Combination of SGLT-2 Inhibitors and GLP-1 Receptor Agonists: Potential Benefits in Surrogate and Hard Endpoints

Background: The treatment of type 2 diabetes mellitus (T2DM) is complex; only a few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy. Methods: The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). Results: SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in Cardiovascular Disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The latter appears to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin. Conclusion: The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding.

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GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side

AJP Renal Physiology ◽

10.1152/ajprenal.00211.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. F1519-F1525 ◽

Cited By ~ 16

Author(s):

Brad P. Dieter ◽

Radica Z. Alicic ◽

Katherine R. Tuttle

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Microvascular Complications ◽

Renin Angiotensin System ◽

Diabetic Kidney ◽

Receptor Agonists ◽

Patients With Diabetes ◽

Glucagon Like Peptide 1 ◽

Patient Side ◽

End Stage

Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.

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MECHANISMS IN ENDOCRINOLOGY: Cardiovascular risk in women with type 2 diabetes mellitus and prediabetes: is it indeed higher than men?

Acta Endocrinologica ◽

10.1530/eje-14-0401 ◽

2014 ◽

Vol 171 (6) ◽

pp. R245-R255 ◽

Cited By ~ 16

Author(s):

Panagiotis Anagnostis ◽

Azeem Majeed ◽

Desmond G Johnston ◽

Ian F Godsland

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Absolute Risk ◽

Cvd Risk Factors ◽

Cvd Risk ◽

Mortality And Morbidity ◽

Blood Pressure Targets ◽

Definite Difference ◽

Cvd Mortality

The relative risk for cardiovascular disease (CVD) events and mortality in diabetic women (in comparison with non-diabetic women) is believed to be greater than that in diabetic men. However, the absolute risk for CVD mortality and morbidity does not appear to be higher in women. In general, there is heterogeneity between studies, and whether there is any definite difference in the CVD risk between sexes at any level of glycaemia is not known. The same arguments also apply when comparing the CVD risk factors, such as lipid profiles and systemic inflammation indices, which seem to be worse in women than in men with diabetes mellitus (DM). The same questions emerge at any given glycaemic state: are women at worse risk and do they have a worse risk factor profile than men? These issues have yet to be resolved. Similar, though less extensive, data have been reported for prediabetes. Furthermore, women with DM are suboptimally treated compared with men regarding lipid and blood pressure targets. Large prospective studies representative of the general population are therefore needed to define the differences between sexes regarding CVD events and mortality at a given glucose level and after adjusting for any other confounders.

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Cardiorenal effects of newer antidiabetic agents

Journal of Atherosclerosis Prevention and Treatment ◽

10.53590/japt.02.1010 ◽

2020 ◽

pp. 48-59

Author(s):

Athanasia K. Papazafiropoulou ◽

Elias Georgopoulos ◽

Stavros Antonopoulos

Keyword(s):

Blood Pressure ◽

Cardiovascular System ◽

Blood Pressure Reduction ◽

Antidiabetic Agents ◽

Mortality And Morbidity ◽

Receptor Agonists ◽

Beneficial Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Optimal Blood Pressure

Chronic kidney disease is a major problem of public health and is associated with increased cardiovascular mortality and morbidity. Its treatment includes multifactorial intervention: optimal blood pressure and intensive glycaemic control. There are many studies – clinical and experimental – demonstrating that classic and newer antidiabetic agents delay the progression of diabetic nephropathy. Glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporters-2 (SGLT-2) inhibitors have renoprotective action. Furthermore, these antidiabetic agents have beneficial effects to the cardiovascular system, including weight loss and blood pressure reduction. Large, randomized, placebo-controlled outcome trials have showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events. Therefore, the present review aims to summarize the existing data regarding the effect of newer antidiabetic agents on kidney function and cardiovascular system.

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Perioperative Myocardial Injury After Elective Neurosurgery: Incidence, Risk Factors and Effects on Mortality.

10.21203/rs.3.rs-553458/v1 ◽

2021 ◽

Author(s):

esra saka ◽

Taner Abdullah ◽

Mert Canbaz ◽

Tugce DINC ◽

Ozlem Polat ◽

...

