D (3:32)

John so the results of this were a little surprising. So a court in advance.

C (3:37)

What I really take away from that is that we should individualize our diabetic care in our senior citizens and having tight control in the wrong senior citizen population could certainly lead to increased mortality. We did see in this study that the folks who were in the older group were much more likely to have hypoglycemia than the lower group. And certainly we've looked at other studies in the last year that associated severe hypoglycemia with increased mortality.

D (4:07)

Was a little bit surprised that when we looked at the subgroup of very tight control in the younger subgroup that.

C (4:14)

Was increased cardiovascular mortality. I'm not completely sure what to make of that. Not sure if it means anything, but.

D (4:20)

I think severe hypoglycemia, tight control, often.

C (4:24)

Walk hand in hand and oftentimes that's not the easiest thing in people.

D (4:28)

If you look at the confidence intervals.

C (4:30)

And everything else that they looked at.

D (4:31)

At the study, there was really a.

C (4:33)

Wide range and really the cardiovascular issue in the younger patients was really the only thing that I viewed as significant.

D (4:44)

Our next article is from the March 2014 edition of Diabetes Care, and it looked at the pharmacogenetics of type 2 diabetes.

C (4:52)

A systematic review.

D (4:54)

So the researchers performed a search of electronic databases and they looked at various original longitudinal studies that looked at the effect of diabetes medicines on incident diabetes, A1C, fasting glucose and postprandial glucose in either patients with prediabetes or type 2 diabetes and looked at genetic variation. The two investigators reviewed titles, abstracts and articles independently of the over 7,000 citations. They included 34 articles that looked at a variety of medicines, including metformin, sulfonylureas, ripaglinide, the glitazones and acarbose. Significant medication gene interactions for glycemic outcomes included a variety of different sites. Overall, they found pharmacogenetic interactions for metformin, sulfonylureas, lopaglinide, the thioglitazones and a carbo consistent with their pharmacokinetics and pharmacodynamics.

B (5:53)

Neil John, you know, it's interesting. We were talking in Journal Club earlier today about the issue of pharmacogenomics and the fact that it's been out there for over a decade. Incredibly exciting, logically makes sense. It's clear that some patients respond to treatment with a given medicine while others do not. Not and wouldn't it be nice if we could for instance, predict ahead of time by genomic testing which patients, when they're given an ACE inhibitor, would get angioedema so we could know not to give those patients ACE inhibitors in the product insert. Currently, for warfarin, there's discussion of genetic testing to decide on initial dosing. Of course that's never panned out because you dose before you ever get the genetic testing back. Genomics has been talked about with regard to Plavix and metabolism Plavix this article reviews the fact that yeah, there appears to be some information that suggests that there's a relationship between response to certain oral hypoglycemic agents and certain genetic characteristics. The reality though is that as exciting as it is, and as much as we hope to someday have individualized medicine where by genetic testing we'll be able to know whether a medicine is going to work, we're a long way from that day to day. And this is an article that remains interesting, shows potential for future promise and really isn't much more than that. Currently our next article from the March edition of Diabetes Care is titled Does a patient managed insulin intensification strategy with insulin glargine and Insulin glulysine provide similar glycemic control as a physician managed strategy? Result of the START study this study looked at patients with type 2 diabetes and A1C levels greater than 7 who also either had nighttime hypoglycemia or morning blood Sugars less than 108 milligrams per deciliter on a titrated up dose of basal insulin, meaning you couldn't titrate that dose any higher without causing further hypoglycemia. Patients were then randomized to either a patient directed titration schedule for short acting insulin prior to the breakfast meal or calling their physician with their blood sugar. Results for recommendations for titration after randomization, all patients continued to receive their fixed glargine dose and they had added glulysine before breakfast. The self titration method here was interesting. The starting dose of glulysine was two units and and they were instructed to self titrate by 1 unit per day to reach a target 2 hour post prandtl level between 90 and 144mg per deciliter. Postprandial sugars were measured 2 hours after the start of breakfast. Those in the physician managed group called their physicians regularly for advice on what to do. So the titration schedule here was simple and what was different then is often done when adding short acting insulin before a single meal as it was with breakfast instead of dinner. What results showed was that after 24 weeks, 28% of participants in the self titration arm versus 21% of the patients in the physician titration arm achieved an A1C level of less than 7 without severe hypoglycemia. The lower end of the 95% composite interval was within the predetermined non inferiority boundary, meaning the two titration schedules worked similarly and were similarly effective.

