C (4:13)

John thanks Neil Compared with the conventional group, the initial DCCT intensive group had beneficial effects on atherosclerosis. This was seen both in carotid intimal thickness and coronary calcium scoring six to 12 years after the end of the periods of randomized treatments. Furthermore, the benefits of intensive treatment increased with attained age. The benefits of the intensive versus conventional treatment were largely explained statistically by the difference between treatment groups in the DCCT hemoglobin A1C levels. Also, former intensive treatment reduced the aggregate cardiovascular risk by 42% and that of major cardiovascular events which include Michigan stroke and cardiovascular deaths by 57%. These long term benefits were also statistically explained by the differences between the groups in the mean A1C levels during the DCCT. Neil, do you want to talk about microvascular disease?

B (5:11)

Thank you John. Let's start with the findings and follow up. For kidney disease during DCCT, intensive therapy reduced the risk of microalbunuria macroalbiuria by 39% and 54% respectively during the follow up study. For years one through eight, participants previously assigned to the DCCT intensive group continued to experience lower rates of microalbinauria and macroalbinaria with risk reductions of 59% and 84% respectively. Beneficial effects of intensive therapy on the development of paired glomerular filtration rate and hypertension became evident during combined follow up with risk reductions of 50% and 20% respectively compared to conventional therapy. With regard to retinopathy, of the over 1400 DCCT subjects, 726 had no diabetic retinopathy and 715 had mild retinopathy at baseline. Individuals were followed for a mean of six and a half years. Intensive therapy compared with conventional therapy showed a reduction in adjusted mean risk for development of retinopathy by 76% and slowed progression of diabetic retinopathy by 54% when compared with conventional therapy following DCCT, the A1C levels in the original intensive as well as the conventional therapy groups converged by year eight. The intensive therapy group and the conventional therapy group were approximately an A1C of 8. Nonetheless, the groups continue to have a durable effect of initial insulin assigned therapy with significantly lower incidence of further retinopathy progression in the intensive care group with a hazard ratio of over 50%. Severe retinal outcomes and procedures to treat them with were reduced by 50% in the original intensive group. With regard to neuropathy, the intensive therapy during DCCT significantly reduced the risk of both diabetic peripheral neuropathy as well as cardiovascular autonomic neuropathy by the end of DCCT by 64% and 45%, respectively. The prevalence as well as incidence of both peripheral neuropathy and cardiovascular autonomic neuropathy remains significantly lower in the originally intensively treated therapy group compared to the conventional group through edic year follow up. 14 John, how do you put all this together?

C (8:07)

Well, I think this is very interesting and this is probably, you know, the most landmark study that's ever come out with diabetes. But 30 years is a long time and there's a lot of very young learners out there. I think it's very akin to saying to my children, there was a time that there weren't seat belts in cars and really that's kind of unfathomable. And to say to younger learners there was a time that there really wasn't a belief that better glycemic control correlated with better outcomes. And this wasn't just extreme people thinking this, this was some of the thought leaders at the time. You know, prior to banting and best, you know, no one with type 1 diabetes lived to have a complication because they died of ketoacidosis. They died of some complication from their acute type 1 diabetes. So suddenly the advent of insulin allowed people to live long enough to have complications. But there really wasn't a clear belief until this trial that if we had better control for folks that they would ultimately do better. The trade off and the long term trade off we've really seen is tighter control is associated with more hypoglycemia. And I think the second shoe that dropped, kind of the smaller shoe that dropped, was then the UK PDS that kind of had some similar evidence that came out with type 2 diabetes. So I really think if I was talking with a resident or student and really saying, you know, these are the two studies I think you should kind of know about in the history of diabetes, it probably would be the DCT trial and the UK PDS trial. And I think the other point to take away from these trials and looking back 30 years is really how someone's glycemic control was early on in the course of their disease really seemed to belie how they were going to do ultimately. So even though kind of both groups really converged with better glycemic control, how someone's glycemic control is early on in the course will really impact how they'll do long term with both macrovascular and microvascular disease. Our first article in this edition is from the November 2013 edition of Diabetes Care and it looked at safety and efficacy of sitagliptin therapy for the inpatient management of general medical and surgical patients with type 2 diabetes. This study was designed to look at the safety and efficacy of sitagliptin for inpatient management of patients with type 2 diabetes on general medical and surgical floors. It was a multi center, open label randomized trial that looked at 90 patients with a known history of type 2 diabetes who are treated with diet, oral diabetic agents or a low total daily dose of insulin less than 0.4 units per kilogram per day. The patients were randomized to receive sitagliptin alone or in combination with glargine insulin or a basal bolus insulin regimen plus supplemental correction doses of lispro. Major study outcomes included differences in daily blood glucose frequency of treatment failures, which was defined as three or more consecutive blood glucoses greater than 240 or a mean daily blood glucose greater than. They also looked at hypoglycemia between the groups. The glycemic control improved similarly in all treatment groups. There were no differences seen in the mean daily blood glucose after the first day of treatment, number of readings within a blood group close target of 70 to 140, number of blood glucose readings greater than 200 or number of treatment failures. The total daily insulin dose and number of insulin rejections were significantly less in the sitagliptin groups compared with the basal bolus insulin group. There were no differences seen in length of hospital stay or the number of hypoglycemic events.

