Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov [TECHNICAL DIFFICULTIES] [ AUDIO IN THE DIABETIC SUBJECTS. SHE [INDISCERNIBLE] EDITOR OF TRANSACTIONS OF THE AMERICAN OPTHALMA LOGIC SOCIETY AND EDITORIAL BOARD OF OP THAT MALLGY. THE AMERICAN ACADEMY OF OPTHALMOLGY, THE RETINA SOCIETY AND OTHERS. AND TODAY SHE WILL PRESENT THE TALK PERSISTENT EFFECTS OF INTENSIVE GLYCEMIAIC CONTROLS [INAUDIBLE] >> IT'S AN HONOR TO BE ABLE TO PRESENT THE DATA WE HAVE BEEN WORKING ON. THIS IS THE EYE STUDY, FOLLOW-UP STUDY LOOKING AT PERSISTENT EFFECTS OF INTENSIVE GLYCEMIAIC CONTROL IN DIABETES 2 DIABETES. I HAVE NO FINANCIAL INTERESTS. THE OBJECTIVE I WANTED TO TELL YOU, TO RECOGNIZE THAT THE ACCORDION EYE STUDY DEMONSTRATED 4 YEARS AFTER THE CLINICAL TRIAL ENDED THE BENEFICIAL EFFECTS OF INTENSIVE GLYCEMIC CONTROL PERSISTED DEBATE BOTH GROUPS WERE VERY SIMILAR. THIS IS A LEGACY EFFECT OR METABOLIC MEMORY WE SEE WITH PATIENTS WITH DIABETIC RETINOPATHY. AS MANY KNOW, THIS IS A LARGE MUTCH -- SNITCH -- [TECHNICAL DIFFICULTIES]. LIST OF NAMES. >> THE EYE STUDY, CONTRIBUTED TO THIS BIG EFFORT. OUR TAKE HOME MESSAGE IS THE LEGACY EFFECT. THIS INTENSIVEBLY GLYIC CONTROL, ONLY 3.7 YEARS IN THE ACCORD STUDY REDUCED PROGRESSION BY 1 THIRD. 4 YEARS LATER THERE WAS A PERSISTENT REDUCTION OF 50% IN THE PROGRESSION OF DIABETIC RETINOPATHY IN PATIENTS THAT WERE ASSIGNED TO INTENSIVE GLYCEMIC CONTROL. IT REALLY DOES MATTER, THIS IS AN IMPORTANT EFFECT FOR PATIENTS WITH DIABETIC RETINOPATHY. TO GIVE YOU A BACKGROUND ON THE ACCORD TRIAL ITSELF, 2003 TO 2009, WE TESTED 3 SEPARATE RESEARCH QUESTIONS ADDRESSING THIS TO REDUCE CARDIOVASCULAR DISEASE IN PERSONS WITH TYPE II DIABETES. YOU'LL HEAR ABOUT THE ACTUAL CARDIOVASCULAR WHEN HIGHWAY HERTZEL GERSTEIN SPEAKS. WE WERE INTERESTED IN TREATING THE LIPIDEMIA WITH 150 MILLION YAMS DAILY PLUS A STATANT, VERSES A PLACEBO AND STATANT. SO THEY WERE RANDOMIZED TO FINO FIBRATE OR PLACEBO. THIS IS A MULTI CENTER TRIALED IN 77 SITES IN THE U.S. AND CANADA, 10,000 PLUS VOLUNTEERS OF TYPE II DIABETES, ESPECIALLY HIGH RISK FOR CARDIOVASCULAR. SO TO GIVE YOU THE RANDOMIZATION, THIS IS A 2 BY 2 FACTORIAL. YOU CAN SEE ALL 10,000 PARTICIPANTS WERE RANDOMSED TO INTENSIVE CONTROL GOING TO A LEVEL LESS THAN 6%. THIS IS VERY LOW. NO OTHER STUDIES GO AS LOW AS THIS. HALF THE PARTICIPANTS, OTHER HALF WERE RANDOMIZED WHICH AIMED FOR 7 TO [INDISCERNIBLE] A1C LEVEL. THEN ON THE BACK DROP OF THIS CONTROL RANDOMIZED PATIENTS OF TWO OTHER TRIALS TO, INTENSIVE TREATMENT TO LESS THAN 120 TO VERSES 140. WE WERE RANDOMIZING PATIENTS, STATIN, PLACEBO VERSES HYDRATE WITH PLACEBO. SO THE EYE STUDY, THE TRIAL GOAL WAS TO LOOK AT WHETHER THESE 3 THERAPIES CAN HAVE ANY EFFECT ON THE PROGRESSION OF DIABETIC RETINOPATHY. THIS WAS A SUBSET OF PATIENTS. WE DID NOT NEED TO SEE 10,000 PARTICIPATE WANTS. OUR SAMPLE SIZE SUGGESTS WE NEED A PROPORTION OF THESE PATIENTS. WE SAW PATIENTS AT BASELINE AND YEAR 4 WITH EXPENSIVE EYE EXAMS -- COMPREHENSIVE EYE EXAMS. WE TOOK FUNDIS PHOTOGRAPHS, WHAT WE DO FOR DIABETIC RETINOPATHY. THESE WERE GRADED AT THE EARLY TREATMENT CLASSIFICATION IN THE, S CENTER. THIS WAS PRIMARY ACCORD MICRO VASCULAR YOU -- OUTCOME. THIS IS THE SCALE USING BOTH EYES, 17 STEP SCALE, SO WE'RE LOOKING AT THE PROGRESSION OF 3 STEPS OR MORE ALONG THE SCALE USING THE 2 STEPS. USING BOTH EYES, RATHER. SO OUR PRIMARY OUTCOME INCLUDES THE PROGRESSION ALONG THE SCALE, INADDITION TO CLINICALLY IMPORTANT ASPECTS THAT PEOPLE SEE FOR DIABETIC RETINOPATHY. THAT INCLUDES LASER PHOTO COAGULATION, A PRIMARY OUTCOME OF PROGRESSION PLUS THE 2 TREATMENTS AS THEY OCCUR. INTERESTINGLY, OUR STUDY SHOWED THAT OUT OF THE 2856 PARTICIPANTS WHO HAD -- WHO WERE IN THE STUDY, APPROXIMATELY 9% OF THEM PROGRESSED. EITHER 3 LEVELS OR [INDISCERNIBLE]. INTERESTINGLY, THIS HAS CHANGED DRAMATICALLY. THIS STUDY WAS DESIGNED IN THE EARLY -- EARLY 2000. WHEN WE DID THAT, WE USED THE OLD DATA FROM THE WISCONSIN STUDY OF DIABETIC RETINOPATHY AND WE ANTICIPATED A MUCH HIGHER RATE, ABOUT 39% WOULD PROGRESS. BUT BECAUSE OF THE DIFFERENCE IN THE TIMING OF THIS, THAT COHORT AND THIS CURRENT COHORT, I THINK IT POINTS TO THE FACT THAT MEDICAL THERAPY HAS IMPROVED DRAMATICALLY. OUR PROGRESSION RATES ARE MUCH OTHER THAN ANTICIPATED. DESPITE THAT, WE FOUND INTERESTING FINDINGS. IF YOU LOOK AT THE RATES, [INAUDIBLE], WE SEE PATIENTS RANDOMIZED HAD 7.5% PROGRESSION VERSES 10.4%. WE NOW [INAUDIBLE] HAD 6.5% REDUCTION OF PROGRESSION, 10.2% PROGRESSED [INAUDIBLE] BLOOD PRESSURE CONTROLS WERE NOT MUCH DIFFERENT. SO THIS TRANSLATED TO A REDUCTION OF APPROXIMATELY .67 ODDS RATIO, IN OTHER WORDS, GLYCEMIC CONTROL -- BLOOD PRESSURE MADE NO DIFFERENCE WITH NEITHER HARMFUL OR BENEFICIAL. WE LOOKED AT VISION LOSS, WE DID NOT EXPECT TO FIND CHANGES. OUR TREATMENTS ARE EXTREMELY VALUABLE AND HIGHLY EFFECTIVE. WE DID NOT EXPECT TO SEE VISION CHANGE. THERE IS NO SPECIFIC DIFFERENCES IN THE TREATMENT GROUPS FOR VISION LOSS. SO IN SUMMARY, FOR THE ACTUAL ACCORD STUDY, THE CONCLUSION