Intensive glucose control in DM1 and long term risk of impaired GFR

Intensive Diabetes Therapy and GFR in Type 1 Diabetes

The DCCT/EDIC Research Group*

NEJM Nov 12, 2011

Abstract

BACKGROUND

An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population.

METHODS

In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m² of body-surface area at two consecutive study visits.

RESULTS

Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m² during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m² (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates.

CONCLUSIONS

The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy.

Key facts:

• Briefly, intensive therapy consisted of three or more injections of insulin daily or the use of an insulin pump, with the aim of achieving a glycated hemoglobin level of less than 6.05% (which was considered to be the upper limit of the normal range). The goal of conventional therapy was the prevention of symptoms of hyperglycemia and hypoglycemia with the use of one or two injections of insulin daily.

• The mean glycated hemoglobin level during the DCCT (1983 through 1993), time-averaged throughout the study, was 7.3% in the intensive-therapy group and 9.1% in the conventional-therapy group.

• The median follow-up period for the two studies combined was 22 years (interquartile range, 21 to 24). During this time, impairment of the GFR developed in 70 participants, of whom 24 had been assigned to DCCT intensive therapy and 46 to DCCT conventional therapy

• Our data suggest that giving approximately 29 persons with type 1 diabetes intensive diabetes therapy for 6.5 years prevents one case of an impaired GFR over a total follow-up period of 20 years.

• Moreover, along with congruent salutary effects on retinopathy, neuropathy, and cardiovascular disease, these effects reinforce current recommendations to target a glycated hemoglobin level of less than 7% in patients with type 1 diabetes.10,11

Long-Term Persistence of Hormonal Adaptations to Weight Loss

Priya Sumithran, M.B., B.S., Luke A. Prendergast, Ph.D., Elizabeth Delbridge, Ph.D., Katrina Purcell, B.Sc., Arthur Shulkes, Sc.D., Adamandia Kriketos, Ph.D., and Joseph Proietto, M.B., B.S., Ph.D.

N Engl J Med 2011; 365:1597-1604October 27, 2011

Background

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.

Methods

We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.

Results

Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).

Conclusions

One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.)

Review - Recurrent/Persistent Primary Hyperparathyroidism

R. Udelsman. J Clin Endocrinol Metab, October 2011, 96(10):2950 –2958

Excellent review from JCEM here.

Useful extracted quotes:

• Persistent 1°HPTH accounts for the vast majority of patients who require reexploration.
• 
  
• The most common cause of persistent 1°HPTH is surgeon inexperience in locating and adequately excising a parathyroid adenoma. Although a subset of these retained glands will eventually be located in ectopic locations, the majority are eutopic and accessible by repeat cervical exploration.
• 
  
• Recurrent 1°HPTH implies that the patient had an initial successful operation, maintaining normal serum PTH and calcium levels for at least 6 months postoperatively,
• and then developed recurrent disease.
• 
  
• Other causes of an elevated serum PTH must be considered. These include mild degrees of secondary HPTH due to renal insufficiency, a renal calcium leak, gastrointestinal tract abnormalities, vitamin D deficiency, as well as a variety of other rare causes.
• 
  
• There are no published guidelines directly applicable to the indications for reoperative parathyroid surgery. It is reasonable to extrapolate recommendations employed for
• the unexplored patient with the caveat that the threshold for surgical exploration should be higher due to the inherent difficulty encountered in the reoperative patient.
• 
  
• Imaging can be broadly divided into noninvasive and invasive studies. The noninvasive studies include ultrasound, technetium 99m sestamibi scans [preferably employing single photon emission computed tomography (CT)], CT scans [preferably four-dimensional (4-D)], occasionally MRI scans, and in some institutions fusion studies including sestamibi-CT scans (11, 12). Invasive studies encompass ultrasound-guided PTH aspiration and angiographic procedures including arteriography and venous sampling for PTH, preferably with on-site PTH analysis to guide the angiographers (13).
• 
  
• All of the imaging studies are less reliable in the redo neck, and false-positive and false-negative results are frequently encountered.
• 
  
• The reoperative neck poses significant technical challenges due to scar formation and distorted anatomy that make it more difficult to identify and safely remove abnormal parathyroid glands. In addition, the external branch of the superior laryngeal nerve and the recurrent laryngeal nerve are at increased risk of injury.
• 
  
• We and others have found the use of a rapid intraoperative PTH assay to be of critical importance in the re-operative patient.
• 
  
• The classic medial approach to the parathyroid glands mobilizing the strap muscles from their midline position by progressive lateral mobilization is generally employed in the unexplored patient. In the redo neck, these muscles become fused to the underlying thyroid gland and trachea. Hence, in the reoperative neck a lateral approach is frequently employed, mobilizing the plane between the medical border of the ipsilateral sternocleidomastoid muscle and the lateralborder of the strap muscles.

Quote for the Day

"The purpose of computing is insight; not numbers."

-RW Hamming

Clinical Inertia as a Clinical Safeguard - JAMA 2011

Article here.

Seems to be the month for sensible articles about Medicine.