D (10:07)

John so Neil, 50% of the folks who take insulin in the United States are really not at control.

C (10:13)

So certainly kind of having a working day in and day out algorithm to add short acting insulin to people on basal insulin and this seems as good as any.

D (10:24)

Couple thoughts is they really have a.

C (10:26)

Very tight 2 hour postprandial sugar when you think that they're asking people to be 99 to 145. Two different postprandial guidelines. American College of Endocrinology has a two hour guideline of under 140. American Diabetes association has 180.

D (10:43)

So they're really keeping people very tightly this like many other things I think.

C (10:48)

When we can empower the patient to really be a partner in their disease, people do better regardless whether it's diabetes, hypertension or anything else we take care of.

B (11:02)

Our next article is from the winter edition of clinical diabetes on SGLT2 inhibitors and a review of mechanism and clinical studies of these medications for glycemic control. SGLT2 inhibitors stands for Sodium Glucose Cotransporter 2 inhibitors and they facilitate reabsorption of glucose back into the plasma from the proximal tubule of the kidney. Inhibiting this process promotes glucosuria and by so doing reduces blood sugar. The resorption of glucose filtered into the glomerular filtrate is the primary mechanism by which the kidney influences glucose homeostasis in healthy individuals. The kidney contributes significantly to glucose homeostasis by resorbing approximately 180 grams of glucose that is filtered by the kidney. Daily resorption occurs in the proximal tubule and is carried out primarily by the SGLT inhibitors. SGLT 2 reabsorbs 90% of the filtered glucose. The renal glucose threshold is the plasma glucose concentration above which the SGLT2 capacity becomes saturated and where urinary glucose excretion occurs, that usually occurs at about 200 milligrams per deciliter. The rate of glucose reabsorption is elevated in patients with type 2 diabetes as well as both the expression and function of SGLT2 mechanisms. The SGLT2 inhibitors suppress that renal glucose reabsorption and therefore increase urinary glucose excretion. SGLT2 inhibition acts independently of insulin and because of that, theoretically and in fact what we see in clinical studies, these agents shouldn't cause hypoglycemia. Given their mechanism, they also should be effective in patients with varying degrees of insulin resistance or beta cell dysfunction. Also, since remember glucose is spilling into the urine, they should be associated and in fact are with weight loss that results from the loss of glucose which has calories into the urine. What clinical studies show, in fact is that placebo adjusted reductions in A1C of up to 1.2% have been reported in studies that range from four weeks on up to 90 weeks in duration. Phase 2 and 3 clinical trials of the SGLT2 inhibitors used as add on therapy demonstrated improved glycemic control with low rates of Hypoglycemia. Reductions in A1C up to 1% from baseline occur in patients with A1Cs of about 8%. A1C decline by up to 2% in one study of dapagliflozin when added to metformin where patients on entry had A1Cs that were above 9%. A pooled analysis of Phase 3 studies showed that the higher the baseline A1C, the greater reduction in A1C with SGLT2 inhibitors, which makes sense. SGLT2 inhibitors also produce weight reductions up to about 4.5 kg in Phase 2 and 3 clinical trials and lower systolic blood pressures in the range of 2 to 10 millimeters of mercury reduction. With regard to safety and tolerability, they show very low rates of hypoglycemia in the clinical trials. Some studies have shown an increased incidence of urinary tract infections, though that increased incidence seems to be small and a significant increase in candida vulvovaginitis.

D (15:01)

John so once again we should, you know, with the new class of medicine.

C (15:06)

We should apply our rubric that we should when we're looking at any of our diabetes medicines. And certainly I don't think this medicine is really going to be our go to monotherapy medicine and it's probably going to be an add on medication after metformin and go in that group of medicines.

D (15:26)

So what are the things we should.

C (15:27)

Look at with medicines? Well, does this medicine cause hypoglycemia no, it does not. Does this medicine lead to weight loss? Yes, it does. This a medicine that has a safety profile that is acceptable? Well, certainly there are kind of plus minuses over whether this causes increased urinary tract infections. Some studies say more than others. It does clearly cause some vulvovaginitis and some balanitis at a more significant rate. So I think that's something we need to take into account. Otherwise the safety profile looks like it's going to be pretty good. And it is going to be a medicine that's going to have, as any newer medicine is going to have, is going to have some increased cost. So I think this is going to be something that's going to fall in. But most important of all of our things is what's the A1C reduction?