IS GLYCEMIA CREAM REDUCED THE PORTION BY APPROXIMATELY 1 THIRD. WE LOOKED AT A NUMBER OF SUBJECTS WE HAD IDENTIFIED APREORI, AND THE -- VERY CONSISTENT, NO TREATMENT EFFECT WITH INTENSIVE BLOOD PRESSURE CONTROL. SO WE WERE INTERESTED IN THE FOLLOW-UP. WE WANT TO KNOW AT 8 YEARS, THE STUDY HAD FINISHED. CLINICAL TRIAL HAD STOPPED. WE WANT TO LOOK 4 YEARS LATER AFTER THE FINISH OF THE CLINICAL TRIAL. DID THE EFFECT OF THE BENEFICIAL EFFECT OF THE INTENSIVE GLYCEMIC CONTROL ACTUALLY PERSIST COMPARED TO STANDARD TREATMENT. WHAT ABOUT FINO FIBRATE AFTER THE TRIAL STOPPED. FINO FIBRATE WAS ALSO STOPPED AS WELL BECAUSE THE CARDIOVASCULAR WAS NULL. THERE WAS NEUTRAL EVENTS FROM THAT. INTENSIVE BLOOD PRESSURE CONTROL HAVE ANY EFFECT WITH FURTHER LONGER FOLLOW UP? WENT BACK AND DID A TYPICAL EYE EXAM AT 8 YEARS, SIMILAR TO BEFORE, SO SOMEBODY HAS 4 YEAR EYE EXAM, SOME MAY NOT. WE LOOKED AT A AS A BASELINE. A PRIMARY OUTCOME DID NOT INCLUDE THE CLINICAL ASPETS, PARTLY BECAUSE WE HAD LOGISTICAL ISSUES. THE MOST IMPORTANT PART WE DID ANALYSIS SHOWING THERE WASN'T MUCH DIFFERENCE. WE ADDED ABOUT 70 EVENTS TO THIS, OUTCOME WITH AND WITHOUT. WOE FELT WE WERE GOING TO BE OKAY WITHOUT THIS EXTRA ADDED ON, JUST LOOKING AT PRIMARY ON THE RETINOPATHY. THOSE THAT ENROLL AND DID NOT PARTICIPATE IN ACCORDION, WE HAD A FAIRLY LARGE LOSS OF FOLLOW-UP. ANALYSIS SUGGESTS THAT THESE RESULTS ACTUALLY HOLD UP. SO PATIENTS WHO DID NOT PARTICIPATE IN THE ACCORDION HAD HIGHER GLYCEMIC CONTROL, AND ALSO PATIENTS HAD HIGHER SITOLLIC BLANKS OTHERWISE THEY'RE VERY COMPARABLE. RETINOPATHY LEVEL WAS SLIGHTLY MORE SEVERE IN THOSE WHO DID NOT PARTICIPATE, AS WE EXPECTED. AND THIS IS WHAT HAPPENED DURING THE STUDY. SO YOU CAN SEE THAT WITH PATIENTS WITH GLYCEMIC CONTROL, GLYCEMIC CONTROL HAD A BIG DROP IN A1C LEVEL. WE STOPPED OUR STUDY EARLY, AND YOU'LL HEAR MORE ABOUT THAT OF SAFE MORTALITY, DUE TO THE INTENSIVE GLYCEMIC CONTROL, YOU CAN SEE THAT WITH TIME, ALMOST BECAME VERY SIMILAR IN TERMS OF THE LEVELS OF A1C. THIS IS DUE TO FOLLOW-UP STUDY IN WHICH WE HAD NO RANDOMIZATION. THIS PERSISTS FOR TRIGLYCERIDES. FOLLOWING THIS, YOU COULD SEE THAT THESE 2 LEVELS RUN VERY, VERY SIMILAR. THE MEAN HDL DID NOT CHANGE VERY MUCH, AND THE BLOOD PRESSURE ALSO HAD A DRAMATIC DROP IN THE SYSTOLIC BLOOD PRESSURE DURING THE COURSE OF THE STUDY, WITH A FOLLOW-UP, AGAIN, VERY SIMILAR. THE FINAL RESULTS, 8 YEARS, WAS THAT THE INTENSIVE GROUP REDUCED THE RISK -- RATHER PROGRESSION RATE WAS 5.8% VERSES 12.7%. THE EFFECT OF THE FINO FIBRATE WENT AWAY. THE BLOOD PRESSURE, AGAIN, REMAINED VERY NEUTRAL. SO THE ODDS RATIO SHOWING THE TREATMENT EFFECT, GLYCEMIAIC CONTROL, THERE WAS A RATIO .42, DESPITE WE HAD STOPPED THE CLINICAL TRIAL BUT THE INTENSIVEUP WAS VERY SIMILAR TO THE STANDARD GROUP IN TERMS OF A1C, AND THE LIPID TREATMENT AND BLOOD PRESSURE TREATMENT WERE NEUTRAL. THERE WAS NO CHANGE AT ALL. WHEN INTENSIVE GLYCEMIC CONTROL DEMONSTRATED A BENEFICIAL EFFECT FOR 4 YEARS, WE FOUND THE EFFECTS WERE CONSISTENT ACROSS ALL THE SUBGROUPS, THE PHENOFIBRAT AND SIMCOE SHOWED NO -- SIMVAS TIN SHOWED NO BENEFICIAL EFFECT. SO THIS LEGACY EFFECT IS VERY SIMILAR TO TYPE II DIABETES, ALSO TYPE 1. TYPE 2 HAS BEEN DEMONSTRATED, TYPE 1, SHOWS SHOW THAT EVEN 25 YEARS LATER, THE CATARACT SURGERY, OTHER SURGERIES WERE MARKEDLY REDUCED IN THE INTENSIVE GROUP. THE REGRESSION RATE STILL CONTINUED TO BE REDUCED. THIS LEGACY THAT IS VERY, VERY POWERFUL AND ACTUALLY PERSISTS, SO NOW WE HAVE GOOD DATA SUGGESTING THAT TYPE II DIABETES IS VERY IMPORTANT. SO WHAT ABOUT THE EFFECT OF FINO FIBRATE? WAS IT BENEFICIAL? WE BELIEVE IT WAS. WE BELIEVE FURTHER TREATMENT NEEDS TO BE DONE. THIS IS CONSIDERED IN SOME EYES OF THE FOLKS READING THIS PAPER SUGGESTING THAT PATIENTS PATIENTS IN THE FINO FIBRATE GROUP IS A SEPARATE ANALYSIS. WHAT IS OF CONCERN, IT DID NOT HAVE PERSONAL CARDIOVASCULAR DISEASE IF WE CAN REDUCE PROGRESSION BY ONE-THIRD THAT'S A HINGE HELP TO SOCIETY. HUMAN HELP TO SOCIETY. OUR NEXT STEP IN THIS ASPECT IS TO DO EAR STUDY IN WHICH THE PRIMARY OUTCOME IS LOOKING AT RETINOPATHY, SUPPORTING THIS THROUGH THE DIABETIC RETINOPATHY CLINICAL RESEARCH NETWORK. WE'RE HOPING TO UNDERSTAND HOW WE CAN ENGAGE OUR MEDICAL PHYSICIANS TO HELP US GET THAT WORD OUT. THAT WOULD BE IMPORTANT. SO IN TERMS OF THE GLYCEMIC CONTROL, WHAT DOES IT DO TO THIS METASTASES MEMORY? -- METABOLIC MEMORY? THIS MAY BE ONE HYPOTHESIS, THERE HAVE BEEN SEVERAL. THERE ARE 2 PAPERS LOOKING AT THE EPIGENETICS OF PATIENTS, LOOKING AT METABOLIC MEMORY AS A RESULT OF GENOME DNA CHANGES, IN TERMS OF THE EPIGENETIC. 2 SETS OF DNA HAS BEEN COLLECTED 16-17 YEARS APART IN THE SAME PATIENTS. THEY PERSIST IN THE DNA METHYLATION OVER TIME AT SOME KEY GENOMIC LOCI ASSOCIATED WITH DIABETIC COMP MIGHTCATIONS. WE DON'T KNOW FOR SURE IF THAT'S TRUE BUT THIS IS CERTAINLY ONE INTERESTING ASPECT THAT THEY CONSIDER TO BE IMPORTANT AS PART OF THE EPIGENETICS PHENOMENON. SO IN SUMMARY, WE HAVE A PERSISTENCE OF BENEFICIAL EFFECTS IN GLYCEMIC CONTROL, RETARDING THE INTERPRETATION OF RETINOPATHY. THIS -- PERSONS WITH TYPE II DIABETES SHOULD CONSIDER INTENSIVE GLYCEMIC CONTROL, NOT BECOME COMPLACENT THINKING BECAUSE THE CARDIOVASCULAR DISEASE AND OTHER THINGS DON'T WORK, BUT VISUAL ACUITY AND VISION FOR DIABETICS AND FOR OUR GENERAL POPULATION IS VERY IMPORTANT. 