Practice Update: DIABETES

VOL. 1 • NO. 1 • 2017

ISSN 2208-1488

OUR EXPERTS. YOUR PRACTICE.

Effect of metformin and lifestyle on coronary artery calcium in the Diabetes Prevention Program

Opinion Recognizing and confirming a direct role of LDL-C lowering with diabetes risk, and subsequently understandings the potential mechanisms for which low LDL-C promotes diabetes may lead to new treatment or prevention approaches. Allison Goldfine &Alessandro Doria

Conference AACE 2017

JOURNAL SCAN Effect of artificial pancreas systems on glycemic control in patients with type 1 diabetes

Individualized model for retinopathy screening in type 1 diabetes

Effect of fasting glucose levels on cardiovascular disease and all-cause mortality

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CONTENTS 3

RESEARCH Editor’s picks 4 Effect of a virtual glucose management service on inpatient glycemic control 5 Effect of metformin and lifestyle on coronary artery calcium in the Diabetes Prevention Program 6 Ophthalmic screening insufficient among youths with diabetes 7 Effect of artificial pancreas systems on glycemic control in patients with type 1 diabetes Microvascular complications 14 Effects of a long-term lifestyle modification program on peripheral neuropathy in obese adults with type 2 diabetes 16 Individualized model for retinopathy screening in type 1 diabetes

Conference coverage 8 American Association of Clinical Endocrinologists 26th Annual Meeting & Clinical Congress lifestyle on coronary artery calcium in the Diabetes Prevention Program Cover 5 Effect of metformin and

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PracticeUpdate® is a registered trademark of Elsevier Inc. © 2017 Elsevier Inc. All rights reserved. ABOUT PracticeUpdate Diabetes provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at www. practiceupdate.com PracticeUpdate and PracticeUpdate Diabetes are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Diabetes has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Editorial Manager Anne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover images: Illustration of glucose and insulin in the body.

8 Women with gestational diabetes requiring insulin at higher risk of postpartum diabetes 9 Three prognostic factors of mortality identified in patients with diabetic ketoacidosis 10 U500 insulin screening of diabetic patients uncovers large amount of undiagnosed 11 Guidelines for treating the new cardiovascular “extreme risk” category have been validated 12 BMI, polypharmacy, lab testing may help diagnose DKA and identify high risk of its recurrence 13 Heart failure deserves more scrutiny as a complication of type 2 diabetes hypercorticolism consistent with Cushing’s syndrome

Obesity 17 Artificially sweetened beverages, stroke and dementia

Cardiovascular complications 18 Sulfonylureas are

My perspective 20 A resurgence of interest in pioglitazone? 22 Reading our blueprints – nature’s lessons in pathophysiology found within our DNA

associated with increased risks of cardiovascular events and death 19 Effect of fasting glucose levels on cardiovascular disease and all-cause mortality

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VOL. 1 • NO. 1 • 2017 VOL. 2 • . X

EDITOR’S PICKS 4

Effect of a virtual glucose management service on inpatient glycemic control Annals of Internal Medicine Take-home message • This multisite study investigated whether the implementation of a virtual glucose management service (vGMS) affected glycemic control among inpatients. After implementation of the vGMS, there was a 39% and 36% reduction in the proportion of hyper- and hypoglycemic patients, respectively, compared with pre-implemen- tation. After implementation of vGMS period, there were 15 severe hypoglycemic events compared with 40 events prior to implementation. • The frequency of hypoglycemia and hyperglycemia among inpatients decreased with the implementation of vGMS.

