CARMELINA - Linagliptin in type 2 diabetes

Rosenstock J, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA

Bottom line: In patients with type 2 diabetes with additional risk for CV or renal adverse events, linagliptin did not reduce the risk of CV events, nephropathy or retinopathy vs placebo over 2.2 years. Linagliptin may increase the risk of acute pancreatitis (NNH 500).

This is consistent with all other trials of DPP-4 inhibitors showing no clinical benefit from this class of medications.

Patients (n=6991)

  • Included

    • Adults with T2DM with HbA1c 6.5-10.0%

    • + antihyperglycemic meds stable for at least 2 months

    • + either high CV or renal risk

      • High CV risk: Existing CAD/stroke/PAD, or micro/macroalbuminuria (urinary albumin:creatinine ratio [UACR] >30 mg/g)

      • High renal risk: eGFR 15-45, or eGFR 45-75 + UACR >200 mg/g

  • Key exclusion criteria

    • ACS/PCI/CABG in last 2 months or PCI/CABG planned

    • Stroke/TIA in last 3 months

  • Typical baseline characteristics

    • 66 y/o, male (62%), white (80%)

    • Diabetes mean duration 15 y, HbA1c 8.0%

    • Ischemic heart disease (27%), HF (27%)

    • eGFR mean 55 mL/min/1.73 m^2: 30-45 (28%), <30 (15%)

    • Meds:

      • Antihyperglycemics: Insulin (58%), metformin (54%), sulfonylurea (32%)

      • ASA (62%), statin (72%), ACEI/ARB (81%)

Intervention & control

  • I: Linagliptin 5 mg PO daily

  • C: Matching placebo

  • Co-interventions: Glycemic control using most available antihyperglycemics (no DPP-4i, SGLT2i or GLP-1 receptor agonists)

Results @ median 2.2 years

Efficacy

  • No reduction in the original primary outcome (“4-point MACE” a composite of CV death, MI, stroke, or hospitalization for unstable angina): Linagliptin 13.3%, placebo 13.2%

    • Hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.88-1.13

    • CV death: 7.3% vs 7.6%

    • Non-fatal MI: 4.5% vs 3.9%

    • Non-fatal stroke: 1.9% vs 2.1%

    • UA hospitalization: 1.2% vs 1.4%

    • Consistent lack of benefit in all subgroups (if anything, HR 1.20 in pts with baseline HbA1c >8%)

  • No effect on death from any cause: 10.5% vs 10.7% (HR 0.98, 95% CI 0.84-1.13)

  • No reduction in kidney outcomes (composite of death due to kidney disease, end-stage renal disease, or sustained -50% eGFR): 6.6% vs 6.5% (HR 0.98, 0.82-1.18)

  • No reduction in retinopathy: 1.0% vs 1.4% (HR 0.73, 95% CI 0.47-1.12)

Safety

  • Serious adverse events: 37.0% vs 38.5%

  • D/C due to adverse event: 10.3% vs 11.5%

  • Possible increase in acute pancreatitis: 0.3% vs 0.1% (NNH 500)

  • No increase in HF hospitalizations: 6.0% vs 6.5% (HR 0.90, 0.74-1.08)

Surrogate outcomes vs placebo

  • HbA1c: At month 3: -0.5%; over entire trial: -0.36%

  • No difference in weight, SBP, DBP, LDL-C, HDL-C

Internal validity

  • Low risk of allocation, performance, detection bias:

    • Computer-generated random sequence;

    • Block-randomized by interactive phone/web system;

    • Participants, clinicians & investigators blinded;

    • Central adjudication of CV & renal events by committee unaware of treatment allocation.

  • Low risk of attrition bias for CV outcomes & death, but unclear for renal outcomes:

    • Low loss-to-follow-up (LTFU) of 0.3% for mortality & 1.3% for CV events, but high (12%) LTFU for kidney outcomes;

    • Modified intention-to-treat (mITT) including all patients as randomized who received study drug for at least 1 dose.