70% OF THE PEOPLE SURVEYED SUGGEST THAT THEY WOULD RATHER HAVE SOMETHING ELSE RATHER THAN INVESTIGATION LOSS. THEY EQUATE IT TO HAVING A MAJOR CATASTROPHIC CARDIOVASCULAR PROBLEM OR EVEN CANCER. SO A PATIENT'S POINT OF VIEW, QUALITY OF LIFE IS VERY IMPORTANT. BENEFICIAL EFFECTS OF FINOFIBRATE WAS TERMINATED WHEN THE DRUG WAS WITHDRAWN. I'D LIKE TO THANK THE PARTICIPANTS WHO SPENT MANY, MANY HOURS WITH US AND THE ACCORDION ACCORD RESEARCH TEAM FOR THIS OPPORTUNITY. THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> THE SPEAKERS HAVE ASKED TO HOLD QUESTIONS UNTIL AFTER THIS IS DONE. I'M PLEASED TO INTRODUCE OUR SECOND SPEAKER, DR. HIGHWAY, AND ENDOCRINOLOGIST AND PROFESSOR, DR. HERTZEL GERSTEIN, WHERE HE HOLDS THE POPULATION HEALTH INSTITUTE CHAIR IN DIABETES RESEARCH. HE IS ALSO DIRECTOR OF DIVISION OF ENDOCRINOLOGY AND METABOLISM, DIRECTOR OF THE DIABETES CARE AND RESEARCH PROGRAM AND DEPUTY DIRECTOR OF THE POPULATION HEALTH RESEARCH INSTITUTE. DR. GERSTEIN CURRENTLY LEADS CLINICAL TRIALS AND STUDIES RELATED TO DIABETES REMISSION. THE PREVENTION AND THERAPY OF DIABETES AND ITS MANY CONSEQUENCES, AND THE ROLES OF DISGLYCEMIA, A TERM HE PRODUCED IN 1995 ON THE DEVELOPMENT OF A VARIETY OF CHRONIC CONDITIONS IN THE GENERAL POPULATION. HIS RESEARCH SPANS OVER 50 COUNTRIES. AND HAS BEEN FUNDED BY THE CANADIAN INSTITUTE OF HEALTH RESEARCH, THE NATIONAL INSTITUTES OF HEALTH, AND THE HEART AND STROKE FOUNDATION AS WELL AS THE CANADIAN DIABETES ASSOCIATION. DR. GERSTEIN HAS PUBLISHED MORE THAN 300 PAPERS, EDITORIALS AND COMMENTARIES, AND HAS RECEIVED SEVERAL HONORS, INCLUDING THE CANADIAN DIABETES ASSOCIATION LIFE TEAM ACHIEVEMENT AWARD IN 2012. TODAY HE'S GOING TO PRESENT DISGLYCEMIA, VASCULOPENIA AND THE CHRONIC CONSEQUENCES OF DIABETES. WELCOME. >> THANK YOU VERY MUCH. IT'S A REAL MEASURE TO BE HERE, ESPECIALLY AT THE NIH WHICH HAS BEEN A REALLY IMPORTANT PART OF MY CAREER AND MY COLLABORATION WITH EMILY AND OTHER PEOPLE AT THE INSTITUTES, PROBABLY ONE OF THE MAJOR HIGHLIGHTS OF MY CAREER. SO I'M GRATEFUL AND HAPPY TOVATE. SO I'M GOING TO TALK ABOUT THIS TOPIC. AND OUR 2 [INDISCERNIBLE] IN THE TITLE. I'LL EXPLAIN THEM AS WE GO. WE'RE TALKING ABOUT THE CHRONIC CONSEQUENCES OF DIABETES. HERE ARE MY DISCLOSURES. AND THESE ARE THE OBJECTIVES HAVE PRESENTATION. SO FIRST, REMIND YOU OF THE CHRONIC CONSEQUENCE OF DIABETES. DESCRIBE THE EFFECT OF DYSGLYCEMIA -- WHICH MEANS AN ELEVATED BLOOD SUGAR LEVEL AND GLUCOSE LOWERING ON CARDIOVASCULAR AND OTHER CONSEQUENCES. RECOGNIZE THE STRONG CONCORDANCE BETWEEN RETINAL DISEASE AND ALL THE OTHER CONSEQUENCES OF DIABETES. AND I WILL PROPOSE AND SUGGEST AN OVER-ARCHING MECHANISM THAT MAYBE EXPLAINS, ALL THE DIABETES RELIGHTED CONSEQUENCES. SO WHAT ARE THE CHRONIC CONSEQUENCES OF DIABETES? IF YOU ASK A MEDICAL STUDENT, THEY PARROT BACK, MICROVASCULAR AND MACRO VASCULAR CONSEQUENCES. I THINK THAT'S A WRONG PARADIGM, WE SHOULD STOP TALKING THAT WAY. THE CONSEQUENCES ARE EXTENSIVE. HERE ARE THE LISTS OF THE CHRONIC CONSEQUENCES OF DIABETES. THESE ARE THINGS THAT OCCUR MORE FREQUENTLY WITH PEOPLE WITH DIABETES THAN WITHOUT DIABETES. SIGNIFICANTLY MORE. SOME OF THEM ARE VERY SPECIFIC TO DIABETES. AND SOME ARE NOT. SO IF YOU LOOK, I WON'T GO THROUGH ALL OF THEM. DIABETES IS STILL THE MOST COMMON CAUSE OF ADULT ONSET BLINDNESS, CERTAINLY WORKING AGE PEOPLE. IN DEVELOPED WORLDS. STRONG FOR CATARACTS, RENAL FAILURE. NEUROPATHIC PAIN M ULCERATIONS, CARDIOVASCULAR OUTCOMES, CIRRHOSIS, CANCERS, 30% HIGHER RISK OF CANCERS. AND A HOST OF PROBLEMS. SOME OF THESE CONSEQUENCES ARE VERY DIABETES SPECIFIC. FOR INSTANCE, THE BLINDNESS. PEOPLE WITHOUT DIABETES CAN GO BLIND. THE DIABETES RELATED BLINDNESS, RETINOPATHY IS VERY SPECIFIC FOR DIABETES. PEOPLE WITHOUT DIABETES DON'T GET THE CHANGES OF DIABETES RETINOPATHY. SOME OCCUR, CARDIOVASCULARLY OCCURS IN PEOPLE WITH DIABETES AS WELL AS OTHER. IT INCREASES THE RISK 3 FOLD COMPARED TO PEOPLE WITHOUT. ONE CAN STEP BACK AND LOOK AT THIS LIST OF DIABETES RELATED CONSEQUENCES. TO A LARGE EXTENT, DIABETES IS A DISEASE OF ACCELERATED AGING, ESPECIALLY FOR THE ONES THAT ARE NOT GLUCOSE SPECIFIC. THAT'S ONE HIGH LEVEL WAY TO THINK OF IT. WHAT CAN THE LINK BETWEEN THESE CONSEQUENCES AND ELEVATED BLOOD SUGAR LEVEL? SO DISGLYCEMIA IS ANY GLUCOSE LEVEL ABOVE NORMAL. A NORMAL LEVEL IS 100 OR LESS. SO ANYTHING ABOVE THAT IS DISGLYCEMIA. FIRST OF ALL, LET'S LOOK TO THE GENERAL POPULATION. THIS IS A META-ANALYSIS OF PERSPECTIVE STUDIES COLLECTED SEVERAL YEARS AGO. AND IF YOU LOOK AT THE RELATIONSHIP BETWEEN HEMOGLOBIN A1C AND CARDIOVASCULAR DISEASE, YOU SEE THAT LEVELS -- THIS IS 100. 