diabetes counseling and education. which is recognized and certified by the. American Diabetes Association. See page 3 of this issue for the …
Diabetes2008
From the 44th Annual Meeting of the European Association for the Study of Diabetes I Rome, Italy
Sponsored by Ya l e U n i v e r s i t y S c h o o l o f M e d i c i n e , Department of Internal Medicine, Section of Endocrinology
2004 2005 2006 2007 2008 2009 2010
Volume 18
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Important data on diabetes presented at the 44th Annual Meeting of the European Association for the Study of Diabetes comes to you in Diabetes 2008, a newsletter CME program that is being offered to you by Yale University School of Medicine Fax or e-mail delivery to your office of Diabetes 2008 will be followed by a Diabetes 2008 booklet EASD and AHA newsletters in the mail After successfully completing the quiz and evaluation therein contained, you will qualify for up to 55 AMA PRA Category 1 CreditsTM to be issued by Yale University School of Medicine Diabetes 2008 is being offered to physicians practicing in the United States After successfully completing this program, participants will be able to:
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DIRECT to the Point
Duration of diabetes is a major risk indicator for the development of retinopathy, a progressive condition with potentially devastating
consequences After 20 years of disease, nearly all Type 1 patients and over 60 percent of those with Type 2 diabetes will have developed some degree of retinopathy There are currently three approaches with long-term, favorable effects on its progression–glycemic control, anti-hypertensive therapy, and laser photocoagulation There is some evidence that inhibition of the renin-angiotensin system RAS may have benefits on diabetic eye disease above that fully accounted for by effects on blood pressure The DIabetic REtinopathy Candesartan Trials DIRECT Program consisted of three randomized, double-blind, placebo-controlled, multicenter studies These were designed to assess if RAS blockade with candesartan, an angiotensin receptor blocker ARB, will halt the progression of retinopathy in Type 1 and Type 2 diabetes patients DIRECT Protect, and even possibly prevent the development of retinopathy in those with Type 1 diabetes DIRECT Prevent The third analysis, DIRECT Renal, determined the impact of candesartan on the development of microalbuminuria Patients enrolled in these studies were normotensive or had their blood pressure BP controlled with anti-hypertensive therapy Retinal
involvement was graded using the Early Treatment Diabetic Retinopathy Study ETDRS 7-step scale based on 7-field stereophotographs performed annually After baseline studies, patients were randomized to treatment with 16 mg candesartan or matching placebo; the dose was increased to 32 mg after one month Any other anti-hypertensive agents were not changed Members of the DIRECT Steering Committee, Drs Chaturverdi UK, Sjolie Denmark, and Bilous UK, presented the DIRECT results on the final day of the EASD meeting A total of 5,231 patients were randomized in 30 countries Type 1 diabetes patients in DIRECT Protect had baseline HbA1c of 85, with 49 having mild proliferative retinopathy PDR and 9 having moderate-tomoderately severe PDR Type 2 diabetes patients in DIRECT Protect were similar, with a baseline HbA1c of 82; 17 had moderate-to-moderately severe PDR In DIRECT Protect, there was no significant change in the progression of retinopathy in Type 1 patients Table 1 However, Type 2 diabetes patients in DIRECT Protect did enjoy a significantly increased 34 likelihood of retinopathy regression DIRECT Prevent demonstrated 18 and 35 decreases in the incidence of retinopathy as per 2-step or
3-step changes on the ETDRS scale, respectively There was no significant difference between groups relative to the incidence of microalbuminuria, but the overall rate was exceedingly low 10 of that observed in the DCCT Of note, however, mean BP in the active-therapy groups in the DIRECT trials was 2 to 4 mmHg lower than placebo When the investigators adjusted for BP, the hazard ratios HR did not change appreciably– suggesting that any benefit on retinopathy may be a direct effect of the drug So, the ARB candesartan appears to reduce the incidence of retinopathy in patients with Type 1 diabetes and retinopathy progression in those with Type 2 diabetes These results may be viewed at: wwwdirect-resultsorg Hazard Ratio DIRECT Prevent: Incident Retinopathy Type 1 Diabetes 2-Step ETDRS change 3-Step ETDRS change DIRECT Protect: Retinopathy Type 1 Diabetes Progression Regresssion Type 2 Diabetes Progression Regression
Data not presented
