Do Glucagonlike Peptide-1 Receptor Agonist and Sodium-glucose Co-transporter 2 Inhibitor Prescriptions in Germany Reflect Recommendations for Type 2 Diabetes with Cardiovascular Disease of the ADA/EASD Consensus Report?

OBJECTIVES: To analyze whether prescription use of GLP-1RA and SGLT2i in individuals with type 2 diabetes with cardiovascular disease (CVD) has increased after the ADA/EASD consensus guidelines (2018) in a German Real-World setting and which clinical characteristics are associated with prescription use of these drugs. METHODS: The Disease Analyzer database (IQVIA) comprises a representative panel of 1,373 general practitioners, diabetologists, and cardiologists throughout Germany (01/2015-12/2020: 12.6 million patients). Newly diagnosed type 2 diabetes (n=45,531) was identified by ICD-10 codes (E11). Matching (1:1) on practice specialty, sex, age, and year of diabetes diagnosis was performed for CVD. Logistic regression models were fitted to obtain adjusted odds ratios (OR) for characteristics associated with prescription use (median follow-up: 1.9 years). RESULTS: Overall, 35% of patients (n=16,006) were treated with glucose-lowering drugs during the first year after type 2 diabetes diagnosis (HbA1c≥7.0%: 80%). GLP-1RA (2.4%) and SGLT2i (8.5%) were rarely prescribed. After the consensus, use of GLP-1RA and SGLT2i increased, however, almost independently of pre-existing CVD (12/2019-11/2020 vs. 12/2017-11/2018: yes, no): GLP-1RA: from 5.7 to 9.2%, 5.2 to 7.6%; SGLT2i: from 13.9 to 20.4%, 12.1 to 16.6%. Among cardiovascular risk factors, the largest OR for GLP-1RA was for obesity (4.5; 95%CI: 3.2-6.3). CVD was moderately related with SGLT2i (1.45; 1.32-1.60) and GLP-1RA (1.35; 1.08-1.69) prescriptions. A weak association was observed between SGLT2i and heart failure (1.18; 95%CI: 1.05-1.32). CONCLUSION: National prescription use of GLP-1RA and SGLT2i did not come close to the recommendation in subjects with CVD issued by the 2018 ADA/EASD consensus.

The Ratio of Regulatory (FOXP3+) to Total (CD3+) T Cells Determined by Epigenetic Cell Counting and Cardiovascular Disease Risk: A Prospective Case-cohort Study in Non-diabetics.

BACKGROUND: Experimental and clinical evidence indicate that inflammatory processes in atherogenesis and the development of cardiovascular complications are promoted by a loss of regulatory T cell (Treg)-mediated immunological tolerance to plaque antigens. Yet, the association between alterations of systemic Treg frequency and cardiovascular disease incidence remains uncertain. METHODS: A nested case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg, comprising a random subcohort (n=778) and primary cases of myocardial infarction (MI, n=276) and ischemic stroke (n=151). Pre-diagnostic FOXP3+ Treg and total CD3+ T-lymphocyte (tTL) frequencies in blood were measured by epigenetic-based, quantitative real-time PCR-assisted cell counting. RESULTS: Multivariate, Prentice-weighted Cox regression analyses revealed that lower Treg/tTL ratios were not associated with the risk of either MI (lowest vs. highest sex-specific quartile; hazard ratio: 0.72, 95% confidence interval: 0.46 to 1.13; Ptrend=0.51) or stroke (HR: 0.90, 95% CI: 0.51 to 1.60; Ptrend=0.78). There were no correlations of Treg/tTL ratios with C-reactive protein, HbA1c, and various lipid parameters. CONCLUSIONS: Among middle-aged adults from the general population, imbalances in the relative frequency of Tregs within the total T cell compartment do not confer an increased risk of MI or stroke.

Treg-Mediated Immune Tolerance and the Risk of Solid Cancers: Findings From EPIC-Heidelberg.

BACKGROUND: Laboratory-based, mechanistic, and prognosis studies suggest that a shift from antitumor immunity towards tumor-immune tolerance plays a major role in carcinogenesis. However, prospective epidemiological studies on the consequences of differing immune tolerance levels prior to clinical manifestation are missing. METHODS: A case-cohort study embedded in EPIC-Heidelberg was conducted comprising incident cases of breast (n = 399), colorectal (n = 185), lung (n = 149), and prostate (n = 378) cancer, which occurred during 6.6 years of follow-up, and a subcohort (n = 807). Foxp3+ regulatory T-lymphocytes and CD3+ T-lymphocytes were measured by quantitative polymerase chain reaction-based DNA methylation analysis in prediagnostic leukocyte samples. Hazard ratios (HRs) for associations of cancer risk with the ratio of both parameters, the "cellular ratio of immune tolerance" (ImmunoCRIT), were estimated using Cox regression models. All statistical tests were two-sided. RESULTS: ImmunoCRIT values were positively associated with the risk of lung (highest vs lowest tertile, HR = 1.98, 95% confidence interval = 1.06 to 3.69, P trend = .0263) and colorectal cancer (HR = 1.59, 95% CI = 0.99 to 2.54, P trend = .0069) after multivariable adjustment, but not with prostate cancer risk. Regarding breast cancer significant heterogeneity by estrogen receptor (ER) status was observed (P heterogeneity = .02), and the ImmunoCRIT was associated with the risk of ER-negative breast cancer (HR = 3.34, 95% CI = 1.52 to 7.35, P trend ≤ .001), but not ER-positive breast cancer. CONCLUSION: The present study indicates that increased peripheral immune tolerance may be an independent risk factor for lung, colorectal, and ER-negative breast cancer, whereas its role on the development of prostate and ER-positive breast tumors remains uncertain.