B (2:55)

Neil John, it's pretty amazing when you think about it that six and a half years of intensive treatment versus standard of care 30 years later has a substantial effect on hard outcomes of major cardiovascular events, decreasing those events by approximately a third. The question we then ask is how is it? Because from the end of the trial on the two groups had essentially the same glucose control and the term for this is is a legacy effect, meaning a period of time where someone is either controlled or uncontrolled years ago causes changes in the vasculature that persist with regard to the development of atherosclerotic plaque, leading to macrovascular disease as well as the development of microvascular disease up to now. Thirty years later we saw the same thing with tenure follow up with the UK PDS trial in type 2 diabetes published in the New England Journal in 2008. The real implications of this have to do with the decisions we make every day in the office and we've talked about in other podcasts the issue of therapeutic inertia and diabetes and the fact that when someone is uncontrolled not reaching their A1C target on a single oral hypoglycemic agent it can take up to two years on the average in a trial of 80,000 people in the 2003 article from Diabetes Care up to two years for treatment intensification and when someone is on two or three oral agents it can take approximately seven years till insulin is added. The important implications of this trial and the follow up of the UK PDS trial for those of us who make decisions every day in the office is that we really have to combat therapeutic inertia because periods where glucose is not controlled today and this year may not have implications for a while, but has important implications years down the road. So the results of this trial and support of the idea of a legacy effect that control now matters far into the future really should affect the way we think about things and our decisions every day in the office. Our next article from Diabetes Care is on the long term benefits of intensive glucose control for preventing end stage kidney disease. Advance on the advance trial reported that intensive glucose control prevents end stage kidney disease in patients with type 2 diabetes. A total of 8,494 advanced participants were followed for median of 5.4 additional years after the end of the trial. In trial hemoglobin A1C differences disappeared by the first post trial visit. The in trial reductions in the risk of end stage kidney disease 7 vs 20 events with a hazard ratio of 0.35 persisted after almost 10 years of overall follow up 29 vs 53 events for a hazard ratio of 0.54.

C (6:14)

John so I think this is a very interesting study and if you think about the advanced trial, remember that about 2/3 of the people in the advanced trial were over the age of 65 and I think when we talk about advance and accord, we think about older folks and we think about the kind of the fallout from these studies was that titer control can actually be associated with increased cardiovascular mortality in a senior citizen population. So maybe our targets need to be higher. So this trial seems to fall in line with everything else, that if we have better control of things that people are going to do better kidney wise. So diabetes in the developed world is now the number one cause of kidney disease and certainly if we do a better job glycemically, I think we're going to do better with regard to kidney disease. So I think the takeaway point is in this population, which is mostly senior citizens, that we shouldn't completely throw the baby out with the bathwater. So I don't think that we need to be pushing people necessarily to a 1Cs of 6.0. If we have to do that on the back of sulfonylureas and other things that put people at risk of hypoglycemia, that increases the chance of death. But I don't think we need to necessarily say that someone is 66 years old and we're going to forego all type of diabetes care because eventually they might live long enough that they are going to have some renal problems and all the consequences that go with that later in life. Our next article is from Diabetes Care and it looked at the association between hospitalization for heart failure and DPP4 inhibitors and patients with type 2 diabetes. An observational study so this was a retrospective observational study using US insurance claims databases. Patients initiated treatment between August 2010 and August 2013, had no use of comparator treatments in the prior 12 months after matching. The study included over 200,000 patients in comparison of DPP4 inhibitors in sulfonylureas and 112,000 in comparisons of saxagliptin and sitagliptin. The hazards ratio for hospitalization for heart failure were as follow. A DPP4 versus a sulfonylurea had a hazard ratio of 0.95 with confidence intervals between 0.78 and 1.15 for patients with baseline cardiovascular disease, hazard ratio of 0.59 with confidence intervals between 0.38 and 0.89 for patients without baseline cardiovascular disease. Looking at saxagliptin versus sitagliptin, the hazard ratio was 0.95 with confidence interval 0.7 to 1.28 for patients with baseline cardiovascular disease and a hazard ratio of 0.99 for patients without baseline cardiovascular disease Neil.