Conflicts of Interest Abound in Diabetes Guidelines Committees

(from Medscape)

Reed Miller

October 12, 2011 (New York, New York) — About half the experts serving on the committees that wrote national clinical guidelines for diabetes and hyperlipidemia over the past decade had potential financial conflicts of interest (COI), and about 4% had conflicts that were not disclosed [1].

Dr Jennifer Neuman (Mount Sinai School of Medicine, New York, NY) and colleagues reviewed the financial ties to industry of 288 panel members who served on 14 guidelines committees in the US and Canada between 2000 and 2010. Results of their study were published online October 11, 2011 in BMJ.

Read more....

If you read nothing else this month, read this

The New Language of Medicine - NEJM 2011

Finally, someone is addressing the real problems in medicine right now. Everything we do should be based on clinical judgement. Now it's a dirty word. Down with flowcharts, guidelines, evidenced based non-sense, public health data miners, physician "extenders", doctor-nurses and bean counters! (And by the way down with electronic medical records until that software technology is at least 50% as good as my iPhone's!!!)

ACTH stim test in diagnosis of aldosterone producing adenoma

Significane of ACTH Stimulation Test in the Diagnosis of an Aldosterone Producing Adenoma

Takuhiro Sonomyam et. al

Abstract

Context: Adrenal venous sampling is the “gold standard” test in the diagnosis of an aldosterone-producing adenoma (APA) among patients with primary aldosteronism (PA) but is available only in specialized medical centers. Meanwhile, an APA is reported to be generally more sensitive to ACTH than idiopathic hyperaldosteronism.

Objective: The aim was to evaluate the diagnostic accuracy of the ACTH stimulation test in the diagnosis of an APA among those with suspicion of PA.

Patients and Setting: Fifty-nine patients admitted to Kyoto University Hospital on suspicion of PA were included in the study.

Interventions: ACTH stimulation tests with 1-mg dexamethasone suppression were performed.

Main Outcome Measure: Plasma aldosterone concentrations (PAC) were examined every 30 min after ACTH stimulation. Receiver-operated characteristics curve analysis was used to evaluate the diagnostic accuracy.

Results: PAC after ACTH stimulations were significantly higher in patients with an APA than in patients with idiopathic hyperaldosteronism or non-PA. Receiver-operated characteristics curve analyses showed that the PAC after ACTH stimulation was effective for the diagnosis of an APA among patients suspected of PA. The diagnostic accuracy was highest at 90 min after ACTH injection, with the optimal cutoff value greater than 37.9 ng/dl corresponding with sensitivity and specificity of 91.3 and 80.6% for the diagnosis of an APA.

Conclusions: Our study indicates that the ACTH stimulation test is useful in the diagnosis of an APA among patients suspected of PA. This test can be used to select patients who are highly suspected of an APA and definitely require adrenal venous sampling.

--------------------------------

Why this study?

- It's always good to review the workup of hyperaldosteronism.

- It's always difficult to make an exact diagnosis (in my opinion), because of limitations of test methods.

- It's always good to see what researchers consider to be the gold standard for diagnosing a particular condition, since their new test has to be measured against some existing standard.

To screen for PA they used aldosterone concentration (PAC) over plasma reninin activity (PRA) to get the aldosterone-renin ratio (ARR). A value of > 20 ng/dL was considered positive. All anti-hypertensive medications except calcium channel blockers and alpha blockers were stopped at least 2 weeks prior.

The captopril challenge test was used to confirm the diagnosis. An ARR of at least 20 ng/dl per ng/ml*h at 60 min after 50 mg captopril was considered positive for primary aldosteronism. Adrenal CT scanning was used for initial localization. They used adrenal venous sampling to definitively subtype the primary aldosteronism.

Subjects that met study criteria underwent ACTH stim testing as follows: 1 mg dexamethasone at 2300h. 0800 0.25 mg cosyntropin. Plasma aldosterone at baseline and every 30 min for 120 min. 20/23 patients in the APA group underwent laparoscopic adrenalectomy and all of those had pathologically confirmed adrenal adenomas.

Why ACTH stim testing? Back in 1978 apparently Kem et al. reported a difference in PAC in response to ACTH between aldosterone producing adenomas (APA) and idiopathic hyperaldosteronism (IHA). The posture stimulation test had made use of the observation that the PAC in IHA patients increased when changing from a supine to standing position based on enhanced sensitivity of the adrenal zona glomerulosa to changes in angiotensin II (AII). However, later reports showed that actually a number of APA are actually responsive to AII (AII-R), therefore making the postural stim test unhelpful in distinguishing APA and IHA. On the other hand, both AII unresponsive APA (AII-U) and AII-R APA were shown to be more responsive to ACTH stim than IHA. Therefore this study was designed to show that the difference in ACTH stim response could be used to distinguish APA from IHA. This could potentially be helpful in locations where adrenal venous sampling is done infrequently.

As seen above, the sensitivity and specificity are fairly high at distinguishing the two conditions at 90 minutes. The idea as far as I can gather is that this test could be used to rule in IHA and spare the need for adrenal venous sampling in those patients and therefore treat medically. Those who are suspected of having an APA would be referred to locations where adrenal venous sampling is done often enough to be deemed accurate.