COMMENT By Susan S Braithwaite MD, FACP, FACE T he authors examine the impact of a virtual glycemic manage- ment service (vGMS) among hospitalized glucose-monitored adult non-obstetric patients. The shared EMR of a three-site hospital system was que- ried for daily case findings of patients having two or more glucose readings ≥225 mg/dL, hypoglycemia <70 mg/dL, or insulin pump use. Each morning, a vGMS team member decided whether to create a vGMS note for entry to the EMR. Once created, a note for a given patient was visible to anyone using the EMR, with stipulation that the contents were merely suggestions. After transi- tion, compared with baseline, per 100 hospitalized patients the proportions of hyperglycemic patient-days had declined from 6.6 to 4.0 (RR, 0.61; 0.59– 0.63) and hypoglycemic patient days from 0.78 to 0.49 (RR, 0.64; 0.57–0.70), whereas the proportion of patient days at goal rose from 10.8 to 11.4 (RR, 1.05; 1.03–1.08; P < 0.001 for all comparisons). Readers may wonder about precon- ditions for success and impact upon personalized decision-making. The article describes the team of 3 indi- viduals who created the virtual notes without exploring issues of minimum acceptable qualifications, liability, or mechanisms for remuneration, while suggesting that cost-effectiveness might become demonstrable in a bun- dled care environment. Training of staff by the reporting institutions and a carefully wrought infrastructure were noted, including an inpatient diabetes committee charged with development of policies and procedures for gly- cemic management. The hospital pharmacies accepted only those insu- lin orders delivered through one of the order sets programmed into the EMR. Well-designed order sets not only pro- tect against glycemic adverse events, but also offer menu alternatives that facilitate provider- and patient-level individualization.

Abstract BACKGROUND Inpatient hyperglycemia is com- mon and is linked to adverse patient outcomes. New methods to improve glycemic control are needed. OBJECTIVE To determine whether a virtual glu- cose management service (vGMS) is associated with improved inpatient glycemic control. DESIGN Cross-sectional analyses of three 12-month periods (pre-vGMS, transition, and vGMS) between 1 June 2012 and 31 May 2015. SETTING 3 University of California, San Francisco, hospitals. PATIENTS All nonobstetric adult inpatients who underwent point-of-care glucose testing. INTERVENTION Hospitalized adult patients with 2 or more glucose values of 12.5 mmol/L or

Well-designed order sets not only protect against glycemic adverse events, but also offer

menu alternatives that facilitate provider- and patient-level individualization.

greater (≥225 mg/dL) (hyperglycemic) and/or a glucose level less than 3.9 mmol/L (<70 mg/dL) (hypoglycemic) in the previous 24 hours were identified using a daily glucose report. Based on review of the insulin/glucose chart in the elec- tronic medical record, recommendations for insulin changes were entered in a vGMS note, which could be seen by all clinicians. MEASUREMENTS Proportion of patient-days clas- sified as hyperglycemic, hypoglycemic, and at-goal (all measurements ≥3.9 and ≤10 mmol/L [≥70 and ≤180 mg/dL] during the pre-vGMS, tran- sition, and vGMS periods). RESULTS The proportion of hyperglycemic patients decreased by 39%, from 6.6 per 100 patient-days in the pre-vGMS period to 4.0 per 100 patient-days in the vGMS period (difference, –2.5 [95% CI, –2.7 to –2.4]). The hypoglycemic proportion in the vGMS period was 36% lower than in the pre-vGMS period (difference, –0.28 [CI, –0.35 to –0.22]). Forty severe hypoglyce- mic events (<2.2 mmol/L [<40 mg/dL]) occurred during the pre-vGMS period compared with 15 during the vGMS period. LIMITATION Information was not collected on patients’ concurrent illnesses and treatment or physicians’ responses to the vGMS notes. CONCLUSION Implementation of the vGMS was associated with decreases in hyperglycemia and hypoglycemia. Association between a virtual glucose man- agement service and glycemic control in hospitalized adult patients: an observational study. Ann Intern Med 2017 May 02:166(9)621- 627, RJ Rushakoff, MM Sullivan, HWMacMaster, et al.

Dr Braithwaite is Clinical Professor of Medicine at the University of Illinois, and President of at Endocrinology Consults and Care in Chicago.

PRACTICEUPDATE DIABETES

EDITOR’S PICKS 5

Effect of metformin and lifestyle on coronary artery calcium in the Diabetes Prevention Program Circulation Take-home message

significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity: 39.5 vs 66.9 AU, p=0.04; CAC presence: 75% vs 84%, p=0.02), but no metformin effect was seen inwomen. Inmultivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric or metabolic factors, by the development of diabetes, or by use/non-use of statin therapy. CONCLUSIONS Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes among men. Effect of long-term metformin and lifestyle in the Diabetes Prevention Program and its outcome study on coronary artery calcium. Circulation 2017 May 05;[EPub Ahead of Print], RB Goldberg, VR Aroda, DA Bluemke, et al. raising the possibility of both direct glucose-dependent and independent vascular protective benefit of metformin. This observation is particularly relevant because, in contrast to the recent experience with empagliflozin and liraglutide, there are no contemporary data supporting a cardioprotective role of metformin. Metformin remains the first-line therapy for diabetes, and also a reasonable treatment for patients with prediabetes, but its “pole-position” should be tested in contemporary management strategies against other new agents. Metformin remains the first- line therapy for diabetes, and also a reasonable treatment for patients with prediabetes, but its “pole-position” should be tested in contemporary management strategies against other new agents.