5.6 IS 100, IT'S PROGRESSIVELY HIGHER RATE, ABOVE NORMAL LEVELS IN THE GENERAL POPULATION. FASTING GLUCOSE LEVEL AS WELL. THIS IS GLUCOSE OF 100. HIGHER RATE ABOVE LEVELS OF 100 IN THE GENERAL POPULATION. IN THE GENERAL POPULATION, THE HIGHER THE GLUCOSE LEVEL, THE HIGHER THE RISK OF CARDIOVASCULAR OUTCOME. YOU ALSO SEE THIS CLEARLY IN PEOPLE WITH DIABETES. SO ONCE YOU GET DIABETES, YOU STILL HAVE A PROGRESSIVE RELATIONSHIP WITH GLUCOSE. YOU SEE HERE, FOR INSTANCE, THIS IS A LARGE REGISTRY IN SWEDEN. TYPE 1 DIABETES. THIS IS A POPULATION BASED STUDY. THEY LOOKED AT CONTROLS. 170,000 CONTROLS VERSES PEOPLE WITH TYPE ONE DIABETES. THE RELATIONSHIP BETWEEN A1C WHICH WASN'T MEASURED IN THE CONTROLS. A1C AND MORTALITY. YOU CAN SEE THAT IN THE CONTROLS, THIS WAS A BASELINE RATE OF MORTALITY, .3% PER YEAR. IF YOU -- AND MATCH PEOPLE WITH TYPE ONE DIABETES, THE HIGHER THE A1C, THE HIGHER THE RATE OR MORTALITY. IN PEOPLE WITH TYPE 1 DIABETES, CLEARLY THE A1C, THE HIGHER THE RATE OF MOTHER TALLTY. YOU SEE THE SAME THING FROM THE SAME SWEDISH REGISTRY, COMPARING CASES TO CONTROLS, FIVE CASES TO CONTROL. NO MATTER WHAT AGE, THE HIGHER THE A1C CATEGORY, THE HIGHER THE MORTALITY, THE HAZARD RATIO MORTALITY COMPARED TO PEOPLE WITHOUT DIABETES. AND WHAT HAPPENED AS YOU GET OLDER, THERE ARE A LOT OF OTHER COMPETING THINGS THAT ARE KILLING YOU, SO YOU DON'T SEE THE EFFECT OF LOWER A1C. BUT THE SINGLE TO NOISE RATIO IS CLEARLY EMERGING. YOU SEE THE SAME PATTERN ACROSS EVERY AGE GROUP IN TYPE II DIABETES. SO WHAT I'VE SHOWN YOU SO FAR IS THAT THERE IS A CLEAR EPIDEMIC EPIDEMIC RELATIONSHIP BETWEEN GLYCEMIA OR DYSGLYCEMIA, AND CARDIOVASCULAR AND MORTALITY, SO IN THE POPULATION, GENERAL POPULATION AND IN PEOPLE WITH DIABETES. NOW, THE NEXT QUESTION, DOES LOWERING THE GLUCOSE LEVEL PREVENT SERIOUS OUTCOMES? I'LL FOCUS ON CARDIOVASCULAR. I'LL SHOW YOU THE OTHER ONES AS WELL. DOES LOWER THE GLUCOSE LEVEL PREVENT SERIOUS OUTCOMES? FOR TYPE ONE DATABASE, THE ANSWER WAS CLEAR IN 1993 AFTER AN INDDK SPONSORED LARGE CLINICAL TRIAL, THAT DR. CHEW REFERRED TO WAS COMPLETED. IT SHOWED WITHOUT A DOUBT THAT MORE VERSES LESS CLEARING REDUCES MANY DIABETES CONSEQUENCES. REDUCED SERIOUS PROGRESSION OF DIABETIC RETINOPATHY, TO SIGHT THREATENING RETINOPATHY BY 63%. REDUCED APPROACHING RENAL DISEASE, 40%, NERVE DISEASE, AS WELL AS -- AND ON FOLLOW-UP, AS DR. CHEW ALLUDED, TO ALSO REDUCED CHRISTMAS EVE DISEASE. I'LL -- CHRISTMAS EVE DISEASE. I'LL SHOW YOU THAT IN A MINUTE. THIS WAS A 6 YEAR LONG STUDY AND AT THE END OF YEAR, REDUCTION OF CARDIOVASCULAR BY ABOUT 45%. WHAT ABOUT -- THIS SHOWED IT HERE. AT THE END OF THE DIABETES CONTROL AND COMPLICATIONS TRIAL, 6 YEARS, THERE WAS A TREND TOWARD LESS CARDIOVASCULAR EVENTS IN PEOPLE WITH MORE VERSES LESS GLY SEEMIC CONTROL. AS THEY WERE FOLLOWED, THIS TREND CONTINUED. BY THE END OF 20 YEARS OF FOLLOW-UP, PEOPLE HAD A 42% LOWER CARDIOVASCULAR RATE THAN PEOPLE WITHOUT THE CONTROL. EVEN FOR ALL CAUSE MORTALITY, AT THE END OF ABOUT 30 YEARS THERE WAS A 33 PERT LOWER RISK OF DEATH FROM ALL CAUSES. IN MORE VERSES LESS INTENSE GLY SEEMIC CONTROLS. AND REMEMBER, THESE ARE PEOPLE WHO WERE YOUNG. SO THEY WERE IN THE EARLY 20s WHEN THIS STUDY ENDED. THEY WERE IN THEIR LATE 20s. SO THIS IS WHAT'S HAPPENING WITH TIME. THE NICE THING ABOUT THIS STUDY IS THAT THE -- THERE WAS A LARGE CONTRAST IN GLUCOSE LEVELS. WHEN YOU ADJUST -- WHEN YOU INCLUDE THE MODEL THE DIFFERENCE IN HEMOGLOBIN A1C THAT OCCURRED JUST DURING THE FIRST 6 YEARS OF THE STUDY, THIS DIFFERENCE BETWEEN THE TWO GROUPS DISAPPEARED. SO YOU SEE BEFORE, 42% DIFFERENCE IN THE EVENT RATE, THE CARDIOVASCULAR EVENT RATE. AFTER ADJUSTING FOR THE UPDATED HEMOGLOBIN, JUST DURING THE ACTIVE PERIOD, 6 YEARS OF FOLLOW-UP, 40% GOES DOWN TO NON SIGNIFICANT. WHICH MEANS THAT YOU CAN EXPLAIN THE CARDIOVASCULAR BENEFIT ON THE BASIS OF THE CONTRAST AND HEMOGLOBIN A1C THAT WAS IN THE FIRST 6 YEARS OF TREATMENT. SO THAT'S SORT OF SUGGESTING THAT THAT MAY BE WHY THERE WAS BENEFIT. WHAT ABOUT TYPE II DIABETES? THESE PEOPLE ARE OLDER. ALL THESE STUDIES ARE DONE IN PEOPLE 50, 60, 70. SO THEY HAD MANY COMPETING THINGS KILLING THEM. NOT JUST DIABETES. PEOPLE DIE OF ALL SORTS OF THINGS. CARDIOVASCULAR EVENTS AND OTHER PROBLEMS. IF YOU LOOK AT THE EFFECT OF TYPE II DIABETES, IN THIS FIRST STUDY DONE IN PEOPLE NEWLY DIAGNOSED, MORE VERSES LESS GLY SEEMIC CONTROL REDUCED BY 21%. DR. CHEW SHOWED YOU IN THE ACCORD TRIAL, 33%. RENAL DISEASE IS REDUCED IN 2 TRIALS, AND THERE -- NERVE DISEASE, THERE WAS NO EFFECT. WHAT ABOUT CARDIOVASCULAR DISEASE? THERE ARE COMPETING THINGS THAT ARE CAUSING CARDIOVASCULAR DISEASE. HAVING SAID, THERE THERE HAVE BEEN 4 OUTCOME TRIALS, ONE IS THE NIH FUNDED STUDY, ACCORD. AND IF YOU LOOK AT OUTCOME, MI, STROKE, CARDIOVASCULAR EVENTS, THE OTHER TWO TRIALS, ALL FOUR TRIALS SHOW A TREND. NON WERE SIGNIFICANT, A TREND TOWARD LOWER CARDIOVASCULAR EVENTS WITH MORE VERSES LESS GLYCEMIC CONTROL, WHEN YOU ANALYZE THEM ALL THERE IS A MODEST 9% REDUCTION IN CARDIOVASCULAR EVENTS, WITH MORE VERSES LESS GLYCEMIAIC CONTROL, NO EFFECT ON CONTROL. THIS IS ANY MI, OVER ALL 15% REDUCTION. NO EFFECT ON HEART FAILURE. THE ACCORD TRIAL HAD A WRINKLE IN IT THAT COMPLICATES THE INTERPRETATION WHICH WAS NOT FROM THE OTHER TRIAL. THERE WAS AN INCREASE IN MORTALITY RATE IN THE INTENSIVE GLYCEMIC TRIAL. TROPICAL STORM HUNDREDS OF ANALYSES, SO IT -- THERE WERE HUPS OF ANALYSES, SO IT MAY BE A CHANCE FINDING. THIS WAS NOT RELATED TO THE DEGREE OF GLUCOSE LOWERING, INTERESTINGLY ENOUGH. 