B (11:55)

Neil John Inpatient management of hyperglycemia is an area that's seen a lot of changes over the last 10 to 15 years, beginning in the early part of the 2000s with a study done in a large surgical ICU setting at a single institution with which showed impressive results with intensive blood glucose management leading to recommendations for IV insulin protocols that were used in many hospitals across the country. What was interesting there is those results were never replicated in other studies that were done. Similar results were not able to be achieved. And then the NICE Sugar study, which came out about five years ago, showed in both surgical and medical inpatients worse outcomes with intensive blood sugar control among medical inpatients. This led to recommendations in 2009 from the American Diabetes association to target good but not intensive control of blood sugars among medical inpatients, and that target being aiming for a blood Sugar less than 180 as the target blood sugar for medical inpatients. This study's interest.

C (13:18)

Our next article is from Diabetes Care and it looked at is neighborhood green space associated with a lower risk of type 2 diabetes? Evidence from 267,000 Australians lifestyle interventions for type 2 diabetes are best positioned for success if participants live in a community that has supportive neighborhood environments. Deprived neighborhoods have increased type 2 diabetes risks. Parks and other green spaces promote a more active lifestyle and might reduce type 2 diabetes risk. So in this particular study they investigated the association between neighborhood green space and the risk of type 2 diabetes in a large group of adult Australians. They looked at 267,000 participants in the 45 and up study. Green space data was obtained from the Australian Bureau of Statistics. The rate of type 2 diabetes was 9.1% among participants in neighborhoods with 0 to 20% green space, but this rate dropped to approximately 8% for participants with over 40% green space within the residential neighborhoods.

B (14:21)

Neil John this study is a nice addition to something we discussed about three months ago where when we went over a working group statement on the socio and cultural determinants of diabetes, it's interesting. It isn't just individual choices and decisions that affect our burden of disease as a society and as individuals. It's also the social milieu in which we live. We saw in that paper, discussions and review of evidence that a decreased rate of walking to work and walking to school leads to increased rates of obesity and diabetes. Issues around food deserts in the inner city and inability to simply go to somewhere local to buy green vegetables leads to increased rates of poor food choices and subsequent obesity and diabetes. And in this study we see that the lay of the land, how much green space there is, has an effect on decisions that people make as individuals about whether or not to exercise, whether or not to walk, whether or not to go outside. And these individual decisions that are made in the context of what's available have very real impacts on the rate of diabetes among individuals in society. So this is another very good example of a social determinant that leads to an effect on diabetes rates. Our next study is on serum omega 3 polyunsaturated fatty acids and the risk of incident type 2 diabetes in men. The study looked at the relationship of omega 3 fatty acids and type 2 diabetes. A total of 2,212 men from the prospective population based ischemic Heart Risk factor study aged 42 to 60 years of age and free of type 2 diabetes at baseline in 1984 to 1989 were followed. Serum omega 3 fatty acids as well as hair mercury as an indicator of fish intake were used as biomarkers. Dietary intake was assessed with a four day food recording. Type 2 diabetes was assessed by self administered questionnaire as well as blood work. 4 years, 11 years and 20 years after baseline, during an average follow up of 19.3 years, 422 men developed type 2 diabetes. Men in the highest versus the lowest serum EPA plus DPA plus DHA, I.e. omega 3 fatty acid quartiles had a 33% lower adjusted risk for type 2 diabetes and there was no effect of mercury on this risk.

C (17:20)

John so this is not a trial of fish oils and this has been a bad year for fish oils. Three separate trials really looked at exogenous fish oil tablets and really did not show a difference with heart disease. This is looking at fish consumption and there was a great article in Jama in 2006 that actually looked at fish consumption. And I think people get so kind of worried about the potential bad things that might possibly be in fish that some people will avoid this. And really people who eat more fish, people who eat it twice a week, which is not a ton of fish, actually have a 17% lower chance of having a cardiovascular event. I think when we're eating fish for dinner, we're not necessarily eating a hamburger for dinner. We're not necessarily eating something that is bad. The Japanese have far and away the highest fish consumption in the world and they probably have the best metrics for heart disease. When you worry about some of the things related to fish, we worry about dioxins and PCBs which are the most cancer producing substances on the planet. But actually the most common source of PCBs in our diet is actually beef and pork and chicken. So it's really not in the fish. With regard to mercury, they're relatively small amounts and it's going to be in our larger predatory fish. And certainly two servings a week is really not going to be that big a deal. We certainly might want smaller children and pregnant women to stay away from it. But I think overall our message to our patients is fish is really a good thing. There is evidence that eating fish, eating natural omega 3 fatty acids, has health benefits that really does not completely translate into this Time to the Pill version.

B (19:08)

For more information and links to the articles that we discussed in this issue, just go to www.diabetesjournals.org. until next week, keep listening and keep learning. Sam.