Abstract 1489: Mechanisms Underlying Cardioprotective Effects Of Glucagon-like Peptide-1 In Ischemia-reperfusion Injury

This study discuss the mechanism of incretin benefit in the heart.

This also is from the expert of incretin in the west side of the hemisphere, Daniel Drucker.  This shows that the DPPIV blunts the benefit of GLP-1.

Kiwon Ban ; Judith Hoefer ; Steffen S Bolz ; Daniel J Drucker ; Mansoor Husain
Depts of Medicine and Physiology, Heart & Stroke Richard Lewar Cntr of Excellence, Banting & Best Diabetes Cntr, Samuel Lunenfeld Rsch Institute, Univ of Toronto, Toronto, Canada
Background: GLP-1 is a member of the gut incretin hormone family, and a GLP-1 receptor agonist (exendin-4) is approved for the treatment of Type-II diabetes. Studies in man post-MI, and in rat and dog models suggest that GLP-1 is cardioprotective. However, the mechanisms underlying the effects of structurally diverse GLP-1 peptides in the heart have not been fully elucidated.
Methods & Results: GLP-1(7–36) (i.e. GLP-1), its cleavage product GLP(9–36), and the degradation-resistant GLP-1R agonist exendin-4 were examined in 30 min of global ischemia followed by 40 min of reperfusion (I/R) in Langendorff isolated heart preparations from both wild-type (WT) and GLP-1 receptor knockout (GLP-1R^–/–) mice. In WT mice, recovery of left ventricular developed pressure (LVDP) following I/R was higher in GLP-1 pre-infused hearts than in untreated controls (79±9 vs. 42±1%; p<0.01). Pre-treatment with 5 nM but not with 0.3~3 nM exendin-4 also protected the heart from I/R injury. Although pre-infusion of GLP(9–36) induced lower recovery than untreated controls (21.4±1%), post-infusion of either GLP(9–36) or GLP-1 augmented functional recovery to a similar extent (59.1±6% and 53.3±6%). Surprisingly, the cardioprotective effects of pre- and post-treatments with both molecular forms of GLP-1 were detected in studies with GLP-1R^–/– hearts (80.1±6% and 55.8±8). Of note, both GLP-1 and GLP(9–36) treatments also demonstrated potent vasodilatory effects, as manifested by increased coronary flow rates in isolated hearts and increased diameters of pre-constricted mesenteric arteries isolated from both WT and GLP-1R^–/– mice. The cardioprotective effects on isolated hearts and vasodilatory effects on isolated mesenteric arteries, induced by GLP-1 was blunted by co-treatment with a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, that blocked conversion of GLP-1 to GLP(9–36). Increased cGMP release in the coronary effluents was also observed following addition of GLP-1 and GLP(9–36) to hearts isolated from WT and GLP-1R^–/– mice.
Summary: These data expand the complexity of GLP-1 biology by illustrating that the beneficial effects of GLP-1 in I/R injury are mediated in part by GLP(9–36) via a NO/cGMP-dependent vasodilatory effect that is independent of the known GLP-1R.

Effects of DPP-4 inhibition on cardiac metabolism and function in mice.

Lenski M, Kazakov A, Marx N, Böhm M, Laufs U.

Source

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Abstract

Type 2 diabetes is associated with an increased risk of cardiac complications. Inhibitors of dipeptidylpeptidase 4 (DPP-4) are novel drugs for the treatment of patients with type 2 diabetes. The effect of DPP-4 inhibitors on myocardial metabolism has not been studied in detail. In wild-type C57Bl6-mice, 3weeks of treatment with sitagliptin had no effect on body weight and glucose tolerance nor on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoAcarboxylase (ACC), phosphofructokinase-2 (PFK2) or tuberin-2 (TSC2) in the left ventricular myocardium. However, in 10week old db/db-/- mice, a model of diabetes and obesity, sitagliptin potently reduced plasma glucose rise in peritoneal glucose tolerance tests and reduced weight increase. The myocardium of untreated db/db-/- mice exhibited a marked increase of the phosphorylation of AMPK, ACC, TSC2, expression of p53 and fatty acid translocase (FAT/CD36) membrane expression. These changes were reduced by DPP-4inhibition. Sitagliptin showed no effect on cardiomyocyte size but prevented myocardial fibrosis in the 10week old db/db-/- mice and reduced expression of TGF-β1, markers of oxidative stress and the accumulation of advanced glycation end products in cardiomyocytes. Working heartanalyses did not show an effect of sitagliptin on parameters of systolic cardiac function. In animals with diabetes and obesity, sitagliptin improved glucose tolerance, reduced weight gain, myocardial fibrosis and oxidative stress. Furthermore the study provides evidence that treatment with sitagliptin decreases elevated myocardial fatty acid uptake and oxidation in the diabetic heart. These observations show beneficial myocardial metabolic effect of DPP-4 inhibition in this mouse model of diabetes and obesity.