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Explain the pathogenesis of Type 2 diabetes, especially the coexisting roles of insulin resistance and insulin secretion Recognize the clinical manifestations of the macrovascular and microvascular complications of diabetes and describe
appropriate therapeutic interventions Recognize the important association between insulin resistance/metabolic syndrome and atherosclerosis in patients with Type 2 diabetes Identify evolving and emerging management strategies for diabetes eg, combination antihyperglycemic therapy, new insulin delivery systems, new glucose monitoring techniques, novel drugs Describe the approach to managing dyslipidemia, hypertension, and cardiovascular risk factors in patients with diabetes
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Yale University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education to physicians Yale University School of Medicine designates this continuing medical education activity for a maximum of 11 AMA PRA Category 1 CreditsTM 55 credit hours per test Physicians should only claim credit commensurate with the extent of their participation in the activity
Supported in part through educational grants from Takeda Pharmaceuticals North America, Inc, Merck Co, Inc, and Amylin Pharmaceuticals, Inc/Eli Lilly and Company It is understood that supporters will in no way control the content of this program
Table 1 Retinopathy Results
in DIRECT
95 CI 067-100 048-087 080-131 070-108 108-168 p value 0051 0003 08 09 02 0009
082 065 102 087 134
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Under Investigation
The past decade has seen a significant increase in the number of oral and injectable glucose-lowering agents available for treating patients with diabetes Each of these carry with them certain risks and benefits and each may not be appropriate for or tolerated by an individual patient Accordingly, although not as acute as in the past, there remains a considerable need for more agents with different mechanisms of action and, hopefully, better side effect profiles International diabetes meetings are often the site for the unveiling of new compounds in early stages of clinical development, spanning the spectrum from safety/tolerability phase 1 investigations, to proof-of-concept and dose-finding phase 2 studies, all the way through larger, multicenter phase 3 trials used for FDA registration Data regarding several interesting novel compounds were presented in Rome this week Despite the recent woes of inhaled insulin, investigators remain
interested in non-injectable ways to deliver this important hormone in both Type 1 and Type 2 diabetic patients Broke-Smith and UK colleagues tested the glucose-lowering effects of an oral insulin formulation CapsulinTM in 16 patients with Type 2 diabetes under suboptimal glycemic control with oral agents for at least 3 months abstract 4 The mean age at baseline was 60255 years, BMI 28334 kg/m2, and HbA1c 7513 During the study, all oral agents except metformin were withdrawn The insulin was administered at a dose of 150 units one hour prior to breakfast and dinner for 10 consecutive days Fingerstick glucose samples were obtained 5 times per day–before and 2 hours after these meals and at bedtime By day 10, the 2-hour post-prandial glucose PPG value was within the ADA target range 180 mg/dl in nearly 36 of participants, whereas this figure was only 10 before oral insulin therapy Of note, the glucoselowering effect was more pronounced following the evening meal No hypoglycemia was reported The investigators concluded that CapsulinTM appeared to be effective in lowering PPG levels safely, perhaps a reflection of delivery via the hepatic portal system, which is, after all, the pathway
through which insulin is normally secreted Caution is advised in over-interpreting this shortterm, non-randomized and unblinded study A new approach with an old drug was proposed by Cincotta and American colleagues abstract 39 This is a quick-release form of the dopamine agonist, bromocriptine, which is usually used to lower prolactin levels in patients with hyperprolactinemia Prior studies have suggested that reduced dopaminergic tone in the hypothalamus is associated with obesity and insulin resistance In this study, 3,070 patients were randomized in a 2:1 fashion to bromocriptine or placebo on top of their usual anti-hyperglycemic therapy All patients had a baseline HbA1c between 75 and 10 mean 83 on one or two oral agents Mean age was 58 years, with 63 of participants being male; the mean BMI was 33 kg/m2 In the entire group, active therapy was associated with a 06 reduction in HbA1c p00001 More patients on bromocriptine achieved the HbA1c ADA target of 7 32 vs 10 on placebo; p00001 In the subgroup of patients on either metformin or a sulfonylurea, the mean HbA1c reduction with active therapy was 07, whereas it was slightly greater in those on a thiazolidinedione TZD 09 This