Keyword(s):

Risk Factor ◽

Mortality Rate ◽

Myocardial Injury ◽

Total Mortality ◽

High Sensitivity ◽

Cardiac Risk ◽

Mortality And Morbidity ◽

Incidence Risk ◽

Anticoagulant Drug ◽

Drug Cessation

Abstract BackgroundPerioperative myocardial injury is an important reason of mortality and morbidity after neurosurgery. It usually is missed due to asymptomatic character. In the present study, we investigated myocardial injury after noncardiac surgery (MINS) incidence, the risk factor for MINS and association of MINS with 30-day mortality in neurosurgery patients.MethodsPatients with cardiac risk who underwent elective neurosurgery were enrolled to the study. The patients’ demographics, comorbidities, medications used, medical history, and type of operation were recorded. The high-sensitivity cardiac troponin (hs-cTn) levels of the patients were measured 12, 24, and 48 hours after surgery. The patients were considered as MINS-positive if at least one of their postoperative hs-cTn measurement values was ≥14 ng/l. All the patients were followed up for 30 days after surgery for evaluation of their outcomes, including total mortality, mortality due to cardiovascular cause, and major cardiac events.ResultsTotal 312 patients completed the study and 64 (20.5%) of them was MINS positive. Long antiplatelet or anticoagulant drug cessation time (OR: 4.9, 95%CI: 2.1-9.4) was found the most prominent risk factor for MINS occurrence. Total mortality rate was 2.4% and 6.2% in patients MINS negative and positive respectively (p = 0.112). The mortality rate due to cardiovascular reasons (0.8% for without MINS, 4.7for with MINS, and p=0.026) and incidence of the major cardiac event (4% for without MINS, 10.9 for with MINS, and p=0.026) were significantly higher in patients with MINS.ConclusionsMINS is a common problem after neurosurgery and, high postoperative hs-cTn level is associated with mortality and morbidity.

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Association of Soft Drink Intake With Cardiovascular Disease Mortality and Morbidity: A Large Prospective Cohort Study

10.21203/rs.3.rs-516666/v1 ◽

2021 ◽

Author(s):

Dan Liu ◽

Peidong Zhang ◽

Zhihao Li ◽

Dong Shen ◽

Xiru Zhang ◽

...

Keyword(s):

Cohort Study ◽

Soft Drink ◽

Population Attributable Fraction ◽

Soft Drinks ◽

Cvd Risk ◽

Mortality And Morbidity ◽

Vegetable Juice ◽

Incidence And Mortality ◽

Using Data ◽

Cvd Mortality

Abstract BackgroundThe associations of SSBs, ASBs and pure fruit/vegetable juices with CVD events have not been thoroughly evaluated. The present study determined the association of soft drinks with CVD and effects of the substitution of alternative beverages for soft drinks and the population-attributable fraction of CVD mortality due to soft drinks.MethodsA cohort study was performed using data from UK Biobank and 168007 participants (mean (SD) age, 55.6 (7.9) years) without CVD/cancer at baseline were eligible for this analysis. Dietary consumption of SSBs, ASBs and pure fruit/vegetable juices was self–reported via a 24–hour dietary questionnaire between 2009 and 2012 and followed up to 2018. ResultsDuring a median follow–up of 7.0-year, we recorded 5922 incident CVD cases and 884 CVD deaths. Multivariable adjusted analyses revealed that compared to non–consumers, participants who consumed >2.5 drinks/day had a higher risk of CVD mortality and incidence with HR (95% CI) of 1.63 (1.22–2.17) and 1.23 (1.09–1.39) for SSBs, and 1.77 (1.23–2.56) and 1.20 (1.02–1.42) for ASBs, respectively. Compared to non–consumers, moderate pure fruit/vegetable juice consumers (>0–2.5 drinks/day) have an 8% (2%–13%)–34% (16%–48%) lower risk for CVD incidence and mortality. There was a positive dose–response association of SSBs per 5% energy with CVD mortality and incidence with HR (95% CI) of 1.15 (1.17–1.25) and 1.06 (1.03–1.10), respectively. Substituting one drink/day of pure fruit/vegetable juice, un–sweetened tea/coffee for SSBs and ASBs was associated with 4%–24% lower risks for CVD mortality and incidence. A reduced SSB intake to below 5% energy may prevent 4% (1%–8%) of CVD mortality.ConclusionSSBs and ASBs was associated with a higher CVD mortality and morbidity. Pure fruit/vegetable juice and un–sweetened tea/coffee are suitable alternatives to SSBs and ASBs to reduce CVD risk.

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Incretin-Based Therapy for Prevention of Diabetic Vascular Complications

Journal of Diabetes Research ◽

10.1155/2016/1379274 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Akira Mima

Keyword(s):

Microvascular Complications ◽

Vascular Complications ◽

Polyol Pathway ◽

Therapeutic Interventions ◽

Mortality And Morbidity ◽

Dipeptidyl Peptidase 4 ◽

Diabetic Vascular Complications ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Glucagon Like Peptide 1 ◽

Artery Disease

Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular and　microvascular complications. Macrovascular complications include coronary artery disease　and cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications.

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Abstract P265: Plasma Phospholipid Trans Fatty Acids, Cardiovascular Diseases, and Total Mortality: The Cardiovascular Health Study

Circulation ◽

10.1161/circ.127.suppl_12.ap265 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Qianyi Wang ◽

Fumiaki Imamura ◽

Rozenn N Lemaitre ◽

Eric B Rimm ◽

Frank M Sacks ◽

...

