This column highlights recent clinical trial data and landmark trials to provide relevant information and links for obtaining trial data and articles to facilitate discussion with patients and other providers. The trial is identified by its acronym, its ClinicalTrials.gov Identifier (NCT Number) and its journal reference. When possible, the reference will include the study design paper and the main outcomes. If the Clinical Trial Study Group has made a slide set available, the link will be included. A summary provides primary outcome results. Selected abstracts also may be highlighted with a summary of the main points.
A Phase 3 Study to Evaluate the Safety of Sotagliflozin in Patients with Type 1 Diabetes Who Have Inadequate Glycemic Control with Insulin Therapy Alone
Study Title Acronym: inTandem3
ClinicalTrials.gov Identifier: NCT02531035
1. Sands, A.T., Zambrowicz, B.P., Rosenstock, J., Lapuerta, P., Bode, B.W., Garg, S.K., Buse, J.B., Banks, P., Heptulla, R., Rendell, M., Cefalu, W.T. and Strumph, P. (2015). Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes Care, 38(7), pp.1181-8. PMID: 26049551
2. Garg, S.K., Henry, R.R., Banks, P., Buse, J.B., Davies, M.J., Fulcher, G.R., Pozzilli, P., Gesty-Palmer, D., Lapuerta, P., Simó, R., Danne, T., McGuire, D.K., Kushner, J.A., Peters, A. and Strumph, P. (2017). Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med,377(24), pp.2337-2348. PMID: 28899222
Sponsor: Lexicon Pharmaceuticals
Study Design: Randomized parallel assignment of sotagliflozin vs. placebo
Primary Outcome Measure: A1c level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization
Results: The primary endpoint was achieved by 200 of 699 patients [28.6%] in the sotagliflozin group compared with 107 of 703 [15.2%] in the placebo group, P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for A1C (difference, −0.46 percentage points), weight (−2.98 kg), systolic blood pressure (−3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the two groups, while overall documented hypoglycemia with a blood glucose level of 55 mg per deciliter or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher (3.0% [21 patients] in the sotagliflozin group compared with the placebo group 0.6% [4 patients).
Summary: These data show that sotagliflozin could be a valuable adjunct therapy in T1D that would not only lower glucose but also weight and SBP. The challenge will be to determine how to predict, and prevent, DKA such that this compound could be used safely in patients with T1D.
Thiazolidinediones or Sulphonylureas and Cardiovascular Accidents.Intervention Trial
Study Title Acronym: TOSCA.IT
ClinicalTrials.gov Identifier: NCT00700856
Vaccaro, O., Masulli, M., Nicolucci, A., Bonora, E., Del Prato, S., Maggioni, A.P., et al., for the Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society. (2017). Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol, 5(11), pp.887-897. PMID: 28917544
Sponsor: Italian Society of Diabetology
Collaborators: Associazione Medici Diabetologi (AMD) and Associazione Nazionale Medici Cardiologi Ospedalieri
Study Design: Open-label randomized parallel assignment
Primary Outcome Measure: A composite endpoint including all-causes mortality, nonfatal MI (including silent MI), nonfatal stroke and unplanned coronary revascularization
Results: TOSCA.IT was a multicenter, randomized, pragmatic clinical trial in which patients ages 50 to 75 years with Type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1) by permuted blocks randomization, stratified by site and previous CV events, to add on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment.
In all, 3,028 patients were randomly assigned, with 1,535 assigned to pioglitazone and 1,493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]).
The study was stopped early on the basis of a futility analysis after a median follow-up of 57.3 months. The primary outcome occurred in 105 patients (1.5 per 100 person-years) who were given pioglitazone and 108 (1.5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79).
Fewer patients had hypoglycemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs. 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer and fractures were not significantly different between treatment groups.
Summary: Unfortunately, the study was stopped early for futility. Therefore, it is not able to prove CV safety of SUs. The futility may be related to the fact that event rates were very low and lower than what has typically been seen in recent CVOTs. However, it does provide safety data regarding both pioglitazone and SU with respect to CV events, rates of heart failure and TZD-specific events such as fractures and bladder cancer. Although there was no CV benefit, the safety data suggest that both pioglitazone and SUs should still be considered as part of combination therapy for glucose control.