centrally-acting agent therefore appears to be modestly effective, with HbA1c reductions on the order of that observed with dipeptidyl peptidase DPP-4 inhibitors Glucokinase GK is an enzyme expressed within pancreatic ß-cells that acts as the first rate-limiting step in the metabolism of glucose Within pancreatic ß-cells GK acts as a sensor of blood glucose Increased GK activity is associated with increased insulin secretion and reduced nethepatic glucose production Pharmacological GK activators, an investigational drug class, appear to reduce glucose through these two mechanisms Zhi and colleagues from the US and Switzerland reported results from a small, double-blind, randomized, placebo-controlled study involving the GK activator RO4389620 in 59 patients with Type 2 diabetes abstract 42 Patients were either treatment naïve or previously treated with oral antihyperglycemic agents The schedule was a single dose on day 1, multiple doses up to 200 mg twice daily on days 3 to 8, and then 200 mg once daily for an additional 6 days Fasting glucose and PPG were measured Plasma exposure to RO4389620 was dose proportional over the tested range, with no appreciable drug accumulation or
effect from concurrent food intake There was a dose-dependent decrease in fasting glucose of up to 33 by day 6 A relative increase in insulin secretion was observed at the higher doses The drug was well tolerated, with the most common adverse effect being headache No significant laboratory or ECG abnormalities were noted during therapy These results are promising in the short term, but need to be confirmed in randomized, double-blind studies In addition, long-term safety data, especially with regard to hypoglycemia, will be needed Another group of investigational antihyperglycemic agents with a unique mechanism of action is the sodium glucose transporter-2 SGLT-2 inhibitors, which enhance renal glucose excretion by decreasing renal tubular glucose reabsorption These drugs produce a modest reduction in plasma glucose levels One such drug, dapagliflozin, is currently in phase 3 trials Woo et al from the US and Mexico presented the results of a 12-week randomized, double-blind, parallel-group study involving 389 treatment naïve Type 2 diabetes patients with inadequate glucose control and low mean glycosuria at baseline abstract 796 They were randomized to several doses of
dapagliflozin or metformin The former was associated with a sustained increase in urinary glucose excretion, with mean glycosuria values climbing to 52 to 85 g/day by week 12, as compared with values of 6 to 11 g/day at baseline With this, mean urinary volumes were increased by 107 ml/day at the lowest dose and by 470 ml/day at the highest dose Despite this, only 14 of patients reported polyuria as an adverse event and there were no reports of nocturia Of particular interest, the decrease in urinary glucose excretion caused a significant reduction in body weight 25 to 34 kg and BMI 08 to 11 kg/m2 However, given the mode of action of these agents we would like to see extensive renal safety data, especially in the elderly, those with chronic kidney disease, on diuretics, or with a history of urinary tract infections before using them clinically To date, the pharmacological management of obesity has been disappointing, with drugs not resulting in enough weight loss, associated with serious side effects, or both One new approach is combination therapy with pramlintide, an amylinomimetic, and human recombinant leptin metreleptin Pramlintide is currently available for use in both Type 1
and insulin-treated Type 2 diabetes patients This injectable is an analogue of amylin, an islet-cell product co-secreted with insulin, that serves to reduce glucagon secretion, delay gastric emptying, and enhance satiety Its cardinal metabolic effect is to reduce post-prandial glycemic excursions Although leptin, an adipocyte signal to central appetite centers, also serves to enhance satiety, early therapeutic studies in obese patients were disappointing It was subsequently learned that obese patients are leptin resistant and enthusiasm for developing leptin analogues waned Koda and US collaborators, however, have now studied this hormone in combination with pramlintide in 177 obese or overweight
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Under Investigation Continued from page 2 subjects over 24 weeks, using a randomized, activecontrolled, double-blind design abstract 83 The mean age was 398 years, 63 female, BMI 320 21 kg/m2, and weight 933 132 kg During a 4-week run-in period, all patients were treated with pramlintide alone 180 mcg twice daily for 2 weeks, then 360 mcg twice