2 OF THOSE TRIALS, ALL 4 DID PROSPECTIVE FOLLOW-UPS AFTER THE TRIAL ENDED. A LEGACY TYPE OF ANALYSIS. AND THE ONE IN NEWLY DIAGNOSED PATIENTS, THE UK STUDIES SHOWED A CLEAR REDUCTION IN MYOCARDIO INFARCTION AND TOTAL MORTALITY AFTER 20 YEARS OF FOLLOW-UP. FIRST TEN YEARS WAS ACTIVE, LAST TEN WAS PASSIVE FOLLOW-UP. A TRIAL IN MEN iVETERANS, WHO HAD THE LARGEST DIFFERENCE IN HEMOGLOBIN A1C DURING THE ACTIVE TREATMENT PHASE, THERE WAS A LEGACY EFFECT AFTER 10 YEARS OF 17% REDUCTION IN CARDIOVASCULAR OUTCOMES. SO THESE TRIALS ALL SUGGEST THAT MORE VERSES LESS CLEARLY HAS BENEFICIAL EFFECTS. TYPE 1, VERY LARGE EFFECTS. TYPE II DIABETES, STILL CLEAR EFFECTS ON THE EYES, PROBABLE EFFECTS ON THE OTHER SYSTEMS. BUT THE STORY IS NOT AS BLACK AND WHITE IN TYPE II DIABETES. ONE INTERESTING SUBANALYSIS OF THE VA TRIAL, IS THEY -- IS THEY DID AN INTERESTING UNLESS WHERE THEY LOOKED AT PEOPLE WHO'S VASCULATURE COULD RESPOND TO INTENSE GLYCEMIC CONTROLS. FOR A THERAPY TO WORK, YOU TEED TO HAVE TISSUE THAT CAN RESPOND TO THE THERAPY. IF YOU HAVE TOTALLY CLASSIFIED BLOOD VESSELS, NO MATTER WHAT YOU DO, YOU'RE NOT GOING TO HAVE AN EFFECT ON VASCULAR DISEASE. WHAT THEY DID IN THIS STUDY IS THEY MEASURED IN A SUBSET, CORONARY ARTERY CALCIFICATION. THEY LOOKED AT THE EFFECT OF MORE VERSES LESS INTENSE GLYCEMIC CONTROL, STRATIFIED ACCORDING TO THE LEVEL OF DECLASS IF CATION. WHAT THEY SHOWED IS THAT THOSE WHO HAD LOTS OF CALCIFICATION, THERE WAS NO BENEFIT IN KENNEDY CENTER. THOSE WHO HAD VERY LITTLE HAD A REDUCTION IN CARDIOVASCULAR EVENTS T MORE CALCIFICATION, THE LESS EFFECT. AGAIN, SUPPORTERS OF THE INFERENCE AND THAT ENGAGED PEOPLE LOWERING DOES HAVE A CARDIOVASCULAR BENEFIT. DOES THIS GLYCEMIA CAUSE DIABETES RELATED OUTCOMES? WELL, I'VE SHOWN YOU THAT THERE IS A CLEAR EPIDEMIOLOGICAL RELATIONSHIP. HIGHER GLUCOSE LEVELS, MORE CARDIOVASCULAR EVENTS AND OTHER EVENTS. GLUCOSE LOWERING IN TYPE 1, PROBABLY TYPE II DIABETES DOES REDUCE EVENTS, MANY TYPES. SO THOSE 2 CRITERIA ARE SUPPORTIVE OF A CAUSAL RELATIONSHIP. ARE THERE OTHER WAYS WE CAN GET AT THIS? WELL, WE KNOW THAT GLUCOSE ELEVATION PRECEDES THE CONSERVATIVE EVENTS. ONE CAN GO TO A NUMBER OF THINGS, BUT THERE IS TWO OTHER APPROACHES. ONE IS RANDOMIZATION ANALYSIS. SO I'M GOING TO EXPLAIN THAT. I'M NOT A GENETICIST. I'LL EXPLAIN IT IN TERMS OF MY ONGOING, MY UNDERSTANDING. IF WE WANTED TO KNOW IF GLUCOSE ELEVATION CAUSES HEART DISEASE, WE COULD RANDOMIZE PEOPLE TO GET GLUCOSE ELEVATION VERSES NOT. THEN MEASURE HEART DISEASE AFTER. THAT'S NOT ETHICAL. WE CAN'T RANDOMIZE PEOPLE TO GET GLUCOSE ELEVATION OR NOT. BUT GOD CAN. AND SO WHAT HAPPENS IS WHEN WE'RE FERTILIZED, DIZZIGATES, WE RANDOMLY GET OR NOT GET GENES THAT INCREASE THE PROPENSITY TO GET GLUCOSE ELEVATION. IF PEOPLE THAT GET THOSE GENETIC VARIANTS, GENES MORE LIKELY TO BE ASSOCIATED WITH LIPID ELEVATION, ALSO GET CARDIOVASCULAR EVENTS, THE INFERENCE IS THE GLUCOSE ELEVATION IS CASING CARDIOVASCULAR EVENTS. THAT'S WHAT IT IS IN A NUTSHELL. WE DID -- THERE IS TWO THAT HAVE BEEN DONE. THIS ONE WAS PUBLISHED JUST A YEAR AGO, EUROPEAN HEART JOURNAL. WHAT IT SHOWED CAREERLY, HERE IS THE SUMMARY, EACH POINT ON THIS GRAPH IS A METAANALYZED BETA COEFFICIENT. IT SHOWS THAT GENETIC VARIANTS, HERE, THAT INCREASE THE -- ASSOCIATED WITH A HIGHER A1C ARE ALSO ASSOCIATED WITH A HIGHER RISK OF CAD. AND GENERIC VARIANCE, DYSGLYCEMIA INCREASED THE RISK OF CAD. THESE ARE DATA COEFFICIENTS. GENETIC VARIANTS THAT REDUCE THE DEGREE OF DYSGLYCEMIA ALSO RECEIVED THE RISK OF CAD, CONSISTENT WITH THE HYPOTHESIS THAT GLUCOSE ELEVALUATION DOES CAUTION CARDIOVASCULAR DISEASE. I THINK THAT COME TO MY CONCLUSION, IN THIS REVIEW, I WROTE IN NATURE LAST YEAR. THAT'S ANOTHER PIECE OF EVIDENCE. IS THIS ANYTHING ELSE THAT MIGHT BE THERE? WELL, ONE WAY TO GO BACK, CAN WE LINK THIS -- CAN WE LINK THE CONSEQUENCES TO EACH OTHER. MAYBE THERE ARE CREWS IN DIABETES RETINOPATHY. AS WE SAID IN THE BEGINNING, DIABETES RETINOPATHY IS THE MOST SPECIFIC CONSEQUENCE OF DIABETES. PEOPLE WITHOUT DIABETES DO NOT GET DIABETIC RETINOPATHY. SO -- AND WHEN WE ACTUALLY -- WHEN DIABETES WAS FIRST DIAGNOSED -- FIRST DEFINED, AS A GLUCOSE LEVEL 2 HOURS AFTER TOLERANCE TEST, 200 ABOVE, GLUCOSE LEVEL 140 THAT DEFINITION WAS BASED ON DISTINGUISHING PEOPLE THAT GET DIABETES RETINOPATHY VERSES PEOPLE THAT DON'T GET IT. SO CAN DIABETES RETINOPATHY TEACH US SOMETHING, ABOUT WHY PEOPLE GET ALL THE CONSEQUENCES OF DECEMBER? SO DOES DIABETIC RETINOPATHY PROVIDE CLUES AS TO WHY PEOPLE WITH DIABETES GET ALL THOSE CONSEQUENCES I