of these agents has evolved in patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease. If cardiovascular goals dictate the decision of starting these medications, their benefits are independent of the degree of metabolic control. If glycemic control is the primary objective, then using these medications confers additional cardiovascular and renoprotective benefits. Neither GLP-1 receptor agonists nor SGLT-2i induce hypoglycemia, but in patients already receiving insulin, the doses of the latter should be reduced when GLP-1 receptor agonist is added to the management. Most of the cardiovascular outcome trials indicate that patients with heart failure, especially with reduced ejection fraction, would derive greater benefit from SGLT-2i. However, GLP-1 receptor agonist medications may have greater beneficial impact on patients with atherosclerotic cardiovascular disease but without heart failure.
      The second obstacle for wider utilization of these drugs is their cost and the bureaucracy involved in the prescribing process. Recent analysis of 3992 Part D Medicare plans during the first quarter of 2019 demonstrated an average annual out-of-pocket cost of over $1000 for SGLT-2i and over $1500 for GLP-1 receptor agonists.
      • Luo J
      • Feldman R
      • Rothenberger SD
      • Hernandez I
      • Gellad WF
      Coverage, formulary restrictions, and out-of-pocket costs for sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in the Medicare Part D program.
      Furthermore, the uncompensated cost of dealing with insurance companies for pre-authorization of these medications for physician offices is prohibitive.
      • Huynh P
      • Toulouse A
      • Hirsch IB
      One-year time analysis in an academic diabetes clinic: quantifying our burden.
      What is now required is a comprehensive cost-effectiveness analysis with both classes of agents with consideration of medical outcomes in addition to the administrative costs to clinicians. The obvious goal is to minimize the administrative cost and burden so more patients can benefit from the proven outcomes of these drugs.
      In conclusion, although not as dramatic as the introduction of insulin into clinical medicine 100 years ago, GLP-1 receptor agonists and SGLT-2i stand to save lives of patients with type 2 diabetes, conferring significant cardiovascular and renoprotective benefits. These 2 classes of medications are now available for therapy of type 2 diabetes and should be used by all clinicians for glycemic, cardiovascular, and renal indications.

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