daily and diet 40 calorie deficit Those that lost 2 to 8 of body weight during this time n139 were then randomized to pramlintidemetreleptin 5 mg twice daily, pramlintide alone, metreleptin alone, or placebo Combination therapy patients lost more weight mean SE, -127 09 than did those on pramlintide alone -8409; p0001 or metreleptin alone -8213; p001 The proportion of patients achieving at least a 10 reduction in weight was 56 with combination
therapy vs 35 with pramlintide and 21 with metreleptin The most common side effects were injection site reactions and nausea/vomiting The investigators correctly suggested that further research is warranted on this integrated neurohormonal approach to weight loss Advances are also being made in the realm of glucose monitoring–one of the more unpleasant aspects of diabetes management for our patients An Israeli group, led by Karasik abstract 1061, reported their initial experience with a noninvasive glucose monitoring device that employs a red/near-infrared sensor at the base of the finger The device temporarily occludes blood flow, resulting in an enhanced, time-dependent optical signal that enables the calculation of glucose concentration
The sensor was tested in 15 patients for 24 hours each, resulting in 1,068 paired glucose values The investigators analyzed a Clark Error Grid, a standard
way to assess the accuracy of sensors, using subcutaneous continuous glucose monitors CGM as the comparator More than 95 of readings were deemed to be clinically acceptable Clarke Error Grid Zone A [similar results] 667 and Zone B [different results that would result in the same therapeutic decision] 284 The device was well tolerated and appeared to be safe The researchers concluded that their results are comparable to those from subcutaneous CGM Larger studies will be needed, but these data are very encouraging From novel monitoring strategies to new therapeutic approaches, the management of diabetes will likely continue to evolve significantly in the foreseeable future Of note, however, the FDA will probably soon require more extensive safety data for any new drug applications in diabetes We suspect that this will likely delay the appearance of any new compounds to the market
An Ounce of Prevention
It is increasingly recognized that physiological abnormalities in glucose homeostasis can be identified well before the
development of Type 2 diabetes In this light, the diabetes research community is currently addressing two major questions: What are the benefits to the individual and to the population of identifying pre-diabetes Table 2 at its earliest stage, and what is the best and simplest means of detecting such mild hyperglycemia? A number of presentations at the EASD this week addressed this issue Faerch et al from Denmark looked at insulin sensitivity and secretion in 3,145 pre-diabetic individuals taking part in a Danish prospective, non-pharmacological intervention study Inter99 abstract 192 They reported that, 5 years prior to their pre-diabetes diagnosis, individuals who later developed isolated impaired fasting glucose i-IFG–ie, IFG but normal glucose tolerance exhibited defective absolute insulin secretion which was followed by insulin resistance In contrast, insulin resistance with secondary ß-cell failure characterized the transition to i-IGT IGT but normal fasting glucose These pre-diabetic states may therefore have different etiological origins This has clear implications for future prevention and treatment of pre-diabetes and overt Type 2 diabetes If clinicians wish to seriously
tackle prediabetes, we will likely require better means of diagnosing this early stage in the development of diabetes Current standards such as fasting plasma glucose FPG and the oral glucose tolerance test OGTT have limitations Phillips and US colleagues hypothesized that simple screening could be accomplished with a 2-step glucose challenge
Table 2 Definitions of Diabetes and Pre-diabetes States
Pre-diabetes/Diabetes State Impaired Fasting Glucose IFG Impaired Glucose Tolerance IGT Diabetes 126 mg/dl
In conjunction with typical hyperglycemia symptoms
Fasting Plasma Glucose 100-125 mg/dl
2-h Plasma Glucose by Oral Glucose Tolerance Test 140-199 mg/dl 200 mg/dl
Random Glucose
200 mg/dl
test GCT strategy–similar to that used in the screening for gestational diabetes abstract 347 This entails a 50g oral GCT at any time of day, regardless of meal status, with a single 1-hour sample If the GCT exceeds a cutoff, patients would then proceed to a 75g OGTT following an overnight fast 1,419 adult volunteers mean age 48 yr, BMI 302 kg/m2, 60 female, 56 black, 5 with diabetes, 21 with diabetes or IGT, and 24 with diabetes, IGT, or IFG had a random plasma and capillary glucose