SHOWED YOU ON THE FIRST SLIDE? ARE THE ABNORMALITIES THAT OCCUR IN THE RETINA -- WHEN YOU LOOK IN THE RETINA, WHAT YOU'RE LOOKING AT ARE [INDISCERNIBLE] AND IF YOU INJECT DIE, YOU'RE LOOKING AT THE CAP LARRY. ARE THE BLOOD VESSELS TELLING YOU WHAT'S GOING ON IN THE BLOOD VESSELS IN THE BRAIN, THE HEART, THE KIDNEYS, THE LIVER, AND ALL THE OTHER PLACES THAT OCCUR? ARE THERE CLUES IN THE EYE THAT TELL YOU WHAT'S GOING ON THROUGHOUT THE WHOLE BODY. WHY SHOULD THOSE CHANGES JUST OCCUR IN THE EYE. IS THE RETINA A WINDOW TO THE MICROCIRCULATION IN ALL TISSUES IN THE WOAD? THAT'S THE QUESTION THAT COMES UP. WE CAN'T SEE THE BLOOD VESSELS IN OTHER PLACES BUT WE CAN IN THE RETINA. SO I HAVE A CLINICAL EPIDEMIOLOGICAL BACKGROUND. SO LET'S LOOK AT THE EPIDEMIOLOGY. FIRST OF ALL, WHAT IS THE RELATIONSHIP BETWEEN RETINOPATHY AND ALL THE OTHER CONSEQUENCES? AS IT TURNS OUT DIABETIC RET RHETT IS A REALLY STRONG RISK FACTOR FOR ALL THE DIABETES CONSEQUENCES. HERE IS A RELATIONSHIP BETWEEN DEATH AND RETINOPATHY. THIS IS A META-ANALYSIS PUBLISHED, SO IF YOU LOOK AT TYPE II DIABETES, YOU CAN SEE WHEN YOU META-ANALYSIS THEM ALL, PEOPLE WITH RETINOPATHY HAVE TWICE THE RATE OF DEATH THAN PEOPLE WITHOUT RETINOPATHY. TYPE 1 DIABETES, PEOPLE WITH RETINOPATHY HAVE 4 TIMES THE RATE OF DEATH COMPARED WITHOUT. ALL TOGETHER, DIABETES VERSES NO DIABETES, NO MATTER WHAT TYPE, 2.5 TO 3 FOLD HIGHER RISK OF DEATH. WHAT ABOUT CARDIOVASCULAR DISEASE? THIS IS ALL DATA. WE'VE KNOWN FOR YEARS THAT RETINOPATHY INCREASES -- IS A RISK FACT FOR CARDIOVASCULAR. WE SHOWED THIS IN THE ACCORD STUDY AS WELL. WE LOOK AT THE ACCORD DATA AS A EPIDEMIOLOGIC STUDY, THOSE WITH THE LEAST BASELINE OF RETINOPATHY HAD THE LEAST CARDIOVASCULAR EVENTS. WHAT WE DID TOGETHER, WOE SAID THAT'S FINE. BUT IF THIS IS TRUE, WHAT HAPPENS IN THE EYES TELLS YOU WHAT'S HAPPENING ELSE WHERE, THEN PEOPLE WHO'S EYE DISEASE PROGRESSES SHOULD GET MORE CARDIOVASCULAR DISEASE THAN THOSE THAT DON'T. AND THAT'S WHAT WE SAW. WHEN WE LOOKED AT THE RELATIONSHIP BETWEEN PROGRESSION OF RETINOPATHY, EYE DISEASE DID NOT PROGRESS, THESE ARE THE ONES THAT IT DID. SO THE PROGRESSION HAD MORE CARDIOVASCULAR EVENTS OCCURRING THAN PEOPLE WHO DID NOT. THAT'S ANOTHER PIECE IN THIS THING. IF YOU LOOK AT THE RELATIONSHIP -- THE RETINAL DISEASE, ALL THE OTHER CONSEQUENCES, WE SEE CONSISTENTLY A STRONG RELATIONSHIP. ISCHEMIC HEART DISEASE, 2-4 TIMES HEART FAILURE. 3 TIMES. 3 TIMES. RENAL INSUFFICIENCY, 3 TIMES. NEUROPATHY, TWO TYPES. AMPUTATIONS, 25 FOLD HIGHER RISK. TYPE II DIABETES, SLEEP APNEA, HIGHER PREVALENCE. CAN INTERPRETATION, TWICE. -- DEPRESSION. SO CLEARLY WHAT'S HAPPENING IN THE EYE TELLS YOU WHAT'S HAPPENING ELSE WHERE. CAN WE GET SOME ANIMAL STUDIES THAT PUSH THIS FURTHER? AND WHEN WE WERE CONTEMPLATING THIS, WELL, WHERE ARE THE CAPILLARIES IN THE HEART. SO THEY'RE IN THE MUSCLE. BUT THEY'RE ALSO -- REMEMBER FOR MEDICAL SCHOOL, THAT'S IN THE CORONARY ARTERIES, THERE ARE BLOOD VESSELS THAT SURROUND THE CORONARY ARTERIES. IF THIS HYPOTHESIS IS TRUE, THEN THAT OF DIABETIC PEOPLE SHOULD BE DAMAGED, DISEASED. YOU CAN'T DO IT IN HUMANS BUT YOU CAN DO IT IN MICE. I CAN'T STUDY A MOUSE. I HAVE COLLEAGUES THAT K I CALLED A COLLEAGUE. WE WROTE THIS GRANT TOGETHER. HE DID THE STUDIES. SO HERE IS A GRAPHIC CARTOON. IS AN ARTERY, HERE IS A [INDISCERNIBLE] AROUND IT. IF YOU TAKE APOE DEFICIENT MOUSE, THEY GET MORE PLEASE STAND BY IF I FEED THEM A HIGH -- PLAQUE IF YOU FEED THEM A HIGH PLAQUE DIABETES. AND WHEN THAT WAS DONE, YOU LOOK AT THE VASA VASOREEM, HERE I SAID IN THE NORMAL MICE. IN THE HIGHO AGREE SEMIC MICE, THERE WAS NO PLACK. HERE IS A PHOTOGRAPH, HERE IS THE NON DIABETIC MICE. LOTS OF RICH VASA VASORUM. IN THE DIABETES MOUSE, THERE IS LOWER DEBSTY. THIS PLOT, THE NORMAL MICE, THEY GET MORE AGENT LEERO SCLEROSIS AND INCREASED DENSITY OF [INDISCERNIBLE] TOGETHER WITH THEIR ATHEROSCLEROSIS. THE DIABETIC MICE GET A LOT MORE PLAGUE AND NO CHANGE OR IT GOES DOWN. SO THERE IS DAMAGE HAPPENING AROUND THE BLOOD VESSELS, AT LEAST IN AN ANIMAL MODEL. AND HERE IS THE RETINA. THE NORMAL GLYCEMIC MICE AND HYPER GLYCEMIC MICE THAT HAVE LESS DENSITY. THERE IS AN INJECTION INTO THE RETINA. THE RETINA CHANGES EARLIER WHEN THE VASA CHANGES IN THE MODEL. CAN YOU DO THIS IN HUMANS? IT'S HARD TO IMAGE CAPILLARIES UNLESS YOU INJECT DIE. ONE GUY PUBLISHED A PAPER, HE WAS CONVINCED YOU CAN LURE AT THE CORE RODED ULTRASOUND. WHEN YOU LOOK AT THE -- INFERENCE AS TO THE HEALTH OF THE CORD CAROED THE. SO HERE IS PATIENTS THAT HAVE LESS ECHO DENSITY, AND PATIENTS WITH DIABETES. THERE IS MORE DENSITY. HE FEELS IN HIS PAPER THIS IS A SIGNAL FOR VASA VASORUM DAMAGE. HIS DATE SHOWIS THERE IS A LOT MORE OF THAT SIGNAL THAN THOSE WITHOUT RET RHETT. THAT'S THE CLOSEST THING TO HUMANS THAT ONE CAN GET TO. IN THAT SAME STUDY, THOSE WITH [INDISCERNIBLE] HAS THE MOST SIGNAL THAN THOSE WOULD YOU TELL US. SO WHAT I TOLD YOU IN SUMMARY, DYSGLYCEMIA OR ELEVATED GLUCOSE LEVEL IS PROBABLY -- I'M PRETTY CONVINCED IT IS, WE CAN ARGUE