Keyword(s):

Fatty Acids ◽

Ischemic Stroke ◽

Trans Fatty Acids ◽

Cardiovascular Health ◽

Total Mortality ◽

Plasma Phospholipid ◽

Health Study ◽

Cardiovascular Health Study ◽

Cvd Risk ◽

Cvd Mortality

Introduction: Whereas trans fatty acids (TFAs) have generally been evaluated as a group, emerging evidence suggests that trans18:2, but not trans18:1 or trans16:1, isomers are especially adverse for health. Few studies have investigated how biomarkers of different TFA isomers relate to CVD or total mortality. Objective: To examine prospective associations of circulating trans16:1n9 (16:1n9t), total trans18:1 (18:1t, the sum of 18:1n5-12), and n9cis/n6trans, n9trans/n6cis, and n9trans/n6trans 18:2 (18:2ct, 18:2tc, 18:2tt) with incident CVD events and total mortality. Methods: We prospectively evaluated 2,788 adults in the Cardiovascular Health Study, age 72±5y, free of prevalent CVD, and having plasma phospholipid TFA measures from blood stored in 1992. CVD events and mortality were centrally adjudicated through 2010, including total mortality, CVD death, CHD death, nonfatal MI (NFMI), and ischemic stroke. Risk associated with each TFA was assessed using Cox proportional hazards adjusting for sociodemographics, lifestyle, dietary habits, prevalent diseases, and the 5 TFA mutually. Results: During 31,863 person-years, 1,681 deaths occurred including 581 CVD and 373 CHD deaths; as well as 383 NFMI and 328 ischemic strokes. 18:2ct was associated with higher CVD mortality (quintile 5 vs. 1 HR 1.48, 95%CI 0.98-2.23, p trend 0.04), but not total mortality or nonfatal CVD events. 18:2tc was related to higher NFMI (HR 1.69, 95%CI 1.06-2.69, p trend<0.01), while 18:2tt was not significantly associated with mortality or CVD endpoints. Similarly, 16:1n9t was positively associated with NFMI (HR 2.96, 95%CI 1.80-4.88, p trend<0.01), and ischemic stroke (HR 2.00, 95%CI 1.19-3.36, p trend 0.02), but not mortality endpoints. 18:1t was associated with lower CVD (HR 0.52, 95%CI 0.34-0.79, p trend=0.01) and CHD (HR 0.49, 95%CI 0.29-0.84, p trend 0.02) mortality, but these findings for 18:1t were substantially (~50%+) weakened when analyses did not mutually adjust for all 5 TFA, which were intercorrelated (r -0.08 to 0.78). Conclusions: Specific 18:2 TFA isomers, 18:2ct and 18:2tc but not 18:2tt, as well as 16:1n9t are prospectively associated with higher incidence of CVD events. 18:1t is associated with lower CVD risk, perhaps owing at least partly to co-adjustment for multiple correlated TFAs. The general specificity of all findings for CVD events, rather than total mortality or non-CVD mortality, is consistent with adverse physiologic effects of TFA on CVD risk factors. These results highlight the need for further investigation of effects and determinants of specific TFA subclasses and isomers.

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Deep learning predicts cardiovascular disease risks from lung cancer screening low dose computed tomography

Nature Communications ◽

10.1038/s41467-021-23235-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hanqing Chao ◽

Hongming Shan ◽

Fatemeh Homayounieh ◽

Ramandeep Singh ◽

Ruhani Doda Khera ◽

...

Keyword(s):

Lung Cancer ◽

Deep Learning ◽

Cancer Screening ◽

Low Dose ◽

Risk Estimation ◽

Lung Cancer Screening ◽

Cvd Risk ◽

Risk Patients ◽

Low Dose Computed Tomography ◽

Cvd Mortality

AbstractCancer patients have a higher risk of cardiovascular disease (CVD) mortality than the general population. Low dose computed tomography (LDCT) for lung cancer screening offers an opportunity for simultaneous CVD risk estimation in at-risk patients. Our deep learning CVD risk prediction model, trained with 30,286 LDCTs from the National Lung Cancer Screening Trial, achieves an area under the curve (AUC) of 0.871 on a separate test set of 2,085 subjects and identifies patients with high CVD mortality risks (AUC of 0.768). We validate our model against ECG-gated cardiac CT based markers, including coronary artery calcification (CAC) score, CAD-RADS score, and MESA 10-year risk score from an independent dataset of 335 subjects. Our work shows that, in high-risk patients, deep learning can convert LDCT for lung cancer screening into a dual-screening quantitative tool for CVD risk estimation.

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