measurement, followed by the 50g GCT with 1-hour samples for plasma and capillary glucose All subjects then underwent an OGTT at a second visit, following an overnight fast The investigators reported that GCT plasma glucose provided areas under the receiver operator characteristics ROC curve of 089, 082, and 081 for detection of diabetes, diabetes/IGT, and diabetes/IGT/IFG, respectively, each higher than for GCT capillary glucose AROC 085, 077, and 076; p005 To detect diabetes or IGT, GCT plasma glucose was better than random plasma glucose and GCT capillary glucose was better than random capillary glucose, both p0001 Multivariate analysis showed that the c-
statistic equivalent to AROC of GCT plasma glucose for the detection of diabetes or IGT was highly significant and independent of age, sex, race, BMI, waist circumference, HDL-cholesterol, systolic BP, and family history p0001 The investigators estimated that the cost of GCT capillary glucose screening should be 5 per person This is an interesting approach, but early identification should only be considered with an eye toward effective diabetes prevention strategies Hanefeld et al from Germany and Canada, in a multi-center
trial, looked at the interaction between different components of the metabolic syndrome, as defined by the National Cholesterol Education Program NCEP–Adult Treatment Panel ATP III, and the development of Type 2 diabetes abstract 223 Subjects n1,368 were taking part in a double-blind, placebo-controlled trial of acarbose in the prevention of Type 2 diabetes STOP-NIDDM Acarbose is an -glucosidase inhibitor that retards proximal small bowel carbohydrate absorption, thereby lowering PPG levels Overall in STOP-NIDDM, acarbose therapy resulted in a 25 risk reduction for diabetes progression in patients with IGT In this
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An Ounce of Prevention Continued from page 3 secondary analysis, the investigators found that IFG, hypertriglyceridemia, low HDL-cholesterol, and hypertension, as single traits, significantly increased the risk for diabetes with HR of 15, 14, 13, and 12, respectively; overall, a diagnosis of metabolic syndrome resulted in a HR of 16 p00001 The annual incidence for diabetes in the placebo group with metabolic syndrome was 187 vs
112 without metabolic syndrome Acarbose reduced the incidence to 135 and 94, respectively, meaning that the number needed to treat for patients without metabolic syndrome was 165 and with metabolic syndrome was 58 The investigators concluded that acarbose reduces the incidence of diabetes in people with as well as without metabolic syndrome However, those with metabolic syndrome appear to enjoy a distinctly greater benefit In a related trial, Tripathy et al of the US examined the impact of pioglitazone on progression from the pre-diabetic state abstract 224 ACT-NOW was a randomized, double-blind, placebo-controlled study to examine whether treatment of IGT with pioglitazone can prevent and/or delay the devel-
opment of Type 2 diabetes A total of 602 IGT subjects age 523 years, BMI 343 kg/m2, 42 male, FPG 10503 mg/dl, 2-hr PPG [OGTT] 1681 mg/dl, HbA1c 55001 were randomized to the TZD 45 mg/day or placebo and returned every 3 months for FPG/HbA1c and annually for OGTT for 2 years or until the development of diabetes Overall, 45 placebo-treated subjects developed diabetes vs 10 in the pioglitazone group 68 vs 15 per year; p0000001 In addition, 42 of individuals on pioglitazone vs 28
on placebo reverted to normal glucose tolerance at study end p 00005 Insulin sensitivity Matsuda Index, 4304 to 7106, p00005 and insulin secretion/insulin resistance index 3102 to 5104, p00005 both improved with the TZD and were unchanged with placebo Adverse events such as weight gain 39 vs 08 kg and edema 22 vs 15 were more frequent with pioglitazone There were 2 cases of heart failure 1 in each group and 13 bone fractures occurred 8 in the pioglitazone group and 5 in the placebo group, all related to trauma The investigators concluded that pioglitazone significantly reduced
the conversion of IGT to Type 2 diabetes in association with improved ß-cell function and reduced insulin resistance Very clearly, there is growing interest in identifying patients at risk and ultimately preventing the progression from pre-diabetes to Type 2 diabetes However, there are many important questions that remain: Would early identification of diabetes risk necessarily result in the implementation of effective preventative strategies? Although lifestyle change and pharmacotherapy are clearly effective over a period of 2 to 3 years in the context of a clinical trial, what would be the overall