WITHOUT, THAT PROBABLY IS A CAUSAL FACTOR FOR SERIOUS HEALTH OUTCOMES. INCLUDING THE HEART, INCLUDING MORTALITY AND OTHER PLACES. ITS EFFECT ON THE EYE AND THE KIDNEY IS EARLIER THAN EFFECT ON BRINGING IN THE HEART AND OTHER PLACES. IF YOU THINK ABOUT WHAT TYPE OF BRAIN PROBLEMS DO PEOPLE WITH DIABETES GET IT'S ALL CONSISTENT WITH SMALL VESSEL DISEASE. THEY GET LITTLE INFARCTS MORE OFTEN. THEY GET MICROBLEEDS, AND THEY GET DEMENTIA AND COGNITIVE DECLINE EARLIER THAN PEOPLE WITHOUT DIABETES. AND WE CAN LOOK AT THAT IN OTHER ORGANS AS WELL. INTENSIVE GLUCOSE LOWERING IN TYPE ONE AND TYPE II DIABETES CAUSES KIDNEY DISEASE EARLIER, AND PEOPLE WITH ESTABLISHED TYPE II DIABETES THERE ARE CO-MORBIDITIES COMPETING WITH THEIR EFFECT IN CARDIOVASCULAR DISEASE. IN MY OPINION, DISGLYCEMIA LIKELY MEDIATES THE CONSEQUENCES. I THINK IT DOES IT, AND I THINK ONE EXPLANATION CAN EXPLAIN ALL CONSEQUENCES, INMAYORED HEALTH THROUGHOUT THE BODY EVERYWHERE, WITH HIGH FOXIA, SECONDARY INFLAMMATION, DAMAGE TO TISSUE, SCARRING, FIBROSIS, THAT LEADS TO YOU NAME IT. BRAIN DISEASE INCREASING THE RISK OF CANCER. CANCER CELLS LOVE LOW OXYGEN AND A LITTLE BIT OF ASDOSIS. AND IT CAN EFFECT IMMUNE FUNCTION, LIVER, KIDNEY, ET CETERA. SO I THINK IF I HAD TO TAKE ONE MECHANISM TO EXPLAIN ALL THE CONSEQUENCES, MAYBE IT IS AT THE MICROCIRCULATION LEVEL, AT THE VASCULOPENIA LEADING TO LOCAL OR DIFFUSE HYPOXIA. THAT IS MY PRESENTATION. I DID PUBLISHING THIS ARTICLE THAT I HAVE GONE THROUGH THE SAME DISCUSSION THAT I'VE JUST GONE THROUGH FOR THE LAST 20 MINUTES. DR. CHEW AND I WOULD BE HAPPY TO ANSWERER QUESTIONS ABOUT OUR PRESENTATIONS. >> I'M START OFF WITH A QUICK QUESTION. THE DATA ARE VERY COMPELLING THAT YOU SHOW ON THE ROLE OF GLUCOSE AND THE PATHOPHYSIOLOGY. I DON'T UNDERSTAND, MYSELF, HOW GLUCOSE DOES THAT. AND SO TO ME, A COMPELLING POSSIBILITY IS THAT IT'S THE INFLAMMATORY RESPONSE THAT INDUCES ALL THE CHANGES THAT YOU'RE FINDING. AND RAISES THE QUESTION OF WHETHER MORE AGGRESSIVE ANTIINFLAMMATORY APPROACHES MIGHT BE AN ADJUNCTS TO THE THERAPY AND STATINS. >> I COULD START WITH THE RETINOPATHY ASPECT OF THAT. CLEARLY, CYTOKINES AND OTHER INFLAMMATORY THINGS ARE UPGRADED IN PATIENTS WITH RETINOPATHY SO OUR TREATMENTS HAVE BEEN REDUCING THE HYPOXIA BY MEASURE ING HOW LASER WORKS. INJECTING STEROIDS CAN BE HELPFUL BUT THE COMPLICATIONS FROM STEROIDS IS HIGH. BUT IT IS ONE OF THE TREATMENTS WE USE. TARGETED BECAUSE WE KNOW THAT INDEPENDENT FROTH FACTOR IS VERY ELEVATED. IT'S A CYCLE, INFLAMMATORY THINGS CAN COME ON. WE DON'T KNOW THE ACTUAL MECHANISM FOR SURE, BUT IT IS A VERY IMPORTANT PART OF IT, INFLAMMATORY. >> HYPOXIA ITSELF -- PARDON ME. HYPOAGREESEMIA ITSELF IS PROBABLY TOXIC TO ENDOTHELIAL CELLS. IF YOU LOOK AT ENDOTHELIAL PROGENITOR CELLS ARE LOWER, NOT AS HEALTHY IN PEOPLE IN DIABETES COMPARED TO WITHOUT. SO WHOLE POINT OF ANGIOGENESIS IS DAMAGE, AND WE SEE THAT IN THE EYE. SO THE FIRST CHANGES THAT OCCUR IN RETINOPATHY, YOU GET HYPOXIC DAMAGE IN THE EYE. MAYBE THE DEGREE GLUCOSE IS DAMAGING THE CAPILLARIES AND THE SUPPORT STRUCTURES. THAT'S LEADING, I THINK, TO INFLAMMATION BECAUSE OF THE HYPOXIA. ALL THE OTHER THINGS COME UP. FIBROSIS, SCARRING, CYTOKINES, EVERYTHING. I THINK IT'S THE BODY'S RESPONSE TO THE HIGH POX YEAHA DUE TO GLUCOSE MEDIATED DAMAGE. I KNOW THERE IS EFFECTS ON GROWTH FACTORS, AND [INDISCERNIBLE] ARE EFFECTED IN HYPOGLYCEMIC INDIVIDUALS. TOO MOLECULAR FOR ME BUT I THINK THAT'S PART OF THE STORY. >> THE ROLE OF THE MICROBIOME IN TERMS OF INDIVIDUALS WHO ARE SUSTAINED ON LOW GLUCOSE FOR 4 OR 5 YEARS OR SOMETHING LIKE THAT, SEEMS TO ME IN SOME OF THE ANIMAL STUDIES, DIETARY MANIPULATIONS, LEAD TO CHANGES WHICH ACTUALLY ARE PERSISTENT, EVEN WHEN THOSE ARE CHANGED. MAYBE THAT'S A LINK TO THE INFLAMMATORY FINDINGS AND OTHERS. >> [INAUDIBLE] NICE PAPER PUBLISHED IN ARCHIVES OF JAMA OF OPTHALMOLGY THAT LOOKS AT FISH CONSUMPTION IN PATIENTS IN SPAIN. PART OF THE LARGE TRIAL, THE PREVENTION OF CARDIOVASCULAR DISEASE, MEDITERRANEAN STUDY THAT WENT ON WHERE THEY HAD A NUMBER OF PATIENTS RANDOMIZED TO 7,000 PATIENTS -- 7,000 PATIENTS RANDOMIZED TO TWO MED DRAINIAN DIETS, ONE WITH LOW FAT AND ONE WITH OLIVE OIL. IT LOOKED LIKE THE MEDITERRANEAN DIET HELPED WITH THE REDUCTION OF RETINOPATHY PERIOD, AND THEY ALSO LOOKED AT CONSUMPTION, OBLIGATIONAL PART TAKE -- OBSERVATIONAL PART, TAKING INTO ACCOUNT EATING FISH TWICE A WEEK. 3 QUARTERS OF THAT POPULATION THAT THEY LOOKED AT, ATE FISH AND THERE WAS A MARKEDLY REDUCTION, ALMOST 46% REDUCTION IN THE RISK OF EYE DISEASE. SO CLEARLY, I THINK THERE IS A ROLE. AND AGAIN, FISH HAS BEEN VERY IMPORTANT. WE'VE DONE TRIALS LOOKING AT OMEGA 3, WHICH BY ITSELF DIDN'T DO ANYTHING FOR EYE DISEASE. EATING FISH WAS VERY IMPORTANT. SO THERE IS SOMETHING THAT WE HAVEN'T CAPTURED. OMEGA 3 BY ITSELF MAY NOT BE GOOD ENOUGH. YOU NEED THE NATURAL STATE OR THERE IS SOMETHING SYNERGISTIC. THERE IS CLEARLY A ROLE THAT MAY BE PART OF THAT. >> I THINK THAT'S -- THE MICROBIOME IS SO HOT T REASON IT'S LOT