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Editorial| Volume 38, ISSUE 6, P1274-1278, June 2016

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Evidence for Good Cardiovascular Outcomes among Patients with Type 2 Diabetes, and Promising Treatment for Patients with Type 1 Diabetes

      This past fall, at the 51st Annual Meeting of the European Association for the Study of Diabetes (EASD), the results of the (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOMES) study were formally released. Launched in September 2010, EMPA-REG OUTCOMES was a safety profile trial, as mandated by the US Food and Drug Administration (FDA) in its 2008 Guidance for Industry, titled, “Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.”

      US FDA. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed April 26, 2016.

      The guidance produced recommendations for finding that a new type 2 diabetes therapy is not associated with an unacceptable increase in cardiovascular risk. Therefore, EMPA-REG was designed to determine the long-term cardiovascular safety profile of empagliflozin and potential benefits of the selective sodium glucose-cotransporter (SGLT)-2 inhibitor on macrovascular and microvascular outcomes.
      • Zinman B.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOMETM).
      SGLT-2 inhibitors block the reabsorption of glucose in the kidneys, thereby promoting excretion of excess glucose in the urine. Through this mechanism, drugs in the SGLT-2 inhibitor class, which includes canagliflozin, dapagliflozin, and empagliflozin, are thought to control glycemia independently of insulin pathways with a low risk of hypoglycemia.
      • Inzucchi S.E.
      • Zinman B.
      • Wanner C.
      • et al.
      SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
      The results of the EMPA-REG OUTCOMES study were well described by the study team in the recent literature, but, briefly, the primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Eligible patients were required to be diagnosed with type 2 diabetes, to be at least 18 years of age, and to have a high cardiovascular risk. Patients were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily. Patients in the 2 empagliflozin groups were pooled in analysis. Of 7020 patients treated over the course of 3.1 years, patients in the empagliflozin group experienced significantly lower rates of death from cardiovascular causes (3.7%, versus 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction).
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      Dr. Silvio Inzucchi, who presented the EMPA-REG OUTCOMES study results at the EASD meeting, received several rounds of enthusiastic applause from the large audience, one round for each of the slides that illustrated the differences between empagliflozin and placebo for the primary outcome, death from cardiovascular causes, death from any cause, and hospitalization from heart failure. From these data, and the excitement evident in the audience, empagliflozin represents a promising therapeutic strategy to target patients with type 2 diabetes and established cardiovascular disease despite an increased rate of genital infection. No other increase in adverse events were observed for patients who received empagliflozin in this trial.
      Recent evidence of an increase in lower limb amputations from the Canagliflozin Cardiovascular Assessment Study (CANVAS), a long-term trial to investigate the safety profile of canagliflozin related to cardiovascular disease, prompted the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency to investigate whether canagliflozin causes an increase in lower limb amputations. Patients recruited into CANVAS were required to have type 2 diabetes; be at least 30 years of age, somewhat older than patients who participated in the EMPA-REG OUTCOMES study; with a history of cardiovascular event, or at least 50 years old with a high risk of cardiovascular events. Despite the differences in lower ages between the 2 trials, the mean ages of patients randomized to receive treatment were similar; the mean age of patients in the EMPA-REG OUTCOMES in the pooled empagliflozin group was 63.1 years and 63.2 years in the placebo group
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      compared with a mean of 62.4 years for all patients randomly assigned to treatment in the CANVAS study.
      • Neal B.
      • Perkovic V.
      • de Zeeuw D.
      • et al.
      Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.
      At this time, the European agency’s PRAC is considering extending its investigation to all approved SGLT-2 inhibitors.
      Another safety profile trial, this one for liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation (LEADER) trial, was briefly described in a March 4, 2016, press release from its manufacturer.

      Novo Nordisk. Victoza® significantly reduces the risk of major adverse cardiovascular events in the LEADER trial. http://www.novonordisk.com/media/news-details.1991879.html. Accessed April 26, 2016.