effectiveness of such strategies in the real world setting? For how long can diabetes be prevented or delayed? In which patients and at what juncture should insulin-sensitizing medications be considered? Finally, what are the cost implications of such interventions? More studies will be required before we know the answers to some of these questions Until then, the reader is referred to the comprehensive consensus statement from the ADA and the EASD, published last year Nathan DM et al Diabetes Care 2007;30:753
Come to Your Sensors
Continuous glucose monitoring CGM currently requires the insertion of a glucose sensor into subcutaneous tissue such that the glucose concentration within interstitial fluid can be measured continuously over an extended period of time, typically 3 to 7 days at a time Table 3 While limited by poor accuracy and precision when introduced some 3 decades ago, CGM technology has advanced appreciably since then Three proprietary devices are now available, although their applicability to clinical practice remains unclear and limited to some extent by their significant cost To date, in small studies, use of these CGM devices has been shown to modestly improve
HbA1c and time within the normoglycemic range as well as to decrease hypoglycemic and hyperglycemic excursions Results from several CGM studies were presented at this weeks meeting Voelmle et al from the US evaluated the role of CGM for the optimization of glucose control in pregnant women with Type 1 diabetes abstract 1066 Glycemic control in 19 patients mean SE age 30542 years and duration of diabetes 15359 years who used self-monitored blood glucose and also initiated CGM at 0 to 24 weeks gestation was compared to that in a control group of 19 patients matched for age, diabetes duration, ethnicity, and normal albumin excretion rates [20 ug/ min] using only self-monitored blood glucose
Table 3 FDA-Approved Real-Time Continuous Glucose Monitoring Devices
Locations Sensor Can be Worn Abdomen, arm, buttock, thigh Abdomen
Device Guardian Real-time Seven STS Freestyle Navigator
Calibrations Initial per 72 Hour Frequency of Hypo- and Calibration Lifespan Glucose Hyperglycemia Time hr of Sensor Readings min Alarms 2 2 10 7 5 4 Every 5 Every 5 Every 1 Yes Yes Yes
Posterior arm, abdomen, buttocks
Baseline HbA1c values were 68089 and 71096 in the sensor and control groups,
respectively p005 Reductions from baseline in mean HbA1c values were seen at all timepoints in the sensor group p0001; Figure 1, importantly without any increase in the percentage of time in the hypoglycemic range The favorable findings from this pilot study are encouraging given the difficulty in managing glucose control safely in pregnant women with diabetes Larger studies are clearly needed to evaluate the clinical implications of CGM in this setting, specifically on gestational and fetal outcomes CGM is becoming an important clinical research tool, given its ability to generate a large amount of glycemic data so that underlying conditions
or medications affecting glucose control can be assessed or compared Pallayova et al from Slovakia utilized CGM to determine the glycemic consequences of sleep apnea in patients with Type 2 diabetes In 30 patients 19 men; age 55578 years, BMI 34774 kg/m2, duration of diabetes 3017 years, HbA1c 7108, the investigators measured mean nocturnal glucose values and various indices of nocturnal glucose variability standard deviation, coefficient of variance, etc in relationship to objectively assessed quality of breathing during sleep abstract 18
The patients with moderate to severe sleep apnea accompanied by severe oxygen desaturation had significantly
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Come to Your Sensors Continued from page 4 increased nocturnal glucose variability p0008 and worse overnight glucose control as compared to those without sleep-disordered breathing, despite no significant difference in HbA1c between subgroups There were strong positive correlations between apnea-hypopnea index AHI and parameters of nocturnal glucose variability p 0005 and a strong positive correlation between AHI and mean nocturnal glucose values r06; p0001 The investigators observed negative correlations between mean nocturnal glucose values and both mean oxygen saturation level r-059; p0001 and minimum oxygen saturation level r-054; p0001 These findings have important implications on patient management in light of the rapidly increasing incidence of
Table 4 Glycemic Control at Study End Following 4 Weeks Treatment With an Insulin Secretagogue