Exenatide Study of Cardiovascular Event Lowering
Study Title Acronym: EXSCEL
ClinicalTrials.gov Identifier: NCT01144338
1. Holman, R.R., Bethel, M.A., George, J., Sourij, H., Doran, Z., Keenan, J., Khurmi, N.S., Mentz, R.J., Oulhaj, A., Buse, J.B., Chan, J.C., Iqbal, N., Kundu, S., Maggioni, A.P., Marso, S.P., Öhman, P., Pencina, M.J., Poulter, N., Porter, L.E., Ramachandran, A., Zinman, B. and Hernandez, A.F. (2016). Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Am Heart J, 174, pp.103-10. PMID: 26995376
2. Mentz, R.J., Bethel, M.A., Gustavson, S., Thompson, V.P., Pagidipati, N.J., Buse, J.B., Chan, J.C., Iqbal, N., Maggioni, A.P., Marso, S.P., Ohman, P., Poulter, N., Ramachandran, A., Zinman, B., Hernandez, A.F. and Holman, R.R. (2017). Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Am Heart J, 187, pp.1-9. PMID: 28454792
3. Holman, R.R., Bethel, M.A., Mentz, R.J., Thompson, V.P., Lokhnygina, Y., Buse, J.B., Chan, J.C., Choi, J., Gustavson, S.M., Iqbal, N., Maggioni, A.P., Marso, S.P., Öhman, P., Pagidipati, N.J., Poulter, N., Ramachandran, A., Zinman, B. and Hernandez, A.F.; EXSCEL Study Group. (2017). Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 377, pp.1228-1239. PMID: 28910237
Sponsor: Amylin Pharmaceuticals; AstraZeneca
Study Design: Randomized parallel assignment of 14752 participants allocated to exenatide once weekly or placebo
Primary Outcome Measure: Composite of cardiovascular death, nonfatal MI or nonfatal stroke
Results: After a median of 3.2 years, 839 of 7,356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and 905 of 7,396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group developed either CV death, nonfatal MI or nonfatal stroke (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00). Intention-to-treat analysis indicated that once-weekly exenatide was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from CV causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for ACS, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma and serious adverse events did not differ significantly between the two groups.
Summary: Unlike the liraglutide CVOT, this trial involving a different GLP-1 RA did not find a CV benefit for weekly exenatide. However, it is reassuring that there was no increase in hospitalization for heart failure, no increase in serious adverse events and no increase in medullary thyroid carcinoma. Therefore, this remains a valuable agent for glucose lowering, but does not have any additional nonglycemic benefits.
FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) Prespecified Analysis CV Safety and Efficacy of the PCSK9 Inhibitor Evolocumab in Patients with and without Diabetes and the Effect of Evolocumab on Glycaemia and Risk of New-Onset Diabetes
Study Title Acronym: FOURIER Diabetes
ClinicalTrials.gov Identifier: NCT01764633
1. Sabatine, M.S., Giugliano, R.P., Keech, A., et al. (2016). Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J, 173, pp.94-101. PMID: 26920601
2. Sabatine, M.S., Giugliano, R.P., Keech, A.C., Honarpour, N., Wiviott, S.D., Murphy, S.A., Kuder, J.F., Wang, H., Liu, T., Wasserman, S.M., Sever, P.S. and Pedersen, T.R.; FOURIER Steering Committee and Investigators. (2017). Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med, 376, pp.1713-1722. PMID: 28304224
3. Sabatine, M.S., Leiter, L.A., Wiviott, S.D., Giugliano, R.P., Deedwania, P., De Ferrari, G.M., Murphy, S.A., Kuder, J.F., Gouni-Berthold, I., Lewis, B.S., Handelsman, Y., Pineda, A.L., Honarpour, N., Keech, A.C., Sever, P.S. and Pedersen, T.R. (2017). Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol, 5, pp.941-950. PMID: 28927706
Study Design: Randomized placebo controlled parallel assignment of 27,564 participants
Primary Outcome Measure: FOURIER: The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or coronary revascularization, whichever occurs first.
Prespecified Diabetes Analysis:
1. CV efficacy and safety of evolocumab by baseline diabetes status: composite of CV death, MI, stroke, coronary revascularisation or hospital admission for unstable angina
2. Risk of new-onset diabetes among patients who did not have diabetes at baseline
Results: In all, 27,564 participants were randomized, of which 11,031 (40%) had diabetes and 16,533 (60%) did not have diabetes (of whom 10,344 had prediabetes and 6,189 had normoglycemia).