DECLARE-TIMI 58 - Dapagliflozin & CV events in type 2 diabetes

Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM

Bottom line: In patients with type 2 diabetes with existing ASCVD or with multiple CV risk factors, dapagliflozin did not reduce the risk of a composite of major adverse cardiovascular events; however, it did reduce the risk of HF hospitalizations (NNT 125) at 4.2 years. Dapaglifozin increases the risk of fungal genital infections (NNH 125) & DKA (NNH 500).

Overall assessment of the evidence for SGLT2 inhibitors shows several differences between agents in this class; empagliflozin appears to have the greatest potential for benefit, whereas canagliflozin has the highest potential for harm.

Context: Summaries of EMPA-REG with empagliflozin & CANVAS with canagliflozin

Patients (n=17,160)

  • Included

    • T2DM with HbA1c 6.5%-12.0%

    • + CrCl 60+ mL/min

    • + either

      • Established atherosclerotic cardiovascular disease (ASCVD; IHD, ischemic CVA, PAD) & 40+ y/o

      • Multiple risk factors: Male 55+ y/o or female 60+ y/o + tobacco use, HTN, or LDL >3.3 mmol/L

  • Key exclusion criteria:

    • Adherence <80% during run-in or considered “at risk for poor medication adherence”

    • Previous SGLT2 inhibitor use

    • Steroid use with equivalent of prednisone 10+ mg/d

    • ACS, decompensated HF or stroke within 8 weeks

    • BP >180/100

    • Recurrent UTIs

  • Baseline characteristics:

    • 64 y/o, male (63%), white (80%), North American (32%)

    • ASCVD (41%): CAD (33%), PAD (6%), CVA (8%)

    • HF (10%)

    • Diabetes duration median 11 y,

    • HbA1c median 8.3%

    • BP 135/85

    • eGFR 85 (7% with eGFR <60)

    • Meds

      • Antihyperglycemics: Metformin (82%), sulfonylurea (43%), insulin (41%), DPP-4i (17%), GLP1 agonist (4%)

      • ASA (61%), ACEI/ARB (81%), beta-blocker (53%), statin or ezetimibe (75%), diuretic (41%)

Intervention & control

  • I: Dapagliflozin 10 mg once daily

  • C: Matching placebo

  • Co-interventions: Other antihyperglycemics per standard of care, excluding SGTL2i or glitazones

Results @ median 4.2 years

Efficacy

  • No reduction in major adverse cardiovascular events (composite of CV death, MI or ischemic stroke): Dapagliflozin 8.8% vs placebo 9.4%

    • Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03

    • CV death: 2.9% in both groups

    • MI: 4.6% vs 5.1% (HR 0.89, 95% CI 0.77-1.01)

    • Ischemic stroke: 2.7% in both groups

  • Reduction in composite of CV death or HF hospitalization: 4.9% vs 5.8%

    • HR 0.83 (95% CI 0.73-0.95)

    • Driven by a reduction in HF hospitalization: 2.5% vs 3.3% (NNT 125, HR 0.73, 95% CI 0.61-0.88)

    • Originally a secondary outcome; switched to co-primary outcome before unblinding of outcomes due to favorable results on this outcome in EMPA-REG & CANVAS.

  • No reduction in death: 6.2% vs 6.6% (HR 0.93, 95% CI 0.82-1.04)

Safety

  • Increased:

    • Diabetic ketoacidosis (DKA): 0.3% vs 0.1% (NNH 500; HR 2.18, 95% CI 1.10-4.30)

    • Genital infection (generally fungal): 0.9% vs 0.1% (NNH 125)

  • Reduced:

    • Serious adverse events: 34.1% vs 36.2% (HR 0.91, 95% CI 0.87-0.96)

  • No difference in

    • D/C due to adverse event: 8.1% vs 6.9% (HR 1.15, 95% CI 1.03-1.28)

    • Amputation: 1.4% vs 1.3%

    • Symptomatic volume depletion: 2.5% vs 2.4%

    • UTI: 1.5% vs 1.6%

Effect on surrogate endpoints:

  • HbA1c -0.4%

  • Wt -1.8 kg

  • SBP/DBP -2.7/-0.7

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Computer-generated block-randomization sequence;

    • Centralized randomization by interactive voice/web response system to blinded kit containing intervention or matching placebo;

    • Low loss-to-follow-up (0.3%);

    • Analyzed by intention-to-treat.

  • Single-blind (patient) placebo run-in phase lasting 4-8 weeks to assess for non-adherence

    • Unclear risk of selection bias: 25,698 entered run-in phase -> 17,160 randomized (i.e. high rate of exclusion during placebo run-in)

Other Evidence

  • A meta-analysis of the 3 major CV outcome trials of SGLT2 inhibitors (CANVAS, DECLARE & EMPA-REG) shows the following overall patterns:

    • CV efficacy

      • Only empagliflozin clearly reduces all-cause & CV mortality (in patients with existing ASCVD, RRR 32%);

      • SGLT2 inhibitors reduce the risk of major adverse CV events (composite of CV death/MI/stroke) in patients with existing ASCVD (RRR 14%), but not in those without ASCVD;

      • SGLT2 inhibitors do not reduce/increase stroke;

      • All SGLT2 inhibitors reduce the risk of HF hospitalization (RRR ~30%), regardless of prior ASCVD or HF.

    • Safety

      • All SGLT2 inhibitors increase the risk of DKA (RR increase by 120%);

      • Only canagliflozin increases the risk of amputations (RR increase 26%) & fractures (RR increase by 11%).

LEADER - Liraglutide in diabetes with high CV risk

Liraglutide and cardiovascular outcomes in type 2 diabetes. NEJM 2016;375:311-22.

Bottom line: In patients with T2DM & high CV risk (~4%/year), liraglutide reduced the risk of death, MI or stroke (NNT ~50) over ~4 years versus placebo.

Notes:

  • Liraglutide's efficacy is not clearly due to its antihyperglycemic effect, but it should likely be considered as a 3rd-line agent (after metformin & empagliflozin) for patients with T2DM above their individualized A1c target;

  • Small trials raise concern for CV safety of liraglutide in HFrEF. I will personally avoid using this drug (or any GLP-1 agonist) in HFrEF until better data shows that it's safe.

 

Patients (n=9340)

  • Included
    • Type 2 diabetes (T2DM) with A1c 7% or more
    • Either
      • Age 50 y/o or greater +
        • CAD (no ACS <14 days of enrolment)
        • Cerebrovascular disease (no stroke/TIA <14 days of enrolment)
        • Peripheral vascular disease
        • HF NYHA functional class 2-3
        • CKD stage 3-5
      • Age 60 y/o or greater +
        • Micro- or macroalbuminuria
        • HTN + LVH
        • LV systolic or diastolic dysfunction
        • ABI <0.9
  • Baseline characteristics
    • Age 64 y
    • Male 64%
    • Diabetes duration ~13 y
    • PMHx
      • MI 30%
      • Stroke/TIA 16%
      • Prior revascularization 39%
      • Symptomatic CAD 9%, documented asymptomatic cardiac ischemia 26%
      • HF 14%
      • >60 y/o with micro/macroalbuminuria (11%), HTN+LVH (5%), ABI<0.9 (<3%)
    • Clinical variables
      • Wt 92 kg
      • BMI 32.5
      • BP 136/77
    • Labs
      • A1c 8.7%
      • eGFR 30-59 (21%), <30 (<3%)

 

Interventions

  • I: Liraglutide (started at 0.6 mg subcutaneously daily, uptitrated as tolerated to 1.8 mg)
    • Median dose 1.78 mg/d
  • C: Placebo
  • Patients in both groups received standard-of-care therapy to lower BP (<130/80), glucose (A1c <7%) & lipids (statin for all patients; LDL-C <2.6 mmol/L if no ASCVD, <1.8 mmol/L if ASCVD)
    • Patients in liraglutide generally had a negligibly fewer initiation medications for these risk factors during trial (e.g. statins initiated in 11% on placebo vs 9.4% on liraglutide), except for insulin initiation (started in 43% on placebo vs 29% on liraglutide)
  • Median duration of therapy 3.5 years

 

Results @ median 3.8 years

  • Composite renal outcome: 15% vs 19%, HR 0.78 (0.67-0.92)
    • Death due to renal disease: 0.4% vs 0.3%, HR 1.59, (0.52-4.87)
    • Dialysis start: 3.1% vs 3.4%, HR 0.87 (0.61-1.24)
    • Persistent doubling of SCr: 4.9% vs 5.5%, HR 0.89 (0.67-1.19)
    • New-onset persistent macroalbuminuria: 0.9% vs 12.1%, HR 0.74 (0.60-0.91) - the least important component of the composite renal outcome, & the only one driving the significant difference
  • Safety
    • Serious adverse events: Liraglutide 49.7%, placebo 50.4%
    • Any adverse event: 62.3% vs 60.8% (p=0.12)
    • Severe hypoglycemia: 2.4% vs 3.3% (p=0.02)
    • Acute gallstone disease (cholecystitis or cholelithiasis): 3.1% vs 1.9% (p<0.001)
    • Acute pancreatitis: 0.4% vs 0.5%
    • Pancreatic carcinoma: 0.3% vs 0.1% (p=0.06)
  • Surrogates
    • @ 3 months: Liraglutide ~7.2%, placebo ~8.2%; difference decreased over time (A1c 0.4% lower with liraglutide on average through trial)
    • Wt 2.3 kg lower with liraglutide vs placebo
    • HR 3 bpm higher with liraglutide vs placebo

 

Generalizability

  • This trial represents a population of patients with long-standing diabetes (~13 years) with suboptimal glycemic control (baseline A1c 8.7%) at very high CV risk (primary outcome rate ~4%/year with placebo)
    • The relative risk reduction for the primary outcome components are likely generalizable to a lower-risk population, though this will ultimately lead to a lower absolute benefit (larger NNT) & perhaps no/minimal reduction in death
  • This trial did not evaluate a "more vs less intensive" glycemic control; it randomized patients with diabetes to liraglutide, which lowers glucose, among many other things, or placebo
    • The liraglutide had better glycemic control than placebo by ~1% at 3 months, but the trial's glycemic control protocol later resulted in much smaller differences in A1c between group
    • The benefit of liraglutide in this setting may be related to improved glycemic control, weight loss, other improvements in metabolic parameters, or to a yet-undefined mechanism
  • Heart failure
    • Only 14% of patients enrolled in this trial had HF, which was not limited to patients with reduced ejection fraction/LV dysfunction. Two small trials raise concerns about the use of liraglutide in individuals with HF:
      • FIGHT: This double-blind RCT of 300 patients evaluated the effect of liraglutide vs placebo in patients with HFrEF (HF with LVEF 40% or lower) hospitalized for HF in the previous 2 weeks on clinical outcomes & LVEF, with or without T2DM. After 6 months, liraglutide did not improve the primary outcome, LVEF, distance on a 6-minute walk test, quality of life, or NT-proBNP. There was, however, a concerning increase in the secondary outcome of death, re-hospitalization/ED visit for CV reasons (liraglutide 63%, placebo 55%, HR 1.34 [1.00-1.80])
      • LIVE: Similarly, this double-blind RCT of 241 patients evaluated the effect of liraglutide vs placebo in patients with stable HFrEF (<45%) NYHA class 1-3 on LVEF. Liraglutide did not significantly improve LVEF or any other echocardiographic measurement vs placebo, but it did increase the risk of cardiac serious adverse events (10% vs 3%, p<0.05). Notably, this was a heterogeneous collection of outcomes that included VT death, VT, AF requiring DC cardioversion, ACS, worsening HF.

Internal validity

  • Risk of bias
    • Low risk of allocation & detection bias
      • Allocation concealment maintained by computerized central allocation
      • Blinding with matching placebo
      • All macrovascular & microvascular outcomes adjudicated by company blind to assigned study intervention
    • Low risk of performance bias
      • Blinding with matching placebo
      • Standardized protocols to control CV risk factors
      • More patients in the placebo group received intensification of medications to reduce CV risk factors (likely because liraglutide produced mild improvements in metabolic parameters), particularly antihyperglycemic agents such as insulin, though this should produce a "conservative bias" towards the null in favor of the placebo group
    • Low risk of attrition bias
      • Analyzed by intention-to-treat
      • Low loss-to-follow-up (3.2% did not complete trial follow-up; 0.3% for mortality)
  • Use of composite primary outcome was completely appropriate
    • All components important (even silent MI is prognostically important)
    • Biologically rational to combine these macrovascular outcomes with overlap in pathophysiology
    • Similar contribution from each component of the composite outcome; MI and stroke both had estimates of effect nearly identical to that of the composite (HR ~0.86), making it appropriate to conclude that liraglutide reduced the risk of the composite, as well as each of the individual components
  • 2-week placebo run-in period to exclude early non-adherence to subcutaneous injections
    • Not a source of bias, but does exclude those individuals least likely to be adherent long-term
  • Per FDA guidance, designed to first prove non-inferiority trial of liraglutide vs placebo (to ensure CV safety to avoid issues as seen with other diabetes drugs rosiglitazone), then - if safe - to show superiority 
    • Not a source of bias; pre-defined & appropriate

Fibrates for CV prevention

References: ACCORD Lipid, FIELD

Bottom-line:

  • In patients taking a statin, the addition of a fibrate does not significantly reduce the risk of CV events.

  • In patients at intermediate-to-high CV risk who are absolutely not able to take a statin, fibrate therapy reduces the relative risk of non-fatal, but not fatal, CV events by ~20%.

    • In my opinion, ezetimibe & bile-acid sequestrants (& soon possibly PCSK9 inhibitors) should be considered before fibrates in these patients.

Patients

Intervention

  • FIELD: Fenofibrate vs matching placebo
    • Fenofibrate given as 200 mg (micronized formulation) PO once daily
    • Non-study lipid-lowering drug: Fenofibrate group 8%, placebo group 17%
    • ~20% in each group discontinued study drug by end of study
  • ACCORD Lipid: Fenofibrate + simvastatin vs simvastatin + matching placebo
    • Fenofibrate given as 160 mg PO once daily
    • Average dose of simvastatin 20 mg/d in both groups (open-label, adjusted to lipid targets)
    • Fenofibrate discontinued in 22%, placebo discontinued in 19% by end of study; ~20% in each group discontinued simvastatin by end of study

Results @ ~5 years

Internal validity

  • Both trials at low risk of bias (including allocation, performance, detection, & attrition bias)
    • Central randomization
    • Patients, clinicians, investigators, adjudicators all blinded to treatment allocation
    • Loss-to-follow-up <1%
    • Analyzed using intention-to-treat principles

Generalizability

  • FIELD represents the effects of fibrate monotherapy in a population with type 2 diabetes at mostly intermediate risk of CV events (estimated ~10-12% over 10 years)
    • Mechanistically, primarily testing the mechanistic effect of lowering triglycerides by ~30% over placebo, as effect on both LDL & HDL modest
  • ACCORD Lipid represents the effects of adding a fibrate to a statin in a higher-risk population of patients with type 2 diabetes (estimated ~25% over 10 years without statin)
    • Again, primarily testing the mechanistic effect of lowering triglycerides, as no discernible effect on LDL or HDL

Other fibrate studies

  • VA-HIT: In 2531 men with CAD not receiving a statin, gemfibrozil lowered trigs by ~30% more than placebo. At a median 5.1 years, this resulted in a 4.4% absolute risk reduction in MI or coronary death (NNT 23).
  • BIP: In 3090 men with CAD not receiving a statin, bezafibrate increased HDL & lowered trigs by ~15% more than placebo. At a mean 6.2 years, this did not result in a statistically significant effect on MI or sudden death.
  • Subgroup analyses from these various trials have provided more confusion than clarity. For example, some studies demonstrate an interaction by baseline triglycerides (VA-HIT, BIP), but not others (FIELD, ACCORD Lipid). The ACCORD Lipid study, but not the BIP trial, found a subgroup interaction based on the combination of low HDL and high trigs.
  • A systematic review of 18 fibrate trials, including the ones already mentioned here, found results largely consistent with the FIELD trial:
    • No reduction in death or fatal CV events;
    • Reduction in CV events, entirely driven by non-fatal coronary events (i.e. non-fatal MI & coronary revascularization): Relative risk 0.81 (0.75-0.89);
    • 5% relative risk reduction in coronary events per 0.1 mmol/L reduction in triglycerides;
    • Notably, ACCORD Lipid was the only trial included in this systematic review which had routine statin administration.