      The press statement suggests that the trial met the primary end point of finding noninferiority and superiority of liraglutide to placebo with a statistically significant reduction in cardiovascular risk over a period of up to 5 years in >9000 adults with type 2 diabetes at high risk of major adverse cardiovascular events. Lirglutide, a glucagon-like peptide (GLP)-1 receptor agonist, stimulates postprandial insulin secretion and acts as an incretin hormone, thus potentiating glucose-stimulated insulin release and suppressing food intake in humans.
      • Harder H.
      • Nielsen L.
      • Thi T.D.T.
      • et al.
      The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes.
      Detailed results from the LEADER trial will be presented at the 76th Scientific Sessions of the American Diabetes Association (ADA) in June 2016. Clinical Therapeutics will report from the ADA meeting and will broadcast our impressions of the LEADER study results and other emerging diabetes research from the floor of the meeting on social media. We encourage readers to follow us on Twitter at @clinthe during June 10–14, 2016, for our ADA coverage.
      Nevertheless, at this time, empagliflozin has generated excitement in the clinical community, and Clinical Therapeutics sought to examine the impact of empagliflozin in clinical practice from the perspectives of a cardiologist and endocrinologist. In this Diabetes Update, Professor Lars Rydén
      • Rydén L.
      • Shahim B.
      • Mellbin L.
      Clinical implications of cardiovascular outcome trials in type 2 diabetes from DCCT to EMPA-REG.
      of the Karolinska Institute in Stockholm contributes a commentary that describes the influence of the EMPA-REG OUTCOMES trial on cardiologists. Professor Rydén
      • Harder H.
      • Nielsen L.
      • Thi T.D.T.
      • et al.
      The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes.
      offers a foundational discussion of the outcomes from a series of important trials, with an explanation for why they resulted in noninferiority results, and the importance of EMPA-REG OUTCOMES in subsequent management of type 2 diabetes. Guntram Schernthaner, MD,
      • Schernthaner G.
      • Schernthaner-Righter M.H.
      • Schernthaner G.H.
      A critical analysis of the EMPA-REG OUTCOME Study: implications for future treatment strategies.
      builds on this discussion by describing the contributions of EMPA-REG OUTCOMES and other cardiovascular outcome trials of antidiabetes agents from the view of an endocrinologist. Dr. Schernthaner
      • Rydén L.
      • Shahim B.
      • Mellbin L.
      Clinical implications of cardiovascular outcome trials in type 2 diabetes from DCCT to EMPA-REG.
      suggests that SGLT2 inhibitors would be preferable to dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with cardiovascular disease, chronic kidney disease, and heart failure. On April 5, 2016, the FDA issued a safety profile review for 2 medications in the DPP-4 class, saxagliptin and alogliptin, because of the increased risk of heart failure, particularly among patients who already have heart or kidney disease.

      U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm. Accessed April 26, 2016.

