BACKGROUND The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. METHODS We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. RESULTS A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P = 0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 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). There was no significant between-group difference in the key secondary outcome (P = 0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. CONCLUSIONS Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)

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Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

The American Diabetes Association and the European Association for the Study of Diabetes have briefly updated their 2018 recommendations on management of hyperglycemia, based on important research findings from large cardiovascular outcomes trials published in 2019. Important changes include: 1) the decision to treat high-risk individuals with a glucagon-like peptide 1 (GLP-1) receptor agonist or sodium-glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), cardiovascular death, or chronic kidney disease (CKD) progression should be considered independently of baseline HbA1c or individualized HbA1c target; 2) GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established cardiovascular disease (CVD) but with the presence of specific indicators of high risk; and 3) SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE, and CVD death, as well as in patients with type 2 diabetes with CKD (estimated glomerular filtration rate 30 to ≤60 mL min-1 [1.73 m]-2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE, and cardiovascular death.

/pdf/management-of-hyperglycemia-in-type-2-diabetes-2018-a-1u146pkf24.pdf

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)

BackgroundDiabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium–glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. MethodsWe randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. ResultsIncident or worsening nephropathy occurred in ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1515920

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient.

The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2).

Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

/pdf/management-of-hyperglycemia-in-type-2-diabetes-2015-a-4q16ecnrp1.pdf

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

/pdf/management-of-hyperglycemia-in-type-2-diabetes-2015-a-231ibsb3i5.pdf

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered Approach

OBJECTIVE We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM).

RESEARCH DESIGN AND METHODS Patients inadequately controlled on MDI insulin ± metformin (mean HbA1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m2; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg ( n = 186), empagliflozin 25 mg ( n = 189), or placebo ( n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1–18, adjusted to meet glucose targets in weeks 19–40, then stable in weeks 41–52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA1c at week 52.

RESULTS Adjusted mean ± SE changes from baseline in HbA1c were −0.50 ± 0.05% (−5.5 ± 0.5 mmol/mol) for placebo versus −0.94 ± 0.05% (−10.3 ± 0.5 mmol/mol) and −1.02 ± 0.05% (−11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA1c of −0.81 ± 0.08% (−8.9 ± 0.9 mmol/mol), −1.18 ± 0.08% (−12.9 ± 0.9 mmol/mol), and −1.27 ± 0.08% (−13.9 ± 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c <7% (<53 mmol/mol) with empagliflozin (31–42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (−9 to −11 international units/day) and weight (−2.4 to −2.5 kg) versus placebo (all P < 0.01) at week 52.

CONCLUSIONS In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.

https://care.diabetesjournals.org/content/diacare/37/7/1815.full.pdf

Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes

Background and Objective: Maintaining adequate glycaemic control reduces the long-term risk of some type 2 diabetes (T2D) complications. Despite this, many individuals with T2D do not have their treatment intensified and remain on suboptimal HbA1c targets. It is therefore important to consider which treatment will enable patients to maintain glycaemic control over time. To date, continuous patient-level data for duration of time spent with HbA1c < 7.0% (53 mmol/mol) and the likelihood of maintaining HbA1c < 7.0% in the PIONEER efficacy trials have not been reported. The PIONEER phase 3a clinical trial programme evaluated the efficacy and safety of oral semaglutide vs active comparators (empagliflozin, sitagliptin and subcutaneous [s.c.] liraglutide) and placebo in patients with T2D. – PIONEER 2–4 and 7 consistently demonstrated that greater proportions of patients achieved HbA1c < 7.0% at week 26 (or week 52 for PIONEER 7) with oral semaglutide compared with active comparators or placebo. Objective: This post hoc analysis of the PIONEER 2–4 and 7 trials aimed to determine the duration of time patients spent with HbA1c. Methods: Mean duration of time spent with HbA1c <7.0%. Proportion of patients achieving HbA1 <7.0% for different time intervals. Estimated odds ratio of achieving HbA1c <7.0% at week 26 (week 24 for PIONEER 7, as week 26 data were unavailable) and week 52 (and week 78 for PIONEER 3). Data are for all randomised patients from PIONEER 2–4 and 7 assigned to receive oral semaglutide or active comparator (empagliflozin, sitagliptin, s.c. liraglutide). Oral semaglutide dose was escalated, starting at 3 mg once daily and increasing to 7 mg after 4 weeks and then to 14 mg after 8 weeks in all trials except PIONEER 7, which used a flexible dose adjustment approach based on HbA1c and gastrointestinal tolerability. Empagliflozin was initiated at 10 mg and escalated to 25 mg after 8 weeks. Sitagliptin was initiated at 100 mg and not escalated. S.c. liraglutide was initiated at 0.6 mg and escalated to 1.2 mg and then 1.8 mg after 1 and 2 weeks, respectively. For each patient, duration of time spent with HbA1c <7.0% was calculated based on the HbA1c–time curve derived using all visits with HbA1c measurements and linear interpolation between two consecutive visits. Study visits were scheduled for every 4–8 weeks. Outcomes were evaluated for oral semaglutide vs active comparators using the on-treatment without rescue medication observation period. Patients who discontinued treatment early or who used rescue medication were considered not in glycaemic control after the event in question. Results: Mean baseline HbA1c ranged from 8.0 to 8.3% (64–67 mmol/mol). Across PIONEER 2, 3 and 7, mean duration of time spent with HbA1c <7.0% was greater with oral semaglutide 14 mg, or flexibly dosed, than with oral competitors empagliflozin 25 mg and sitagliptin 100 mg [Figure 2]. – Similar mean duration was observed between oral semaglutide and s.c. liraglutide 1.8 mg in PIONEER 4. There was a significantly greater likelihood of maintaining HbA1c <7.0% for >75% of the trial duration compared with empagliflozin 25 mg and sitagliptin 100 mg [Figure 3]. – Similar proportions were observed between oral semaglutide 14 mg and s.c. liraglutide 1.8 mg Summary: Oral semaglutide 14 mg, or flexibly dosed, resulted in a greater duration of time spent with HbA1c <7.0% vs empagliflozin and sitagliptin. Oral semaglutide 14 mg resulted in a similar duration of time spent with HbA1c < 7.0% to s.c. liraglutide, despite a longer dose escalation with oral semaglutide. The odds of maintaining HbA1c <7.0% at weeks 24/26 and 52 (and 78 for PIONEER 3) were significantly greater with oral semaglutide vs empagliflozin, sitagliptin and s.c. liraglutide. Conclusion: In patients with T2D, oral semaglutide may lead to longer sustained glycaemic control vs oral comparators, on an individual level

Guillaume Frappin

Papers

Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes

Abstract 171: Greater time spent in glycaemic control with oral semaglutide vs oral comparators