Evolocumab significantly reduced CV outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0.83 (95% CI 0.75–0.93; p=0·0008) for patients with diabetes and 0.87 (0.79–0.96; p=0·0052) for patients without diabetes.
Levels of A1C and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes or normoglycaemia. Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1.05, 0.94–1.17), including in those with prediabetes (HR 1.00, 0.89–1.13).
Summary: The two important points that were learned from this analysis are:
1. there is no increase in diabetes in people treated with this PCSK9 inhibitor; and
2. the addition of the PCSK9 inhibitor, evolocumab, to statin therapy for patients with diabetes whose LDL-C was not below 70 mg/dL is associated with a decrease in MACE with a benefit that starts in the first year then increases dramatically after the first year of therapy.
Based on these data, one needs to consider PCSK9 therapy for anyone with diabetes and a history of ASCVD who has not attained an LDL-C below 70 on statin therapy. However, because the CV event rates was not lowered to that of the participants without diabetes it seems reasonable to conclude that there are more factors that must be considered for CV prevention in people with diabetes.
Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial
Study Title Acronym: CONCEPTT
ClinicalTrials.gov Identifier: NCT01788527
1. Feig, D.S., Asztalos, E., Corcoy, R., De Leiva, A., Donovan, L., Hod, M., Jovanovic, L., Keely, E., Kollman, C., McManus, R., Murphy, K., Ruedy, K., Sanchez, J.J., Tomlinson, G. and Murphy, H.R.; CONCEPTT Collaborative Group. (2016). CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial – Study protocol. BMC Pregnancy Childbirth, 16, p.167. Erratum in: BMC Pregnancy Childbirth, 16, p.249. PMID: 27430714
2. Feig, D.S., Donovan, L.E., Corcoy, R., Murphy, K.E., Amiel, S.A., Hunt, K.F., Asztalos, E., Barrett, J.F.R., Sanchez, J.J., de Leiva, A., Hod, M., Jovanovic, L., Keely, E., McManus, R., Hutton, E.K., Meek, C.L., Stewart, Z.A., Wysocki, T., O’Brien, R., Ruedy, K., Kollman, C., Tomlinson, G. and Murphy, H.R.; CONCEPTT Collaborative Group. (2017). Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial. Lancet, 390, pp.2347-2359. Erratum in: Lancet, 390(10110), p.2346. PMID: 28923465
Sponsor: Mount Sinai Hospital, Canada
Collaborators: Sunnybrook Research Institute; Jaeb Center for Health Research; Cambridge University Hospitals NHS Foundation Trust; University of Cambridge
Funding Obtained From: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network and National Institute for Health Research.
Study Design: Multicenter, open-label, randomized controlled trial with parallel trials for pregnant participants and participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone with randomization stratified by insulin delivery (pump or injections) and baseline A1C.
Primary Outcome Measure: Change in A1C from randomization to 34 weeks’ gestation in pregnant women and to 24 weeks or conception in women planning pregnancy
Results: In all, 325 women (215 pregnant, 110 planning pregnancy) were randomized as follows:
• capillary glucose monitoring with CGM: 108 pregnant and 53 planning pregnancy; and
• capillary glucose monitoring without CGM: 107 pregnant and 57 planning pregnancy).
There was a small difference in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs. 61%; p=0·0034) and less time hyperglycemic (27% vs. 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycemia episodes (18 CGM and 21 control) and time spent hypoglycemic (3% vs. 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 hours (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycemia (0·45; 0·22 to 0·89; p=0·0250), and one-day shorter length of hospital stay (p=0·0091). The primary outcome did not demonstrate an apparent benefit of CGM in women planning pregnancy.
Summary: This study shows that use of CGM in pregnancy does increase time in range and decreases hyperglycemia. Interestingly, there was no decrease in hypoglycemia, although the time below range was very low at 3-4%. Based on these data, one could argue that use of CGM should now be standard of care for all pregnant women who have Type 1 diabetes.
It is interesting that the group planning for pregnancy did not show a benefit when using CGM. It would be of interest to compare these women to age-matched controls who are not planning for pregnancy to see if their overall control was better than one would expect for their age.
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About our expert: Kathleen Wyne, MD, PhD, FACE, FNLA, Associate Professor, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH