B P4 C31 Diabetes and the Cardiovascular System Flashcards
Diabetes mellitus (DM) involves _____, resulting in hyperglycemia.
Insufficient production of insulin
and/or
Failure to respond appropriately to insulin
Type 2 DM is characterized by insulin resistance and relative insulin deficiency (>90% of all DM cases), whereas type 1 is defined by _____.
Absolute insulin deficiency
ADA Diagnostic Criteria for DM
- Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hr.
Or
- Two-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
Or
- Glycated hemoglobin (A1c) ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay.
Or
- In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).
Patients with DM have a _____fold increased risk for CHD, CV mortality, all-cause mortality, and CV hospitalization compared with those without DM.
2-4 fold
Diabetes entails an increased risk for myocardial infarction (MI). Across the spectrum of acute coronary syndrome (ACS) events, in which DM may affect more than _____ in three patients, those with DM have worse CVD outcomes
1/3
Hyperglycemia affects approximately _____patients with acute stroke and is associated to a _____fold increased risk for adverse clinical outcomes.
1 in 3; 1/3
2-6 fold
CHD,DM increases the risks of stroke (twofold increase
In the ambulatory setting, DM associates independently with a _____fold increased risk for HF over that in persons without DM, and patients with DM have worse outcomes once HF has developed
2-5 fold
In patients with AF, DM increases stroke rate by _____%. The CHA2DS2–VASc score includes DM and guidelines recommend anticoagulation for all DM patients who have AF.
2-3.5%
Very high risk patients are those with DM and _____, as well as those with target organ damage such as left ventricular hypertrophy or chronic kidney disease (CKD)
Established CVD
Patients with DM and _____ major risk factors are also considered to be at very high risk, as multiple risk factors in DM increase risk including CV death
3 or more
The high-risk category includes those with DM duration _____ years without target organ damage plus any other additional risk factors.
Who are considered at moderate risk?
High risk:
>/= 10 years without target organ damage plus any other additional risk factors.
Moderate risk:
Younger patients (type 2 DM aged <50) with a DM duration less than 10 years and without other risk factors
The principal vascular perturbations linked to hyperglcemia include:
(1) endothelial vasomotor dysfunction
(2) vascular effects of advanced glycation end products (AGEs)
(3) adverse effects of circulating free fatty acids (FFAs),
(4) increased systemic inflammation
(5) prothrombotic state
The myriad mechanisms contributing to endothelial dysfunction include _____, all of which contribute to perturbations in the regulation of blood flow
(1) abnormal nitric oxide biology
(2) increased circulating endothelin and angiotensin II
(3) reduced prostacyclin (i.e., prostaglandin I2) activity
_____ characterize diabetic dyslipidemia, and contribute to aggravated atherosclerosis.
High triglyceride (TG) levels
Low levels of HDL-C
Increased small, dense LDL particles
Perturbations in the coagulation and fibrinolytic pathways and in platelet biology add to the prothrombotic risk in DM. These abnormalities include:
Increased circulating tissue factor, factor VII, von Willebrand factor, and PAI-1
Decreased levels of antithrombin III and protein C
__________ remain the pillar of prevention of the atherosclerotic complications in DM.
As recommended by the American Diabetes Association (ADA), American Heart Association (AHA), European Society of Cardiology (ESC), and European Association for the Study of Diabetes (EASD), therapeutic lifestyle targets include ______
Lifestyle interventions
- Smoking abstinence
- 150 minutes or more of aerobic activity weekly
- Weight control
- Healthy diet habits
Daily aspirin therapy is no longer recommended for patients with DM without ________, except in those with a very high ASCVD risk
Without established atherosclerotic cardiovascular disease (ASCVD)
Each component of the diabetic dyslipidemia profile associates independently with CVD risk, including _____.
Increased
Small, dense LDL particles
ApoB
TG
Decreased
HDL-C
Despite extensive research in modifying TG and HDL-C levels, the reduction of _____ remains the cornerstone of therapeutic lipid intervention in patients with DM.
LDL-cholesterol
Class I recommendations ACCF/AHA Recommendations for Secondary Prevention of CV Disease specific to patients with DM
Care for DM should be coordinated with the patient’s primary care physician and/or endocrinologist. (C)
Lifestyle modifications including daily physical activity, weight management, blood pressure control, and LDL cholesterol management are recommended for all patients with DM.(B)
ACE inhibitors (or ARBs for those with ACE inhibitor intolerance) should be started and continued indefinitely in patients with DM, unless contraindicated. (A)
Use of aldosterone blockade in post-MI patients without significant kidney dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, who have a left ventricular ejection fraction </=40% and DM. (A)
Class I recommendations according to the ACCF/AHA Recommendations for Management of Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction (UA/NSTEMI) and ST-Segment Elevation Myocardial Infarction (STEMI) in Patients with Diabetes
ACE inhibitors should be given and continued indefinitely for patients recovering from MI with diabetes unless contraindicated. (A)
Long-term aldosterone receptor blockade should be prescribed for patients with MI without significant renal dysfunction (estimated creatinine clearance should be >30 mL/min) or hyperkalemia (potassium should be <5 mEq/L) who are already receiving therapeutic doses of an ACE inhibitor, have an ejection fraction less than 40%, and have DM, with or without clinical heart failure. (A)
ACCF/AHA Recommendations for the Diagnosis and Management of Heart Failure in Patients with Diabetes
IC
For patients with DM (all of whom are at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines.
IC
Physicians should control systolic and diastolic hypertension and diabetes mellitus in patients with HF in accordance with recommended guidelines.
IIa (B)
Empagliflozin should be considered in patients with type 2 DM to prevent or delay the onset of HF and to prolong life.
IIa (C)
Treating dysglycemia should be considered to prevent or delay the onset of HF.
IIb (A)
ACE inhibitors can be useful to prevent HF in patients with DM.
IIb (C)
ARBs can be useful to prevent HF in patients with DM.
The 2018 Guideline on the Management of Blood Cholesterol endorsed by multiple groups recommends _____-intensity statin therapy in adults aged 40 to 75 years with DM regardless of estimated 10-year ASCVD risk.
Moderate intensity
Adults with DM who have multiple ASCVD risk factors or prevalent ASCVD should receive a _____-intensity statin with the aim to reduce LDL-C by 50%.
High intensity
Diabetic patients with very high CVD risk should achieve an LDL-C target of less than ___ mg/dL or achieve a decrease in LDL-C of at least 50%
55 mg/dL
Ezetimibe inhibits the intestinal cholesterol transporter _____.
Niemann-Pick C1-like 1 (NPC1L1)
Most other patients with DM are categorized as “high risk,” with an LDL-C target of at least less than ___ mg/dL.
70 mg/dL
The _____ Trial assessed the effect of more intensive LDL-C targets with simvastatin/ezetimibe versus standard target control using simvastatin in 18,144 patients following ACS events.19 After a mean follow-up of 5.7 years, ezetimibe/simvastatin yielded a significant 6.7% relative risk reduction (RRR) for the primary composite endpoint. In the subgroup of patients with DM, the beneficial effect on outcome was stronger than in patients without DM with a hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.78 to 0.94.20 The results in this subgroup were mainly due to a lower incidence of MI and ischemic stroke.
The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)
Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with antibodies such as alirocumab or evolocumab reduce LDL-C by _____% over statins,with similar effects in patients with or without DM
40-60%
The _____ trial showed a significant 15% RRR for the primary composite endpoint of CV death,MI,stroke,hospitalization for unstable angina,or coronary revascularization with evolocumab versus placebo in 27,564 patients with clinically evident CVD.23 At study baseline,11,031 patients (40%) had DM.
Evolocumab significantly and consistently reduced cardiovascular outcomes in patients with and without DM at baseline.
Evolocumab did not increase the risk of new-onset DM in patients without DM at baseline (HR, 1.05, 0.94 to 1.17), including patients with prediabetes (HR,1.00,0.89 to 1.13).23
FOURIER Trial
In the _____ trial, alirocumab significantly reduced the risk of the primary composite endpoint (CV death, MI, stroke, or hospital admission for unstable angina) compared with placebo, with an HR of 0.85 (95% CI 0.78, 0.93).24 In a subgroup analysis of patients with DM, alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycemic category, but a greater absolute risk reduction in the incidence of the primary outcome in patients with DM (2.3%, 95% CI 0.4 to 4.2) than in those with prediabetes (1.2%, 0.0 to 2.4) or normoglycemia (1.2%, −0.3 to 2.7; absolute risk reduction pinteraction=0·0019). Alirocumab did not increase the incidence of DM
ODYSSEY OUTCOMES Trial
Fibrates are agonists of the nuclear transcriptional regulator _____ that lower TGs and modestly increase HDL-C.
Peroxisome proliferator–activated receptor alpha (PPAR-a)
Omega-3 fatty acids (fish oil) can reduce circulating TGs up to _____%, and hold promise in the treatment of diabetic dyslipidemia.
40%
The _____ trial randomized 12,536 patients with impaired fasting glucose, impaired glucose tolerance, or DM who randomly received either a 1-g capsule containing at least 900 mg (90%) of ethyl esters of n-3 fatty acids or a capsule containing 1 g of olive oil daily. The primary outcome was CV mortality. Over a median follow-up of 6.2 years with 1155 CV deaths to analyze, there was no effect on the primary outcome with fish oil versus control (9.1% vs.9.3%,respectively; P = 0.72).
Outcome Reduction with an Initial Glargine Intervention (ORIGIN) Trial
However, the _____ trial examined a higher dose of highly purified eicosapentaenoic acid (icosapent ethyl, 2 g twice daily) in patients with established CVD or with DM and other risk factors, who had been receiving statin therapy and who had a fasting TG level of 135 to 499 mg/dL (1.52 to 5.63 mmol/L) and a LDL-C level of 41 to 100 mg/dL (1.06 to 2.59 mmol/L). Compared with placebo, icosapent ethyl significantly reduced the combined endpoint of CV death, non-fatal MI, or non-fatal stroke with a HR of 0.75; (95% CI, 0.68 to 0.83) in the overall population, with a similar benefit in the sub- group of patients with DM
REDUCE-IT Trial
The subcutaneous injection of _____, a small interfering RNA that targets PCSK9 mRNA offers a novel strategy to reduce LDL-C.
Inclisiran
In the _____ trial inclisiran associated with marked declines in LDL-C in both patients without and with DM.
ORION-1
BP targets for patients with DM have historically been more aggressive than for the overall population, with a goal of less than _____ mmHg in patients with DM, and a target of less than _____ mmHg in those not tolerating the lower goal.
<130/80
<140/80
_____ are cornerstones of therapy for hypertension in DM because of their favorable effects on diabetic nephropathy and CVD outcomes
ACEi and ARBs
Data from randomized trials of patients with and without hypertension underpin the recommendation for _____ as first-line agents for treatment of hyper- tension in the patient with DM.
ACEi
The _____ trial compared ramipril (10 mg daily) with placebo in patients at increased risk for CVD and found that ramipril was superior to placebo in the DM subset of 3577 patients for the primary outcome of CV death, MI, and stroke (RRR, 25%; P = 0.004) and for overt nephropathy (RRR, 24%; P = 0.027).
Heart Outcomes Prevention Evaluation (HOPE)
The DM sub-analysis of the _____ trial, which tested perindopril versus placebo; showed an RRR of 19% among the 1502 participants with DM.
These results and those from meta-analyses support the consideration of ACE inhibitors for all patients with DM who have prevalent CVD, a clustering of CVD risk factors, or nephropathy with or without albuminuria.
EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease)
Data on CV outcomes with ARBs are much less robust than those on ACE inhibitors, particularly in patients with DM. The_____ trial enrolled 5926 patients with intolerance to ACE inhibitors, randomly assigned to receive telmisartan (80 mg daily) or placebo, 2118 of which had DM.30 The overall trial failed to achieve statistical superiority for telmisartan versus placebo on the primary composite of CVD death, MI, stroke, and HF hospitalization (HR, 0.92; 95% CI 0.81 to 1.05), with a completely neutral point estimate in the subset with DM
Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND)
In a sub-analysis of the _____ trial, the CVD effects of chlorthalidone compared with both lisinopril and amlodipine were similar in patients with DM or impaired fasting glucose, despite modest but statistically significant increases in incident DM associated with chlorthalidone use.
Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Indapamide combined with perindopril in the _____ trial of 11,140 patients with DM showed superior CV outcomes.
Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE)
The use of beta blockers should be primarily limited to patients with ____ (carvedilol, metoprolol succinate, or bisoprolol) and _____.
HFrEF and MI
Four classes of antihypertensive medications reduce CVD risk in patients with DM:
ACE inhibitors
ARBs
Calcium channel blockers
Thiazide diuretics (chlorthalidone, indapamide)
The ADA and AHA recommend daily aspirin (75 to 162 mg/day) for all patients with DM who have _____, with use for primary prevention no longer recommended, though it may be considered in those at very highest ASCVD risk.
Established ASCVD
The _____ trial enrolled 15,480 patients with DM without established ASCVD, randomized to aspirin 100 mg daily versus placebo.There was a modest risk reduction for the primary composite of vascular death, MI, or stroke (RR 0.88; 95% CI, 0.79 to 0.97) in the context of increased risk for major bleeding, (RR 1.29; 95% CI, 1.09 to 1.52), with bleeding hazard counterbalancing the benefits.
ASCEND
Though proven effective for patients following ACSs and coronary stenting, _____ remains the preferred therapy over P2Y12 receptor antagonists such as clopidogrel, prasugrel, or ticagrelor for chronic stable primary and secondary risk prevention.
Aspirin
For patients with type 2 DM and prevalent coronary artery disease but without prior MI, results from the _____ randomized trial demonstrated the net clinical benefit of ticagrelor 60 mg twice daily added to low-dose aspirin versus low-dose aspirin alone in the large sub- set of patients with prior coronary stenting (n = 11,154), leading to the conclusion that ticagrelor should be considered as an add-on to aspirin in patients with DM and a history of percutaneous coronary intervention (PCI) who have tolerated antiplatelet therapy, have high ischemic risk, and low bleeding risk. However, the reduction in the primary outcome was achieved at the expense of increased major bleeding, with a highly significant 2.3-fold increase in thrombolysis in myocardial infarction (TIMI) major bleeding, including intracranial bleeding.
THEMIS
Metformin, a biguanide, reduces blood glucose pri- marily by decreasing hepatic glucose output and perhaps by other mechanisms. Metformin, associated with:
Modest initial weight reduction
Favorable effects on lipid levels
Decrease in inflammatory markers
Improvement in coagulation profiles
Low risk for hypoglycemia
In the ____- of various glucose-lowering strategies in a population of patients with newly diagnosed type 2 DM, patients who were overweight at study entry were eligible for randomization to a policy of more intensive glucose control with metformin versus usual care.Those treated with metformin had statistically superior outcomes for all DM-related end- points (RRR, 32%; 95% CI 13% to 47%), DM-related death (RRR, 42%; 95% CI 9% to 63%), and all-cause mortality (RRR, 36%; 95% CI 9% to 55%).
United Kingdom Prospective Diabetes Study (UKPDS)
A second trial, the _____ study, randomized 390 patients with insulin-treated type 2 DM to metformin versus placebo. The effect on the primary composite outcome, including micro- and macrovascular complications, was neutral. However, the secondary outcome of major adverse CV events fell in the metformin group (RRR, 39%; 95% CI 6% to 60%), similar in magnitude to the macrovascular risk reductions seen in the UKPDS. Given the relatively small size and few CV events to analyze in both these trials, the CV efficacy of metformin remains uncertain, particularly in statin-treated patients.
HOME
The new cut points are based on the estimated glo-merular filtration rate (eGFR) instead of serum creatinine. Metformin is now given to patients with an eGFR less than 60 mL/min/1.73 m2, with safety reassessed for those taking metformin with an eGFR less than ___ mL/min/1.73 m2, and with metformin contraindicated or to be stopped at an eGFR less than ___ mL/min/1.73 m2.
Safety reassessment: <45 mL/min/1.73 m2
Discontinue: < 30 mL/min/1.73 m2
Regarding iodinated contrast administration, metformin need not be interrupted if the eGFR is greater than ___ mL/min/1.73 m2, but should still be held in patients whose kidney function is below this level until no decrement in kidney function can be documented.
No need to hold Metformin for EGFR > 60 mL/min/1.73 m2
On the basis of safety, tolerability, low hypoglycemia risk, CV clinical outcomes data, and relatively low cost, _____ is widely considered the first-line drug for type 2 DM in the absence of contraindications or intolerance.
Metformin
They lower glucose by augmenting insulin release through inhibition of adenosine triphosphate (ATP)–dependent potassium (KATP) channels in pancreatic beta cells.
Sulfonylureas
Although _____, a first-generation sulfonylurea, increased CV and all-cause mortality in an early randomized trial, no such adverse CV safety signals have emerged from subsequent randomized trials with assignment to second- and third- generation sulfonylureas.
Tolbutamide
In the _____ trial, while glimepiride was associated with significantly more hypoglycemia than the dipeptidyl peptidase 4 (DPP4) inhibitor (see below) linagliptin, major adverse CV events were equal between the two randomized groups. This finding is further evidence that glimepiride at least was safe for the heart, since as a group the DPP4 inhibitors are known to be safe themselves.
CAROLINA
_____ decrease glucose levels by increasing insulin sensitivity of target tissues and induce a wide variety of nonglycemic effects mediated through activation of the nuclear receptor PPAR- , including some favor- able effects on intermediate markers of CVD and CVD risk.
Thiazolidinediones (e.g., rosiglitazone, pioglitazone)
The _____ study assessed the effect of a glucose-lowering medication on CV clinical outcomes. Treatment with pioglitazone yielded a significant 16% RRR for the prioritized secondary composite major adverse cardiovascular event (MACE) endpoint of all-cause mortality, nonfatal MI, and stroke compared with placebo in patients with type 2 DM and prevalent CVD at study entry, treated during a 34.5-month follow-up period, although the effect on the primary endpoint did not achieve statistical significance. These data were considered hypothesis-generating because of failure to meet the primary outcome.
Prospective Pioglitazone Clinical Trial in Macrovascular Events (the PROactive study)
The _____ study compared the CV effects of pioglitazone to several sulfonylureas in 3028 patients with type 2 DM not controlled on metformin monotherapy, most of whom did not have CVD.55 The HR for the primary MACE outcome was 0.96 (95% CI 0.74 to 1.26), so no apparent benefit.
TOSCA-IT
However, a randomized open-label CV outcome trial,_____, showed a neutral effect of rosiglitazone on CV outcomes in high-risk patients taking metformin or sulfonylureas. The rosiglitazone product label has since undergone updating to reflect this finding, but the drug remains infrequently used.
RECORD
TZD increases the risk for _____, with a small but consistent increase in risk for new or worsening HF. The labels for these agents warn against their use in patients with HF, and are contraindicated in patients with New York Heart Association (NYHA) class III or IV HF and a caution against their use in any patient with HF.
Peripheral edema
Although the mechanism of the observed increase in edema and HF remains with the use of TZD is unclear, it appears to result primarily from _____ with no evidence to date of pernicious cardiac effects of these drugs
Increased renal sodium reclamation and plasma volume expansion,
More recently the _____ trial randomly assigned 12,537 patients with CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or prevalent type 2 DM to treatment with insulin glargine or standard care management. This had dual primary trial outcomes of (1) nonfatal MI, nonfatal stroke, or death from CV causes, and (2) these events plus revascularization or hospitalization for HF. After a median follow-up of 6.2 years, insulin glargine and placebo groups showed no difference in first co-primary outcome (2.94 vs.2.85 events per 100 patient-years;P = 0.63) or the second co-primary outcome (5.52 vs. 5.28 per 100 person-years; P = 0.27).
ORIGIN
Only one trial has assessed CV outcomes between two different types of basal insulins. _____ randomized 7637 patients with T2DM to either insulin degludec or glargine or insulin. The incidence of the primary MACE outcome proved similar at 8.5% versus 9.3% (HR, 0.91; 95%, CI 0.78 to 1.06). Fewer patients using degludec, however, experienced severe hypoglycemia (4.9% vs. 6.6%; rate ratio, 0.60; P < 0.001).
DEVOTE
The DPP4 inhibitors selectively inhibit the action of dipeptidyl peptidase 4, a circulating enzyme that degrades the endogenous incretin hormones glucagon-like protein (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), which stimulate glucose-appropriate insulin secretion and/ or inhibit glucagon release. Inhibiting DDP4 therefore potentiates _____ action, reducing glucose levels.
GLP-1 and GIP
In the _____ trial, 16,492 patients with type 2 DM or at increased risk for atherosclerotic CV disease randomly received blinded treatment with saxagliptin, 5 mg daily (or 2.5 mg daily in patients with eGFR à50 mL/min/1.73 m2) versus placebo. Saxagliptin had no effect on the primary composite out- come of CV death, MI, and ischemic stroke , but unexpectedly increased hospitalization for HF (HR, 1.27; 95% CI 1.07 to 1.51), an observation that remains poorly understood and requires further exploration and assessment in the other outcomes trials evaluating the DPP4 inhibitor.
Saxagliptin Assessment of Vascular Out- comes Recorded in Patients with Diabetes Mellitus (SAVOR)—TIMI 53
In the _____ trial, 5380 patients with type 2 DM and a recent ACS event randomly received alogliptin versus placebo. Alogliptin had no effect on the primary composite outcome of CV death, MI, and stroke (HR, 0.96; upper 97.5% confidence limit = 1.16). In a subsequent report, HF hospitalization as the first event of an expanded MACE composite that included HF occurred similarly between patients assigned to alogliptin versus placebo (HR, 1.07; 95% CI 0.79 to 1.46), yet hospitalization for HF was statistically higher in alogliptin-treated patients without prevalent HF at trial entry (HR, 1.76; 95% CI 1.07 to 2.90).
Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE)
The _____, assessed the CV effects of sitagliptin versus placebo in 14,671 patients with type 2 DM and prevalent ASCVD. Sitagliptin had no effect on the primary composite outcome of CV death, MI, stroke, and hospitalization for unstable angina (HR, 0.98; 95% CI 0.88 to 1.09). In contrast to SAVOR and EXAMINE, the sitagliptin group did not experience increased HF hospitalization rates (HR, 1.0; 95% CI 83 to 1.20) in subgroups with or without HF at baseline.
Trial Examining Cardiovascular Outcomes with Sitagliptin (TECOS)
In the _____ trial, involving 6979 patients and a median follow-up of 2.2 years, the primary MACE outcome occurred with equal frequency in the linagliptin and placebo groups (HR, 1.02; 95% CI, 0.89 to 1.17; P < 0.001 for noninferiority).
Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA)
The aforementioned _____ trial was unique amongst recent type 2 DM CV outcomes trials using an active comparator, the sulfonylurea, glimepiride. With 6042 patients followed for a median of 6.3 years, the risk of developing the primary MACE outcome was equivalent between the treatment groups (HR, 0.98 [95.47% CI, 0.84 to 1.14]; P < 0.001 for noninferiority).
Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA)
Therapeutic benefits with GLP-1 RAs in addition to glucose lowering include associated _____. They do not increase the risk of hypoglycemia unless used with other drugs that themselves increase the risk (e.g.,sulfonylureas,insulin).
Weight loss (typically 3 to 4 kg)
Modest improvement in BP and lipid profiles
The first GLP-1 RA CV outcomes trial, the _____, tested lixisenatide in 6068 patients with recent ACS and found no change in the primary composite MACE outcome (HR, 1.02; 95% CI 0.89 to 1.17)
Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA)
However, in the second CV outcome trial of this class to report, _____, involving 9340 patients with a median follow-up of 3.8 years.
Patients were randomized in a 1:1 fashion to either liraglutide 1.8 mg once daily (n = 4,668) or matching placebo (n = 4,672
Liraglutide reduced the risk of MACE by 13% (HR, 0.87; 95% CI 0.78 to 0.97), with directionally concordant results for CV death (HR, 0.78; 95% CI 0.66 to 0.93), nonfatal MI (HR, 0.88; 95% CI 0.75 to 1.03), and stroke (HR, 0.89; 95% CI 0.72 to 1.11).
In addition, the active therapy group had reduced all-cause mortality (HR,0.85;95% CI 0.74 to 0.97). HF hospitalization did not differ.
Based on this trial, liraglutide was given a label indication for reducing MACE in type 2 DM patients with established CVD.
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)
The LEADER trial showed that liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, was superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and high CV risk.
This trial thus establishes the CV safety profile of liraglutide for use in patients with DM2, and is in fact, one of the first large-scale DM2 trials to show an improvement in hard CV outcomes with simultaneous improvements in glycemic control in a high-risk population.
In the _____ trial
70 3297 patients were randomized to weekly semaglutide versus placebo and followed for a mean of 2.1 years.
The risk of the primary MACE outcome fell by 26% in the active therapy group (HR, 0.74; 95% CI, 0.58 to 0.95; P < 0.001 for noninferiority), an effect driven predominately by a 26% RRR in MI and a 39% in stroke, but no apparent effect on CV death
Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6)
In the _____ trial (N = 9463 over 1.6 years),the RRR for MACE 22% lower in the albiglutide group (HR, 0.78, 95% CI, 0.68 to 0.90). Albiglutide is no longer marketed, however.
Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes)
In the _____ trial (N = 9901, 69% of whom had no established CVD at baseline, 5.4 years)
Patients were randomized in a 1:1 fashion to either dulaglutide 1.5 mg once weekly (n = 4,949) or matching placebo (n = 4,952). Both medications were administered as a subcutaneous injection.
Dulaglutide showed a RRR of 12% (HR, 0.88, 95% CI 0.79 to 0.99) in MACE, with a 24% RRR in nonfatal stroke.72 REWIND extended the benefits of GLP-1 RAs to primary prevention and garnered dulaglutide the first indication by the FDA of reducing CV events in patients with type 2 DM at high CV risk but not necessarily with overt CV disease
Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND)
Dulaglutide is a novel drug for the treatment of type 2 diabetes and functions as a GLP-1 agonist. These drugs reduce hyperglycemia in patients with type 2 diabetes and are also known to cause slight reductions in weight and blood pressure. However, pulse can increase with the use of these agents, but in this trial, suggests no adverse CV consequences. Similar results have been noted with other GLP-1 agents as well. The renal benefits noted in this trial are similar to those noted with SGLT-2 inhibitors, and may be due to a combination of better glycemic and blood pressure control, although other undefined mechanisms are also likely to be responsible.
Finally,in the first CV outcome trial involving an oral GLP-1 RA, _____ (N = 3183 over 16 months)
Randomly assigned to receive oral semaglutide or placebo
There was a non-significant 21% RRR in MACE (HR, 0.79, 95% Cl 0.57 to 1.11 P < 0.001 for noninferiority),with a large and significant reduction in CV death (HR, 0.49, 95% CI 0.27 to 0.92.).
PIONEER 6 (A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes)
In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo.
The combined benefits from both injectable (SUSTAIN 6) and oral (PIONEER 6) earned the injectable formulation by the FDA a label indication to reduce MACE in type 2 DM patients with established CVD.
The most comprehensive meta-analysis of GLP-1 RA CV outcome trials, found the category to have RRRs of 12% for MACE, 12% for CV death, 16% for stroke, and 9% for HF hospitalizations
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the newest class of antihyperglycemic drugs, block a SGLT in the proximal tubule of the kidney, increasing urinary excretion of glucose as well as sodium.This effect results not only in glucose lowering but also in _____.
Modest reductions in body weight (approx. 2 kg)
and
BP (approximately 4/2 mmHg
The first completed CV outcome trial to assess the effect of an SGLT2 inhibitor, _____, tested whether empagliflozin compared with placebo influences the incidence of CV events.
The study enrolled a high-risk population of patients with type 2 DM and prevalent ASCVD. It enrolled 7020 patients with longstanding DM (57% for >10 years) with mean follow-up of 3.1 years.
The trial demonstrated a significant 14% RRR in the primary MACE (HR, 0.86; 95% CI 0.74 to 0.99). A 38% RRR in CV death (5.9% vs. 3.7%; HR, 0.62; 95% CI 0.49 to 0.77) drove this result. In addition, empagliflozin significantly reduced the risk of hospitalization for HF by 35% (HR, 0.65; 95% CI 0.50 to 0.85).
The HF benefit applied to those without prior HF, suggesting that empagliflozin could prevent not only the clinical deterioration of HF but also its occurrence.
EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients )
The results of this trial indicate that empagliflozin is superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and established CVD. Further, it appears to have a salutary effect on renal outcomes too, including the need to initiate renal replacement therapy. There was also a significant mortality benefit with empagliflozin. It reduced HF and all-cause hospitalizations among patients with and without baseline HF.
The _____ program involved 10,142 patients with type 2 DM at high CV risk who were randomized to another SGLT2 inhibitor, canagliflozin, or placebo.
About two-thirds had established CVD while approximately one-third had risk factors only.
The canagliflozin group experienced nearly identical risk reductions to those seen in EMPA-REG OUTCOME for MACE (HR, 0.86; 95% CI, 0.75 to 0.97), HF hospitalization (HR, 0.67; 95% CI, 0.52 to 0.87), and progression of CKD (HR, 0.60; 95% CI, 0.47 to 0.77).
The estimate for CV mortality (HR, 0.87; 95% CI, 0.72 to 1.06) did not approach the major reduction observed in EMPA-REG OUTCOME.
CANVAS (Canagliflozin Cardiovascular Assessment Study)
AE: Doubling in the risk of lower limb amputations (HR, 1.97; 95% CI, 1.41 to 2.75) and a smaller increase in the risk of fracture
In addition, two adverse effects of canagliflozin were found in CANVAS: a doubling in the risk of l_____ (HR, 1.97; 95% CI, 1.41 to 2.75) and a smaller increase in the risk of _____ (HR, 1.23; 95% CI, 1.04 to 1.52).The mechanisms behind these complications of therapy are unknown.Other SGLT2 inhibitors have not shown similar effects.
Lower limb amputation
Fracture
In the _____, 17,160 patients (59% of whom were without established CVD at baseline) received dapagliflozin or placebo.
After a mean follow-up of 4.2 years, the MACE outcome proved equivalent between the two groups (HR, 0.93, 95% CI 0.84 to 1.03) but the other co-primary outcome of CV death and HF hospitalization fell significantly (RRR 17%; HR, 0.83, 95% CI 0.73 to 0.95), driven by a 27% reduction in the risk of HF hospitalization.
CKD progression also occurred less often in the dapagliflozin group (HR = 0.76; 95% CI 0.67 to 0.87.)
DECLARE-TIMI58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events )
The DECLARE–TIMI 58 trial showed that dapagliflozin is superior to placebo in improving glycemic control and noninferior but not superior for reducing MACE in patients with DM2 and high CV risk.
The _____ trial primarily assessed the effect of canagliflozin on renal outcomes in 4401 type 2 DM patients with eGFR 30 to 90 mL/min/1.73 m2 and prevalent macroalbuminuria. The positive primary outcome in favor of canagliflozin, was a 30% RRR in CV death or end-stage kid- ney disease, a doubling of the creatinine level, or death from renal causes, with the risk of the renal-specific component of the broader composite reduced by 34%.The canagliflozin group also experienced a lower risk of MACE (HR, 0.80; 95% CI, 0.67 to 0.95.) and hospitalization for HF (HR, 0.61; 95% CI, 0.47 to 0.80.).
Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE)
The _____ trial, compared ertugliflozin with placebo in 8238 patients with type 2 DM and established CVD.This was the only SLGT2i CV outcome trial to miss its primary superiority endpoint (MACE). HF hospitalizations occurred less frequently in the ertugliflozin group, however (HR, 0.70; 95% CI 0.54 to 0.090)
Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS CV)
In the most recent meta-analysis of SGLT2 inhibitor CV outcome trials, RRRs for MACE, CV death, HF hospitalization, and CKD progression were estimated to be _____, respectively.The MACE benefit was significant only in those participants with established ASCVD.
MACE: 10%
CV Death: 15%
HF Hospitalization: 32%
CKD progression: 38%
The _____ trial compared intensive versus standard glucose control in 10,251 patients with type 2 DM who had high CVD risk, achieving a HbA1c of 6.4% versus 7.5%. This trial halted early due to an excess of all-cause mortality in the intensively treated group (257 vs. 203 events; P = 0.04), with no significant difference observed in the primary composite CVD endpoint of CV death, MI, and stroke (HR, 0.90; 95% CI 0.78 to 1.04
ACCORD
The _____ trial enrolled 11,140 patients with type 2 DM who had CVD, microvascular disease,or another vascular risk factor at study entry. Patients randomly received intensive glucose control with gliclazide plus other drugs in the intensive arm, compared with standard control with other drugs. Similar to the ACCORD trial, the ADVANCE trial did not show statistically significant improvement in the composite CVD outcome of CV death, MI, and stroke with intensive control (achieved HbA1c of 6.4% vs. 7.0%), despite the ascertainment of 1147 events (RRR, 6%; 95% CI −6% to 16%)
ADVANCE
In the _____, 1791 U.S. veterans with type 2 DM and inadequate glucose control randomly received either intensive or standard glucose control. Despite a wide separation in glucose control values (HbA1c of 6.9% vs. 8.4%) and ascertainment of 499 primary MACEs, this trial also found no significant improvement in CV outcomes with intensive control (29.5% vs. 33.5%; P = 0.14). However, follow-up data obtained 3.3 years later in 78% of the initial study population suggest that intensive glucose control compared with standard therapy leads to a significant 17% reduction (P = 0.04) of the primary endpoint.
Veterans Affairs Diabetes Trial (VADT)
Intensive glucose control favorably affects _____ disease risk, but its importance in CVD risk modification remains uncertain.
Microvascular disease risk
The 2018 consensus report from the ADA and the EASD now advises the use of either a _____ after metformin monotherapy in those with established atherosclerotic CVD. For those in whom HF or CKD predominates the clinical picture, _____ would be favored
ASCVD: Metformin then GLP-1 RA or an SGLT2 inhibitor
HF/CKD: SGLT2i
_____ of ACS patients have previously diagnosed DM.6,94 Moreover, many patients present with an ACS event as the first complication of DM, previously undetected DM is also common, affecting up to an additional 20% to 25% of ACS patients
1/3
Given the stress hyperglycemia associated with ACS events that may confound blood glucose testing, screening should extend beyond assessment of fasting blood glucose and include _____.
HbA1C testing and/or pre-discharge oral glucose tolerance testing
The _____ trial enrolled 620 patients with hyperglycemia at presentation with MI, randomly assigned to insulin infusion acutely, followed by multidose subcutaneous insulin injection or usual care, with significant mortality reduction demonstrated in the insulin-treated group during long-term follow-up.
Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI)
In the _____ trial, which included 2840 patients with DM, the estimate of treatment benefit of clopidogrel in this subpopulation of 15% RRR was numerically similar to the overall trial results (14.2% vs. 16.7%; P > 0.05).
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)
Prasugrel added to aspirin, compared with clopidogrel plus aspirin, significantly reduced the CVD risk in the DM subset of the _____ trial, including patients with ACS undergoing a primary invasive management strategy (12.2% vs. 17.0%; P < 0.001).101,102 In the DM subset, prasugrel did not lead to a significant increase in major bleeding com- plications (2.6% vs. 2.5%).
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38)
The _____ trial, however, which enrolled patients with MI treated medically without revascularization, randomly assigned to treatment with clopidogrel or prasugrel, found no significant differences were between the groups in the primary composite outcome of CV death, MI, and stroke in the overall trial population, or in the DM subset, in which the interaction of treatment efficacy of prasugrel by DM status observed in the TRITON trial was not evident.
Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS)
In the _____ trial, which enrolled 18,624 patients with an ACS, with or without ST-segment elevation, randomly assigned to receive ticagrelor or clopidogrel, ticagrelor (a nonthienopyridine P2Y12 antagonist) significantly reduced the primary composite outcome of death from vascular causes, MI, and stroke (9.8% vs. 11.7%; P < 0.001).Similar findings pertained to the subset of 4662 patients with DM at study entry.
Platelet Inhibition and Patient Outcomes (PLATO)
In the _____, a randomized trial comprising patients with MI events complicated by HF, losartan versus captopril associated with a trend toward increased mortality (RR, 1.13; 95% CI 0.99 to 1.28), although the observed differences were not statistically significant
Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL)
In contrast, the _____, which enrolled patients within 10 days of an acute MI complicated by HF, including 3400 patients with DM, showed no significant difference in mortality between patients randomly assigned to treatment with captopril and those treated with valsartan, and effects in the DM subset mirroring those observed in the overall study cohort. Thus, ARBs should be considered an alternative only for patients intolerant of ACE inhibitor
Valsartan in Acute Myocardial Infarction Trial (VALIANT)
The _____ compared the mineralocorticoid- selective aldosterone antagonist eplerenone to placebo, added to optimal therapy, in a population of 6632 patients with MI and decreased ejection fraction (EF) who had either clinical HF or, in the absence of manifest HF, DM. In the overall study cohort, treatment with eplerenone compared with placebo reduced the risk of CV death by 17% (RR, 0.83; 95% CI 0.72 to 0.94), with numerically similar observations in the subset of 2232 patients with DM
Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
On the basis of the EPHESUS trial, the use of an aldosterone antagonist for patients with DM and reduced EF (with or without clinical HF) after MI is recommended in ACS,10,92,93 except in patients with impaired kidney function (creatinine _____ mg/dL) or hyperkalemia (potassium concentration [K+] >_____ mEq/L).
> 2.0 mg/dL
> 5.0 mEq/L
Biologic effects that support the incremental efficacy of beta blockers in the setting of DM include:
(1) Restoration of the sympathovagal balance in patients with DM with autonomic neuropathy
(2) Decreasing fatty acid metabolism within the myocardium, reducing myocardial oxygen demand
Therefore, all patients with ACS should receive beta blockers, independent of their DM status, in the absence of contraindications. The selection might consider the variable effects of available beta blockers on glycometabolic parameters, favorable for _____ and unfavorable for others (e.g.,_____),although these considerations have uncertain clinical relevance
Favorable: Carvedilol, Labetalol
Unfavorable: Metoprolol, Atenolol
Patients with DM and STEMI should undergo reperfusion therapy in the absence of contraindications, preferentially with a strategy of _____ when available
Primary PCI
Angiographic studies show that patients with DM are more likely to have:
Left main CAD
Multivessel CAD
Diffuse and small vessel disease
The largest such trial, the _____ trial, randomized 2368 patients with DM with obstructive CAD either to immediate revascularization (coronary artery bypass grafting [CABG] n = 347; PCI n = 765) in addition to OMT or OMT alone. After 5 years, no significant differences were noted in the combined endpoint of death, MI, or stroke between groups. How- ever, the CABG stratum subgroup, despite having more advanced CAD, showed a significantly higher rate of freedom from major adverse car- diac and cerebrovascular events (MACCE) and death compared with OMT alone (77.5% vs. 69.6%; P = 0.01). In contrast, in the PCI stratum compared with OMT alone, there was no difference in freedom from MACCE (77% vs. 78.9%; P = 0.15).108
Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D)
Among patients with diabetes and stable coronary artery disease, a strategy of revascularization by PCI or CABG failed to demonstrate superiority to medical therapy over a mean of 5.3 years
Examining outcomes by the prerandomization intended revascularization strategy (PCI or CABG), there was no mortality or myocardial infarction benefit from PCI compared with medical therapy. In the CABG stratum, mortality was similar versus medical therapy; however, MI was less with CABG versus medical therapy.
This study builds upon the COURAGE trial (tested PCI vs. medical therapy) which showed that many diabetic patients with less extensive coronary disease and stable controlled angina can be safely managed with an initial treatment strategy of optimal medical therapy. However, in the present study among patients with more severe and diffuse atherosclerotic coronary disease, CABG was associated with reduced adverse outcomes (MI).
The _____ trial assessed an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or an initial conservative strategy of medical therapy alone and angiography if medical therapy failed in 5179 patients with CAD and moderate or severe ischemia including 2164 patients with DM.110 The primary outcome was a composite of death from cardiovascular causes, MI, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% CI, 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, −1.8 percentage points; 95% CI−4.7 to 1.0) suggesting that the initial invasive strategy did not reduce the risk of ischemic cardiovascular events or death from any cause. The results did not differ between patients with or without DM.
ISCHEMIA
The _____ trial assessed an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or an initial conservative strategy of medical therapy alone and angiography if medical therapy failed in 5179 patients with CAD and moderate or severe ischemia including 2164 patients with DM.110 The primary outcome was a composite of death from cardiovascular causes, MI, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest.At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% CI, 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, −1.8 percentage points; 95% CI−4.7 to 1.0) suggesting that the initial invasive strategy did not reduce the risk of ischemic cardiovascular events or death from any cause. The results did not differ between patients with or without DM.
ISCHEMIA
A subanalysis of the 452 patients with DM with left main or three-vessel CAD enrolled in the _____ trial of PCI versus CABG demonstrated higher rates of MACCE with PCI using paclitaxel-eluting stents (PES) compared with CABG at 1 year (26% vs. 14.2%; P = 0.003), and after 5 years of follow-up (46.5% vs. 29.6%; P < 0.001),112 differences driven by more repeat revascularization in the PCI group at 1 year (PCI 20.3% vs.CABG 6.4%;P < 0.001) and at 5 years (PCI 35.3% vs.CABG 14.6%; P < 0.001).With respect to lesion complexity according to the SYNTAX score, only patients with DM with more complex disease (SYNTAX score33) had a treatment benefit of CABG.
Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX)
Based on these trials, the 2014 ACC/AHA guideline upgraded its previous recommendation in favor of _____ from class II (A) to class I (A) in patients with DM and stable CAD, in particular if a left inferior mammary artery (LIMA) graft can be anastomosed to the left anterior ascending (LAD) artery, provided the patient is other-wise a good candidate for surgery.
CABG over PCI
Similarly, the 2019 ESC Guidelines on Diabetes, prediabetes and CVD recommend _____I in patients with DM and triple-vessel disease.
CABG over PC
Both CABG and PCI receive a class I recommendation for patients with _____.
2VD with proximal LAD stenosis or left main stenosis with low complexity
Once _____ is present, DM portends an especially adverse prognosis for subsequent morbidity and mortality.
HF
_____ remains the principal risk factor for HF in DM patients
IHD
Contributors to the increased risk of HF in DM due to IHD may include
(1) Increased disease burden
(2) Prevalence of silent or atypical symptoms of ischemia delaying diagnosis and intervention
(3) Suboptimal use of therapeutic interventions
(4) Perturbed sympathovagal balance
(5) Prothrombotic milieu
(6) Impaired coronary endothelial function
(7) Abnormal myocardial metabolism
Among patients with type 2 DM, risk of HF increases _____% for every increment of 10 mm Hg in systolic BP
12-14% per 10mm Hg BP increase
The myocardium uses predominantly _____ under aerobic conditions, but increasingly shifts to glycolysis and pyruvate oxidation during ischemia
FFAs
The dominance of FFA utilization in diabetic hearts contributes to energetic inefficiency by augmenting oxygen demand for FFA oxidation compared to _____ and by mitochondrial uncoupling with associated deterioration of efficiency of ATP production.
Glucose oxidation
Deposition of AGEs within the myocardial ECM adversely affects _____ cardiac function, largely attributable to AGE cross-linking of matrix collagen.
Both systolic and diastolic
There is currently no therapy proven to improve the prognosis of patients with HFpEF. The main goal of therapy is to:
(1) Preserve left ventricular function
(2) Treat comorbidities such as COPD, hypertension, obesity, AF, and risk for CKD, and consider treatment with RAAS blockers
_____ should be first-line agents for the prevention and treatment of HFrEF in patients with DM, with ARBs as alternatives.
ACEi
_____ compared sacubitril/valsartan to enalapril in patients with HFrEF. The trial enrolled 8442 patients with class II to IV HF and with EF of 40%. Overall, sacubitril/valsartan significantly reduced the risk for composite outcome of HF hospitalization and CV death (HR, 0.80; 95% CI 0.73 to 0.87), death from any cause (HR, 0.84; 95% CI 0.76 to 0.93), and CV death (HR, 0.80; 95% CI 0.71 to 0.89). In the subset of 2907 patients with DM at baseline (39.4%), sacubitril/valsartan versus enalapril had comparable efficacy on the composite of HF hospitalization and CV death as observed in the overall trial, but there was heterogeneity of the effect on CV death. Morbidity seems to be improved by sacubitril/valsartan over enalapril in patients with or without DM, but there is no clear mortality benefit of sacubitril/ valsartan over enalapril in patients with DM. Sacubitril/valsartan therapy led to a greater reduction in HbA1c levels and a lower rate of insulin initiation over 3 years of follow-up compared with enalapril in patients with DM.
PARADIGM HF
It is therefore reasonable (as it is with other life-limiting comorbidities) to consider more liberal glycemic targets for patients with DM and advanced HF, such as HbA1c target of less than _____% with the avoidance of hypoglycemia
8%
Thiazolidinedione medications have a propensity to increase plasma volume and to precipitate incident or worsening HF; their use requires caution in patients with any degree of HF, and they are contraindicated in patients with NYHA class _____ HF. Data from the aforementioned IRIS trial, however, suggest that with dose reduction/ titration, pioglitazone may be used safely without increasing HF risk
Class III or IV
As noted previously,SGLT2 inhibitors (_____) significantly reduced HF hospitalization in placebo-controlled CVOTs in patients with prevalent ACSVD or with risk factors
Empagliflozin
Canagliflozin,
Dapagliflozin
Ertugliflozin
Data from the _____ trials suggest that the beneficial effect of SGLT2 inhibitors in HFrEF extends to HF patients without DM
DAPA-HF and the EMPEROR-Reduced
The underlying mechanism of the beneficial effects of SGLT2 inhibitors on HF-related endpoints remain unclear, but may include:
(1) Plasma volume reduction without neurohumoral activation seen with traditional diuretics
(2) Effects on cardiac energetics through altered metabolic fuel supply
(3) Direct effects on cardiac function through alterations in mitochondrial ion channels
Two randomized trials of liraglutide versus placebo in patients with HFrEF, with or without DM, failed to demonstrate benefit and each had trends toward worse outcomes with liraglutide, so some caution is warranted with regard to GLP-1 RA use in ______ HFrEF until further data are available.
Moderate to severe HFrEF
DM drugs contraindicated/not advisable for patients with HF
Thiazolidinediones
Saxagliptin
Liragluitide - used in caution
Summary of GLP 1 trials
Exenatide
Lixisenatide
Liraglutide
SC Semaglutide
Oral Semaglutide
Dulaglutide
Albiglutide
Exenatide - EXSCEL
Lixisenatide - ELIXA
Liraglutide - LEADER
SC Semaglutide - SUSTAIN-6
Oral Semaglutide - PIONEER-6
Dulaglutide - REWIND
Albiglutide - HARMONY
Management of cardiovascular disease in patients with type 2 diabetes: clinical approach and key recommendations.