B (9:00)

John the conclusion of this trial showed that there was no, and I'll quote from the article, there was no association between heart failure or other selected cardiovascular outcomes and treatment with a DPP4 inhibitor compared to sulfonylureas and no difference between saxagliptin relative to sitaglipt. It really raises the question of how do you get at truth? So that recognized that's what this observational trial showed and then recognized that. In early April, the FDA issued a Drug Safety Communication warning about the risk of heart failure with two DPP4 inhibitors, saxagliptin and alligliptin, and that was based on two randomized controlled trials. Saxagliptin was studied in the Savor trial, which is a large prospect, multicentered randomized double blind placebo controlled trial of over 16,000 patients with type 2 diabetes who had established cardiovascular disease or were at high risk of cardiovascular disease. They were followed for two years on the average and there were more cases of heart failure, 3.5% of the cohort versus 2.8% in the saxagliptin group versus the placebo group group. Similarly, in the Examin trial which studied alligliptin, it was a placebo controlled trial. Over 5,000 patients, type 2 diabetes who had established cardiovascular disease or an acute coronary syndrome recently were followed for one and a half years. More patients randomized to the alligliptin group, 3.9% experienced at least one hospitalization for heart failure compared to patients randomized to placebo, which was 3.3%. Based on those two very large randomized trials, the FDA issued a Drug Safety Communication alerting health care professionals as well as patients to the possibility of the increased risk of heart failure, particularly in patients who already had heart or kidney disease with these two medicines. It's a reminder that we should never use the results of any single trial as the sole indicator of how to make clinical decisions. It's the accumulated information from a range of trials, both observational and randomized trials, that get us as close as possible to truth. I think here we need to be aware of the FDA warning and move ahead with caution in people who have either congestive heart failure or renal disease with this class of medications. Our next study from Diabetes Care is titled Cardiovascular Risk Factor Targets and Cardiovascular Disease Event Risk in Diabetes. The authors studied over 2,000 adults 28 to 86 years of age with diabetes but without known cardiovascular illness from three different cohorts of 2018 patients with diabetes 43% male, 55% African American, 41, 32 and 41% were at the set targets for blood pressure, LDL cholesterol and hemoglobin A1C, respectively. 41, 26 and 7% were at target levels for any 1, 2, or all 3 factors, respectively being at blood pressure, LDL cholesterol or A1C. Target levels related to A 17%, 33% and 37% lower cardiovascular risk and 17, 41 and 36% lower coronary heart disease risk, respectively. Those subjects with 1, 2 or all 3 risk factors at target levels versus those who had none at target levels had incrementally lower adjusted risks of cardiovascular events, that is 36% for those with 1 at target, 52% for those with 2 at target, and 62%, respectively for 3 at target, and incrementally lower adjusted risks of cardiovascular heart disease.

C (13:27)

JOHN so I think this study outlines a couple things and one of the things I think that is so exciting and so challenging for taking care of diabetes is there's a lot of different things we need to keep an eye on. And I think one of the things that makes us excited as clinicians is we have to keep keep up on things and we're having to know as guidelines change and things like that, that we can't singularly focus on one particular thing. I think it also shows that kind of more more control in more different areas does better. I think, which is interesting, is that they talk about an LDL goal of under 100, which is no longer the kind of the goal with the lay of the land, with the changing of guidelines and having a blood pressure control of under 130 over 80, which is no longer the ADA standard of care. So I think it's important that we keep track of A1C, keep track of blood pressure, and that we do keep track of lipids regardless of what the governing body at any one time place says is what we should be doing. But I think focusing on many different areas, kind of fighting this front on many different levels is going to lead for the best outcome for our patients. Our next article is from Diabetes Care and it looked at metabolic syndrome components and its association with symptomatic polyneuropathy independent of glycemic status. So this study looked at symptomatic distal symmetric polyneuropathy. In the Health, Aging and Body Composition study. It looked at subjects aged 70 to 79 years at baseline and they were stratified by glycemic status and the number of additional metabolic syndrome components. DSP was defined as neuropathic symptoms on a questionnaire plus at least one of three confirmatory tests heavy monofilament, perineal conduction velocity or vibration threshold. Of over 2,300 participants with neuropathy with a mean age of 73.5 years of age, 21% had diabetes, 29.9% prediabetes and 52.8 metabolic syndrome and overall 11.1 had distal symmetric polyneuropathy stratified by glycemic status. The DSP prevalence increased as the number of metabolic syndrome components increased. Overall, they found that independent of glycemic status, symptomatic DSP is more common in those with additional metabolic syndrome components.