Measure of Glycemia Mean SD glucose mg/dl MAGE SD mg/dl Mean SD maximal glucose
mg/dl Mean SD minimal glucose mg/dl Median min-max of time BG: 70 mg/dl 140 mg/dl 200 mg/dl 20 0-44 180 1-52 10 1-11 00 0-58 270 2-91 30 0-40 10 0-35 185 2-95 25 0-35 0699 0749 0168 Repaglinide 118 21 77 18 211 28 59 19 Glimepiride 128 32 100 28 249 53 64 18 Gliclazide 121 23 107 43 244 54 62 13 p-value 0463 0011 0028 0658
Across the 3 treatment groups BGblood glucose, MAGE Mean amplitude of glycemic excursions during 72 hours based on CGMS
Figure 1 HbA1c Over Time in Pregnant Women with Diabetes
80 75 p041
Mean SE HbA1c SMBG CGM p003 p009 p013 p015 p020
70 65 60 55 50
I Baseline I 3 I 4 I 5 I 6
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coexisting diabetes and sleep apnea and their impact on cardiovascular morbidity and mortality In a multicenter, open-label study, Li et al from China randomized 60 newly diagnosed Type 2 diabetes patients to receive the rapid-acting insulin secretagogue, repaglinide 1 mg three times daily, or one of the longer-acting sulfonylureas, glimepiride 1 mg once daily or gliclazide 30 mg once daily, each being titrated to a fasting blood glucose FBG target of 126 mg/dl abstract 17 Glucose concentration was monitored by a CGM system for 72 hours
at the end of a 4-week treatment period The treatment groups were comparable at baseline based on patients age, BMI, FBG, and HbA1c After 4 weeks of treatment, mean glucose values during 72 hours were similar in the 3 groups Table 4 However, mean ampli-
tude of glycemic excursions MAGE was significantly lower in repaglinide as compared with glimepiride and gliclazide p0006 and 0007, respectively; no difference was found between glimepiride and gliclazide p0581 The same trend was observed in the mean maximal glycemic values p0016, 0016, and 0948, respectively Mean minimal glycemic values were similar for the 3 groups, as were the percentages of time during which patients experienced hypoglycemia 70 mg/dl and hyperglycemia 140 and 200 mg/dl These results suggest that glycemic excursion profiles can vary with different insulin secretagogues despite similar glucose control–differences that can be assessed with CGM The implications on clinical outcomes from such differences remain unclear
So Many Posters, So Little Time
Pandya and US researchers compared glycemic control ie, achievement of HbA1c 7 in patients with Type 2 diabetes who were treated with metformin and pioglitazone,
either in combination or sequentially, first with metformin, later augmented with the TZD abstract 921 A total of 561 adult study patients were identified from the Integrated Healthcare Information Services claims database 01/01/00 to 03/31/07; 213 and 348 were treated with the combination and augmentation approaches, respectively A significantly higher proportion of patients in the combination therapy group achieved goal HbA1c at all evaluation timepoints between 6 and 24 months each p 00001 According to logistic regression, controlling for age, gender, baseline HbA1c, comorbidities, prior resource utilization, and prior medication use, the clinical advantage of combination therapy was greater among patients with baseline HbA1c 9 odds ratio [OR] 013-015; all p0001 than among those with baseline HbA1c between 7 and 9 OR 036-043; all p00025 These data suggest that the early use of combination oral antihyperglycemic agents may actually result in a long-term clinical benefit over the more traditional sequential, augmentation therapy –especially among patients with higher baseline HbA1c levels It would be interesting to see if these results could be confirmed by other groups and
using other types of combinations Spruce et al from the United Kingdom abstract 1252 carefully measured the force applied during Semmes-Weinstein 10g monofilament testing, purportedly a reliable method to assess for the presence of peripheral neuropathy Prior studies, however, had been conducted using automated equipment Peak force applied by 20 trained individuals was assessed using a research grade strain gauge Significant differences in both mean and median peak force were found between all subjects p0021 In addition, a highly significant difference was observed between subjects for the total range of peak force p 0001 This small study demonstrates that the total range of peak force applied from a monofilament varies significantly between subjects The clinical reliability of the 10g monofilament may be more unstable than previously thought, once the human variable is factored in
Silvio E Inzucchi, MD Robert S Sherwin, MD
Editors, Yale University, New Haven, Connecticut
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