IS BECAUSE IT'S NOVEL. THERE IS A LOT OF INTERESTING THINGS THAT MAY OCCUR, CHANGES IN THE -- THE TROUBLE WE HAVE THE MICROBIOME, WE DON'T HAVE A GOOD WAY OF MEASURING. WE DON'T HAVE A BANK OF 10,000 PEOPLE WITH STOOL SAMPLES. EVEN IF YOU HAVE THE STOOL SAMPLES, HOW DO YOU CHARACTERIZE THE MICROBIOME FROM ONE PERSON TO THE OTHER? SO CLEARLY, IT'S A NEW FACTOR THAT MAY EXPLAIN MANY THINGS. PROBABLY MORE IMPORTANT AS EXPLAINING PEOPLE WHO GET OR DON'T GET DIABETES IN THE FIRST PLACE. AND AS OPPOSED TO THE CONSEQUENCES OF DIABETES. BUT FACTORS MADE BY BACTERIA IN THE SCHOOL, GET INTO THE SITUATION AND THEY COULD BE VERY IMPORTANT COFACTORS THAT MAY PROMOTE CONSEQUENCES OF PEOPLE THAT GET DIABETES AND MAY EFFECT GLYCEMIC RESPONSE TO FOOD AND PANCREATIC RESPONSE. WE DON'T KNOW YET. 25 YEARS AGO WHEN WE DIDN'T KNOW, WE SAID IT WAS GENETIC. TODAY WHEN WE DON'T KNOW WE SAY IT'S MICROBIAL. EPI GENETICS WE'RE SAYING, TOO, BECAUSE WE DON'T KNOW THAT VERY WELL. >> I ADDRESS THIS TO BOTH SPEAKERS, BOTH VERY GOOD. I LIKE ONE OF THEM IN PARTICULAR, I HAPPEN TO KNOW HER VERY WELL. THERE IS A LITTLE BIT OF A PARADOX HERE. WE DEFINE DIABETES ON THE BASIS OF A GLOWED GLUE COWS THAT CORRESPONDS WITH RETINOPATHY. YOU POINTED THAT OUT. YES THIS TERM DYSGLYCEMIA COULD BE APPLIED TO IMPAIRED FASTING GLUCOSE OR IMPAIRED GLUCOSE TOLERANCE. WE DON'T TREAT THAT BY ANY FDA APPROVED MECHANISM. NOW, IF WE DID TREAT THAT, WE WOULD BE PUSHING THE A1C LEVELS DOWN TO WHERE THIS IS AN INCREASED MORTALITY IN THE ACCORD STUDY. HOW DO THE SPEAKERS ADDRESS THIS SORT OF APARADOX ON THE BASIS OF WHAT YOU POINTED OUT TODAY? >> I'LL JUST START. FIRST OF ALL, YOU'RE RIGHT, WE DON'T TREAT IT. AND WE DON'T -- BUT HAVING SAID THAT, FROM HAVE BEEN STUDIES WHERE IT HAS BEEN TREATED. THE OLDEST IS A STUDY THAT WAS AN NIH FUNDED STUDIES 30 YEARS TON IN CHINA BY PETER BENNETT AND OTHERS, THEY DID STUDIES TO SEE IF YOU CAN PREVENT DIABETES. TEST DISGLYCEMIC, THEY WERE GIVEN A COMPREHENSIVE THERAPY DIET AS WELL AS DRUGS. TO SEE IF THAT COULD REDUCE DIABETES. THESE PEOPLE HAVE BEEN FOLLOWED FOR 30 YEARS. THOSE WITH DIABETES HAVE LESS CARDIOVASCULAR AND LESS MORTALITY, 30 YEARS AGO, DESPITE THE FACT THAT STUDY ENDED AFTER 5 YEARS. THIS FIVE YEAR -- THIS DELAY OF DIABETES ACTUALLY REDUCED LONG TERM MORTALITY. AND THERE HAS BEEN ANOTHER STUDY, NIDDK FUNDED STUDY THAT DPP, WHICH ALSO TREATED PEOPLE WITH MED FORMEN. -- METFORMIN. AND THEY HAVE NOT YET FOLLOWED PATIENTS LONG ENOUGH TO SEE IF THERE IS MORTALITY OR CARDIOVASCULAR BENEFIT BY GLUE CLOSE LOWERING, BUT MAYBE THERE WILL BE SOMETHING. WE DON'T KNOW, WE'LL FIND OUT. THE THIRD POINT, THE MORTALITY IN ACCORD AS I SAID BEFORE, WE DON'T KNOW IF IT'S REAL. IT HAS BEEN -- THE ONLY TRIAL, THE ONLY TRIAL THAT SHOWED A MORTALITY SIGNAL. JOHN MCCAIN, A WELL NON BIOSTATION WROTE A VERY NICE PAPER WITH A BUNCH OF HYPOTHESIS. THIS MAY BE A CHANCE POWER. EVEN WITH A PELL POWERED STUDY, ONCE IN A WHILE YOU GET A SIGNIFICANT EFFECT WITH ANOTHER. THERE MAY BE SPECIFIC DRUGS USED OR SOMETHING ELSE. TO MAKE THE POINT, THAT PEOPLE THAT DIED IN THE ACCORD TRIAL WERE THOSE IN THE INTENSIVE GROUP WHO'S GLUCOSE LEVELS DIDN'T GO DOWN, DEBITE BEING IN THE INTENSIVE GROUP. WE DON'T UNDERSTAND THAT SIGNAL. WE DON'T KNOW. AS YOU KNOW, THERE IS NOW TRIALS OF METFORMIN AND PEOPLE IN THE GENERAL POPULATIONS TO SEE IF WE CAN LIVE FOREVER. SO WE'LL SEE. >> YOU HAVE INDICATED A SIGNIFICANT REDUCTION IN EYE DISEASE. I WAS WONDERING, IS THERE REAL EVIDENCE OF ACTUAL REVERESAL OF SOME DEGREE OF REVERSAL OF EARLY VASCULAR DISEASE? I DON'T THINK YOU ADDRESSED THAT. THAT PERHAPS THERE IS SOME INDICATION IN -- ON A LONG TERM CONTROL OF GLUCOSE. >> THAT'S A VERY GOOD QUESTION. WE TRIED TO LOOK AT REGRESSION, AS WELL AS, THE RETINOPATHY. SOME OF IT MAY BE REGRESSION TO THE MEAN, THE WAY WE'RE DOING THE ANALYSIS. WE DON'T SEE IT WITH THE GLYCEMIC CONTROL THAT WE'VE LOOKED AT. BUT HAVING SAID, WHEN WE GIVE THERAPIES, INJECTION OF THE DRUGS TO BLOCK THE GROWTH FACTOR WE DO SOME SOME REGRESSION, THERE IS SOME IMPROVEMENT IN THOSE CASES OF EYES THAT ARE BEING TREATED. AND YOU ACTUALLY SEE THAT. AND ALSO BEEN SAID THAT YOU MIGHT SEE IT IN THE CELL, BECAUSE THE ABSORPTION OF THAT DRUG. WHETHER THERE IS VERY SPECIFIC MECHANISMS FOR THAT, THE GLYCEMIC CONTROL ITSELF WE HAVEN'T BEEN ABLE TO ESTABLISH AS SHOWING REGRESSION. >> I THINK -- I AGREE WITH THAT COMPLETELY. IT MAY VERY WELL BE, LIKE MANY THINGS, WHEN THERE IS TISSUE DAMAGE, IT BECOMES SCAR TISSUE AND FIBROSIS. OTHER THANKS MAY IMPEDE THE ABILITY TO REMODEL AND REBUILD THE EYE. SO CLEARLY STOP THE PROCESS, SLOW THE PROCESS. FROM PROGRESSING. BUT PROGRESSION IS A HARDER THING TO DO. IN MOST OF THESE, IT'S VERY HARD. WITH THE BEST THERAPIES. WE DON'T SEE IT IN DISEASE WHEN WE GET AGGRESSIVE RENAL THERAPY. WE SEE PARTIAL, NOT A LOT OF REGRESSION BACK TO THE ARENAL FUNCTION, ET CETERA. >> WELL, I WANT TO THANK BOTH SPEAKERS FOR GREAT TALKS AND THE HOUR IS NOW UP, SO WE'LL ADJOURN. THANK YOU. >> THANK YOU.