D (16:19)

And this certainly seems to have a.

C (16:21)

Wide range when we look at the clinical studies, anywhere from down to 0.4 as we're going to see in our next study that we're going to talk about, to as high as 2 point reduction and in some of the other trials. Overall, the higher the A1C reduction has been in studies where someone had a higher A1C at baseline. So in the studies where you're looking at someone in the sevens, you're probably going to get less of a response than someone who's in the 9s and 10s.

B (16:53)

Our next article from Diabetes Care is on Depagla 4 is effective as add on therapy to sitagliptin with or without Metformin 24 week multi center randomized double blind placebo controlled study. This was a 24 week multicenter randomized double blind placebo controlled parallel group phase 3 study with 24 week blinded extension period. Over 400 patients were randomized to receive dapagliflozin 10mg daily or placebo added to sitagliptin 100mg a day with or without metformin at a dose of greater than 1500 milligrams a day. Baseline A1C was 7.9% and fasting glucose was 162 milligrams per deciliter for the dapagliflozin group and approximately the same for the placebo group. At week 24, Dapagliflozin significantly reduced mean A1C levels by 0.5% for versus placebo which was 0%. Dapagliflosin reduced body weight versus placebo by 2.1 kg versus 0.3 kg and reduced A1C levels in patients with baseline values greater than 8 by 0.8% versus 0% for placebo.

D (18:17)

John so this study looking at dapagliflozin.

C (18:22)

Which was recently approved by the FDA January 8th of 2014 echoes a lot.

D (18:28)

Of the things we talked about when.

C (18:30)

We talked about a class review of the medication.

D (18:33)

So in this particular article you had.

C (18:35)

People whose A1Cs were elevated but not incredibly so, and you saw a modest reduction of A1C as a add on third medicine.

D (18:44)

A 0.5 point.

C (18:47)

Reduction in A1C was a well tolerated medicine with not a.

D (18:52)

Whole lot of side effect profile and.

C (18:54)

Certainly saw the weight loss that we would be expecting. Our next article is from Diabetes Care.

D (19:02)

And it looked at a randomized controlled trial of cognitive behavioral therapy or CBT looking at adherence and depression in patients with uncontrolled type 2 diabetes. 87 adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual including medication adherence, self monitoring of blood glucose, lifestyle counseling, a provider letter, documented psychiatric diagnosis. The patients were then randomized to an intervention arm which included nine to 11 sessions of CBT immediately after acute treatment. Adjusting for baseline, the CBT group had a 20.7% point greater oral medication adherence on electrical pill count, a 30 percentage point greater self monitoring of blood glucose adherence, 6.44 points lower depression scores and a 0.72 unit lower A1C relative to the standard intense therapy group analysis at 4, 8 and 12 months follow up indicated that the CBT group maintained 24 percentage points higher medication adherence, 17 point percentage points greater adherence to self monitor blood glucose 0.63 units lower of A1C.

B (20:21)

Neil John, I think this is a very exciting study. Two important aspects of it. First, it's a reminder that patients with any chronic disease, including diabetes, actually have about twice the rate of depression as the population at large. So if you look at a large group of patients with diabetes, about 25% of them also suffer from from concomitant depression. And that needs to be addressed because other studies that we've reviewed, actually a couple last year show that patients who are depressed with diabetes have poorer adherence to medications and not surprisingly poor A1C outcomes likely secondary to issues around lifestyle and taking their medicines. Second point, lifestyles and important and things that impede our ability to carry out our goals need to be addressed directly with behavioral techniques. Adding more medications, different medications isn't the only approach. CBT is well documented in through over 500 studies to have efficacy on things like depression, anxiety, also insomnia. This is a wonderful study showing that CBT that directly addressed problem solving skills, behavioral change, increasing pleasurable activities, and decreasing depressive symptoms in patients led to very real results with proven increase in pill adherence and an improvement importantly in a 1C that is on the same level as most of the new medications that we use as ADD on therapy. So I think this shows that CBT is an available technique for helping an important subgroup of our patients with diabetes. For more information and links to the articles that we discussed in this issue, just go to www.diabetesjournals.org until next week.

D (22:34)

Keep listening and keep learning.

E (22:37)

Sam It.