Once again, the A4M (Advancement for Anti-Aging Medicine) Conference in December of 2019 did not disappointment. The advancements in functional medicine treatments and assessments for prolonging life, assessing the causes of autoimmune disease, and addressing cardiovascular disease risk never cease to amaze me. Modern biological medicines first came on the market in 1982 with the development of human insulin. From this point on the pharmaceutical industry has made huge advancements in the underlying biochemical mechanisms behind a host of disease processes, ranging from diabetes and cardiovascular disease to cancer and autoimmune disease.
I must admit, when I first heard about the use of biological treatments (monoclonal antibodies) in the treatment of Crohns and Ulcerative Colitis, as well as cancer, 14 plus years ago, I assumed that medical science would soon have the answers to all health concerns. Shortly there after, with some of the side effects being reported from the use of infliximab and bevacizumab, I realized that most of these agents fail to address the underlying cause of disease. The discovery and development of many of them however are life saving and being so targeted they allowed for practitioners like myself to better integrate additional treatments such as neutraceuticals, dietary and lifestyle changes.
Recently, there has been an explosion in the discovery and development of a new era in biological medicines called peptides. Insulin, being the first natural peptide therapy ever used in humans was actually discovered in 1912, so in retrospect I am kind of surprised it took another century to develop treatments similar to insulin for a host of health conditions. One of these new agents that I have an interest in is liraglutide, which is a glucagon-like peptide-1 receptor agonists. Victoza (TM) was the first of these products marketed as an adjunct to oral diabetes treatments as well as being used as a weight loss agent, by helping obese patients with satiety. Since then, liraglutide is becoming popular in anti-aging medicine by modulating glucose levels, insulin levels as well as energy production and oxidation. liraglutide has also been shown to modulate autophagy and reduce neuroinflammation. Autophagy is a process whereby the body cleanses itself of old or damaged cells (cellular senescence) to promote production of new healthy cells through stem cell stimulation. Autophagy is critical in slowing down or reversing the aging process and although agents like liraglutide can promote autophagy for the lazy and wealthy, fasting has as a similar effect to liraglutide for people that have the willpower to stick to fasting or intermittent fasting regimes.
This recent meta-analysis and randomized controlled trial outlines some of potential benefits of these agents on cardiovascular risk and diabetes. The down side of these medications are their expense as well as the requirement for subcutaneous injection, while the up sides seem to be getting more and more appealing. In the next year, pending on whether my insurance covers these medications, I am going to start a trial on eradicating senescent cells in my body using liraglutide, while continuing my intermittent fasting regime 4 to 5 days per week. I am also hoping to start another biological agent this year called Repatha as a trial to lower my lipoprotein (a) levels. Stay tuned.
Giugliano D, Maiorino MI, Bellastella G, et al. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis including the REWIND and PIONEER 6 trials. Diabetes Obes Metab. 2019 Aug 2. doi: 10.1111/dom.13847. (Systematic review)
A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80-0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68-0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.
Ledesma G, Umpierrez GE, Morley JE, et al. Efficacy and safety of linagliptin to improve glucose control in older people with type 2 diabetes on stable insulin therapy: A randomized trial. Diabetes Obes Metab. 2019 Jul 12. doi: 10.1111/dom.13829. (Original study)
AIM: To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy.
MATERIALS AND METHODS: This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged =60 years and body mass index =45 kg/m2 . HbA1c and fasting plasma glucose were measured at study visits, and participants assessed glycaemic control with a self-monitoring blood glucose device. Adverse events (AEs) were reported during the study.
RESULTS: Three hundred and two participants were randomized 1:1 to linagliptin 5 mg qd and placebo, with one third of patients from Japan. Study population age and HbA1c (baseline mean ± SD) were 72.4 ± 5.4 years and 8.2 ± 0.8%, respectively; ~80% of participants were aged =70 years; 80% had macrovascular complications, one third had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 ; and half had been diagnosed with diabetes for >15 years. Linagliptin significantly improved glucose control at 24 weeks (HbA1c-adjusted mean change vs. placebo: -0.63%; P <0.0001) and the probability of achieving predefined HbA1c targets without hypoglycaemia (HbA1c <8.0%: OR 2.02; P <0.05 and HbA1c <7.0%: OR 2.44; P <0.01). Linagliptin versus placebo was well tolerated, with similar incidences of AEs, including clinically important hypoglycaemia (blood glucose <54 mg/dL) or severe hypoglycaemia.
CONCLUSIONS: Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.