B (15:51)

Neil John I think this study is very interesting because clinically not all the patients that I see who have a peripheral neuropathy have diabetes. It's always been puzzling because after referring them to neurology and after an extensive workup, there's often no clearly identified cause. And seeing this study which shows that there's a relationship between metabolic syndrome and peripheral neuropathy might explain some of those patients who who otherwise have unexplained peripheral neuropathies, which is really a very difficult illness for patients to deal with. In addition, anecdotally it seemed to me for many years that many of these patients eventually went on to develop diabetes. Many had pre diabetes. Again, that anecdotal observation is supported by the data in this study as one of the largest predictors of neuropathy or correlates to neuropathy in this study was prediabetes. When we look at the breakdown of what of the components of metabolic syndrome are most closely associated with peripheral neuropathy, it really did seem to be prediabetes and waist circumference. So this study supports what many people have observed in their clinical practice that there are many contributors to peripheral neuropathy and many of those contributors are included in the metabolic syndrome. Our next study from Diabetes Care is titled Very low calorie diet and 6 months of weight stability and type 2 diabetes pathophysiologic changes in responders and non responders people with type 2 diabetes duration of 0.5 to 23 years with 30 total patients followed a very low calorie diet for 8 weeks. All oral agents or insulins were stopped at baseline following a stepped return to an isocaloric diet. A structured individualized program of weight maintenance was provided to patients. Glucose control, insulin sensitivity, insulin secretion and hepatic and pancreas fat content were quantified at baseline after return to an isocaloric diet and after six months to permit the primary comparison of change between post weight loss and six months in responders. Responders were defined as achieving a fasting blood glucose less than 7 millimoles per liter after return to an isocaloric diet. Weight fell from 98 kg to 83 kg and remained stable over six months. Twelve of the 30 participants achieved fasting plasma glucose less than 7 millimoles per liter after return to an isocaloric diet. These were the responders and 13 of 30 after six months responders had a shorter duration of diabetes and a higher initial fasting plasma insulin level. Hemoglobin A1C fell from 7.1% to 5.8% in responders and from 8.4 to 8% in non responders.

C (19:07)

Sean so this is not necessarily new news to us. So this is something that Egyptians knew 3500 years ago. This is something they knew in India 2500 years ago. And in fact, if you look before of the advent of insulin in the United States, if you were a type 1 diabetic, you lived to be about, you lived about 10 months after your diagnosis. There was a sanitarium in New Jersey that was run by a Dr. Allen that kept people on extreme low calorie diets around 400 calories and actually extended these folks who were living about 10 months into be several years. And actually several patients lived long enough to see the advent of insulin. So in this particular particular trial, they gave people a commercial product and Optifast and gave them about 600 calories a day. And a lot of people did better. And I think we see this when we refer people who have diabetes onto a bariatric program where they lose a lot of weight through a calorie restriction and a lot of the folks who run 1, 2, 3 multiple diabetes medicines suddenly find themselves coming off this. So I don't think this is something that's necessarily novel. I think it would say to us, though, that perhaps we can achieve some of the wonderful response we're seeing in surgery through some very, very, very low calorie diets. Now, how well people are going to be able to adhere to a 600 calorie a day diet is pretty, pretty difficult. But I think even for our folks who are just starting out being diagnosed with diabetes, and actually the people who were just diagnosed seem to do a little bit better when we really should hit people that they do potentially have something that they could change the course of this river if they change what they're doing with regard to eating with regard to exercising and trying to have a significant weight loss.

B (20:54)

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.