      Sven Kohler, MD,
      • Kohler S.
      • Salsali A.
      • Hantel S.
      • et al.
      Safety and tolerability of empagliflozin in patients with type 2 diabetes.
      contributed a research report for this Diabetes Update which describes the safety profile of empagliflozin with the use of pooled data from 17 randomized, Phase I, II, and III clinical trials plus 6 extension studies, consisting of patients with type 2 diabetes treated with placebo (n = 3695), empagliflozin 10 mg (n = 3806), or empagliflozin 25 mg (n = 4782).
      We also highlight the research of Wayne Weng, PhD, and his colleagues
      • Weng W.
      • Liang Y.
      • Kimball E.S.
      • et al.
      Longitudinal changes in medical services and related costs in a single cohort of newly diagnosed type 2 diabetes patients, 2006 to 2012.
      who examined changes in medication treatment patterns, health care costs, and comorbidities over a 6-year period after a new diagnosis of type 2 diabetes, representing the first effort of its kind to follow a single US cohort of newly diagnosed patients with type 2 diabetes. In this cohort of 35,017 patients, Weng, et al
      • Weng W.
      • Liang Y.
      • Kimball E.S.
      • et al.
      Longitudinal changes in medical services and related costs in a single cohort of newly diagnosed type 2 diabetes patients, 2006 to 2012.
      presents changes in inpatient costs, outpatient utilization, outpatient services costs, and outpatient drug utilization. Apropos to the current public debate about prescription costs, Weng et al
      • Weng W.
      • Liang Y.
      • Kimball E.S.
      • et al.
      Longitudinal changes in medical services and related costs in a single cohort of newly diagnosed type 2 diabetes patients, 2006 to 2012.
      found a relatively small percentage of overall costs for antidiabetes medications from year 1 to year 6.
      In June 2015, investigators from the Inducing Remission in Type 1 Diabetes with Alefacept (T1DAL) trial introduced study results at the 75th Scientific Sessions of the ADA. Alefacept, a full human fusion protein binding to CD2 on T cells, was the first biological agent approved by the US FDA for the treatment of moderate-to-severe chronic plaque psoriasis.
      • Jenneck C.
      • Novak N.
      The safety and efficacy of alefacept in the treatment of chronic plaque psoriasis.
      The T1DAL trial was to determine whether alefacept slows or halts destruction of the β cells in the pancreas as a type 1 diabetes therapy. The efficacy and adverse effects of alefacept in the treatment of psoriasis were described elsewhere.

      Lebwohl M, Christophers E, Langley R, et al., Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol. 2003;139:719–727.

      T1DAL represents an important and new line of investigation for the management of type 1 diabetes, testing the hypothesis that specific targeting of memory T cells with alefacept will lead to sustained preservation of β-cell function.
      • Rigby M.R.
      • Harris K.M.
      • Pinckney A.
      • et al.
      Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients.
      In this Diabetes Update, we include a new analysis of T1DAL data, by Ashley Pinckney, MS, and her colleagues
      • Pinckney A.
      • Rigby M.R.
      • Keyes-Elstein L.
      • et al.
      Correlation between hypoglycemia, glycemic variability and c-peptide preservation after alefacept therapy in patients with type 1 diabetes: analysis of data from the T1DAL Trial.
      at the Immune Tolerance Network.
      The environment of therapies for the treatment and management of diabetes, both type 1 and type 2, continues to evolve, as the number of adults with diabetes worldwide has nearly quadrupled since 1980, with an increase in nearly every single country on the planet.
      NCD Risk Facator Collaboration (NCD-RisC)
      Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants.
      The updated Position Statement of the ADA and the EASD continues to recommend metformin as the first-line therapy and dual or triple combination therapy with metformin and other agents, including thiazolidine, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 receptor agonists, and insulin.
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      Nevertheless, the selection of drugs recommended by the ADA/EASD position statement is not universally available to patients with diabetes. For example, in some countries in sub-Saharan Africa, Eastern Europe, Asia, and South America, insulin is expensive relative to the total health care budget and has to compete with other demands, in particular, for antiretroviral drugs.
      • Gill G.V.
      • Yudkin J.S.
      • Keen H.
      • et al.
      The insulin dilemma in resource-limited countries. A way forward?.
      In a survey of 6 countries, Bangladesh, Brazil, Malawi, Nepal, Pakistan, and Sri Lanka, metformin was estimated to cost a single day’s wages, whereas 1 month of treatment with intermediate-acting insulin preparations were estimated to cost more than several days’ wages.
      • Mendis S.
      • Fukino K.
      • Cameron A.
      • et al.
      The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries.
      In the United States, the mean price of antidiabetes drug prescriptions increased from $56 in 2001 to $76 in 2007 because of increasing use and prescription prices for glitazones, ultra-short-acting insulins, long-acting insulins, exenatide, and sitagliptin.
      • Alexander G.C.
      • Sehgal N.L.
      • Moloney R.M.
      • et al.
      National trends in treatment of type 2 diabetes mellitus, 1994-2007.
      In this month’s Diabetes Update, Weng reports that antidiabetes drug costs for the patients in that cohort increased by 95.8% during the 6-year study.
      • Weng W.
      • Liang Y.
      • Kimball E.S.
      • et al.
      Longitudinal changes in medical services and related costs in a single cohort of newly diagnosed type 2 diabetes patients, 2006 to 2012.
      Among uninsured, publically insured and privately insured patients with type 2 diabetes, cost-related medication nonadherence represents a significant cause of substantially higher glycosylated hemoglobin levels than medication-adherent patients, with nonadherence rates ranging from 40% among patients without health insurance, 31% and 25% for patients with Medicaid and Medicare respectively, and 18% for privately insured patients.
      • Piette J.D.
      • Wagner T.H.
      • Potter M.B.
      • et al.
      Health insurance status, cost-related medication underuse, and outcomes among diabetes patients in three systems of care.
      Prescription assistance programs and reduced prescription copayments represent important mechanisms for making current-generation antidiabetes medications available to patients with limited financial resources. For example, by eliminating copayments for any patient without health insurance, we identified that the average proportion of days covered (PDC) for participating patients with type 2 diabetes was 70.55%, indicating an adequate level of medication adherence.
      • Ryan J.G.
      • Fedders M.
      • Jennings T.
      • et al.
      Clinical outcomes and incremental costs from a medication adherence pilot intervention targeting low-income patients with diabetes at risk of cost-related medication nonadherence.
      Thus, the medication nonadherence rate in our patient population of uninsured, financially challenged patients was 29.45% (PDC < 70.55%), suggesting that causes other than cost continued to contribute to inadequate medication-taking behaviors. Aside from inadequate medication-taking behavior because of cost-related reasons, access to nongeneric antidiabetes medications such as those discussed here may be limited or nonexistent among some low-income and uninsured patients, patients covered through highly restricted insurance plans in the United Staets,

