The earliest study that used the term metabolic memory was in type I diabetes. Investigators in that study found that intensive glucose lowering reduces diabetic complications, including diabetic kidney disease. When intensive glucose lowering efforts stop, and the patient returns to usual care sugar control becomes worse again, but the patients who received a period of more aggressive early glucose lowering continue to have less trouble. They continue to have fewer complications. Metabolic memory means that prior aggressive glucose control has sustained benefits even after a return to more usual sugar management. Here is the key point. Short-lived high glucose swithches on genes that should be quiet and these changes in gene expression persist even when glucose returns to levels that are normal or near normal.
Tight glucose control in the ACCORD trial led to 22% more deaths in type 2 diabetes compared with less tight control. The study was stopped prematurely because of these excess deaths. Aggressively lowering glucose with any medicine approved for the purpose caused more deaths. On the other hand, with a protocol-driven approach with equally aggressive targets for blood pressure, glucose, and LDL-cholesterol control along with encouraging patients to stop smoking and using low-dose aspirin therapy, there are powerful benefits reducing diabetic complications. Both the ACCORD trial and the Steno-2 trial used aggressive glucose targets. Here is the difference. Instead of allowing any medicine approved to lower glucose to be used as in ACCORD the Steno-2 trial used an OMT protocol including losartan, lisinopril, calcium channel blockers for hypertension, atorvastatin for cholesterol, and metformin for diabetes. These medications protect cells and organs. It matters how you lower the glucose. These drugs block the downstream effects of genes that have been inappropriately switched on. They block epigenetic effects.
The Steno-2 trial compared usual care vs OMT in patients with type 2 diabetes chronic kidney disease. After 8 years of treatment, the difference in outcomes was so great, it was unethical to continue usual care, and both groups received OMT for the remainder of the study. That is where metabolic memory comes into play. Even though both groups received OMT after eight years, the outcomes benefit for the early OMT patients continued to increase compared with usual care over the next five years for thirteen years of follow-up.
The old idea of metabolic memory said that intensive sugar lowering early in diabetes provides ongoing benefit compared with usual care. The patients in Steno-2 were not patients with early diabetes. They had chronic kidney disease. That can happen early, but it usually occurs in patients who have had diabetes longer. It is a marker for very high risk of heart attack and stroke. Even though this is late disease, OMT provides much better outcomes for 8 years. That advantage persists when all patients are on OMT. Going on OMT after eight years did not produce as much benefit for the usual care patients. The difference between the early OMT patients and the usual care patients continued to increase. That is almost certainly because of epigenetic changes. OMT slowed down the number of genes that were switched on in response to increased oxidant production, inflammation, asymmetric dimethylarginine, switched on mTOR, and switched off AMPK. In usual care, epigenetic change is accelerated and persistent, making OMT later less effective. Once again, this is a massive anomaly in the old science. Producing great results in diabetes is not just about glucose lowering. OMT improves those results when started earlier in disease.
Fascinating!!