      Chu C-F, Lal LS, Felder TM, et al. Evaluation of Patient Assistance Program Eligibility and Availability for Top 200 Brand Name and Generic Drugs in the United States. 2012. http://conservancy.umn.edu/handle/11299/122764. Accessed April 28, 2016.

      and patients in developing and other resource-poor countries.
      The ADA position statement and the American Association of Clinical Endocrinologists treatment guidelines for the management of type 2 diabetes both recommend self-management and medication management to obtain adequate diabetes control.
      • Bloomgarden Z.T.
      • Handelsman Y.
      Approaches to treatment 2: Comparison of American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) type 2 diabetes treatment guidelines.
      Although lifestyle interventions, including weight loss and increasing physical activity, are universally considered important for controlling diabetes, especially as a first-line therapy, the limited long-term success of lifestyle programs to maintain glycemic control among patients with type 2 diabetes suggests that most patients will benefit from an antidiabetes medication regimen to achieve adequate diabetes control.
      • Nathan D.M.
      • Buse J.B.
      • Davidson M.B.
      • et al.
      Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.
      Appropriate integration of recommended medication management depends on multiple factors at the patient, provider, and system levels, but system factors include patient access to medication. There are limited empirical data with which to describe the range of antidiabetes medications on the formularies of health care systems that serve high proportions of low-income, undocumented, and underinsured people, but anecdotal evidence suggests that prescribers in those systems are encouraged, either by policy or extra paperwork, to offer their patients only a narrow selection of antidiabetes medications, consisting of generics and perhaps a few branded options. Those decisions are typically made on a cost-effectiveness basis by hospital formulary committees, representing system barriers to accessing new generation antidiabetes medications. Therefore, the real-world implications of advanced antidiabetes medications, in terms of managing glycemia and reducing risk of poor outcomes, including death from cardiovascular causes, death from any cause, and hospitalization from heart failure, will be limited to those patients with access to these medications and who are willing to use them as prescribed.

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