• This long-term intervention study investigated the incidence of coronary heart disease (CHD) among 3234 individuals with prediabetes. After an average 14 years of follow-up, 2029 participants had subclinical atherosclerosis based on coronary artery calcium (CAC) measurement. Participants with lifestyle interventions did not have a significant difference in CAC from the placebo group. Men in the metformin group had a significant reduction in the presence and severity of CAC compared with the placebo group. However, there was no significant difference between women in the metformin and placebo groups. • Among men with prediabetes or early diabetes, metformin may protect against coronary atherosclerosis.

Abstract BACKGROUND Despite the reduced incidence of coronary heart disease (CHD) with intensive risk factor management, people with diabetes and prediabetes remain at increased CHD risk. Dia- betes prevention interventions may be needed to reduce CHD risk. This approach was exam- ined in the Diabetes Prevention Program (DPP) and its Outcome Study (DPPOS), a long-term intervention study in 3234 subjects with predia- betes (mean [±SD] age 64±10 yrs) which showed reduced diabetes risk with lifestyle and met- formin compared to placebo over 3.2 years. METHODS The DPPOS offered periodic group COMMENT By Benjamin Morgan Scirica MD T he DPP study, published in 2002, demonstrated that, compared with placebo, an intensive lifestyle modi- fication program or metformin significantly reduced the risk of developing diabetes and improved cardiometabolic risk factors over an average follow-up of 3.2 years. In this publication, the investigators from the follow-up extension study (named DPPOS) report the long-term effect on coronary artery calcium (CAC) measurements of the initial randomization to metformin or life- style compared with placebo. After 10 additional years of follow-up, CAC was measured in 2029 patients. Overall, CAC severity was greater in men than in women. And, in men, those patients originally randomized to metformin had less severe CAC than those randomized to placebo (age-adjusted mean CAC severity: 39.5 vs 66.9 AU, P = 0.04; CAC

lifestyle sessions to all participants and con- tinued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants using coro- nary artery calcium (CAC) measurements after 14 years of average followup. The CAC scores were analyzed continuously as CAC sever- ity, and categorically as CAC presence (CAC score>0), and reported separately in men and women. RESULTS Therewere no CAC differences between lifestyle and placebo intervention groups, in either sex. CAC severity and presence were

presence: 75% vs 84%, P = 0.02). There was no difference in CAC between the group assigned to lifestyle modifica- tion compared with those assigned to placebo, or between any treatment in women. It is reasonable to hypothesize that the degree of CAC in women in this study was low enough that there was no opportunity to prevent calcifications, but it could also signal a potential differentia- tion in treatment effect. It is disappointing to see no difference in men assigned to the lifestyle modification arm, although CAC can be modulated (worsened) with intense exercise. In the original DPP study, intensive lifestyle intervention was more effective than metformin for glucose control and prevention of diabetes; yet, in this long- term follow-up, metformin was the only strategy to reduce CAC therapy, thus

Dr Scirica is Cardiologist and Director at Inovation, Cardiovascular Division, Brigham and Women’s Hospital, and Associate Professor of Medicine at Harvard Medical School.

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EDITOR’S PICKS 6

Ophthalmic screening insufficient among youths with diabetes JAMA Ophthalmology Take-home message • This longitudinal cohort study used 2001–2014 data from the Clinformatics Data Mart database from a managed care network to retrospectively examine patterns of ophthalmic screening among patients younger than 21 with a new diagnosis of type 1 diabetes (T1D) or type 2 diabetes (T2D). Recommendations for ophthalmic screening following a diabetes diagnosis have been released by organizations such as the American Academy of Ophthalmology (5 years after a T1D diagnosis and at diagnosis of T2D) and by the American Diabetes Association (3–5 years after a T1D diagnosis at age 10 or above or at diagnosis of T2D). Despite these recommendations, the study found that only 64.9% and 42.2% of patients with T1D and T2D, respectively, received an ophthalmic examination within 6 years of diagnosis. Individuals in lower-income households (net worth ≤US$25,000) were less likely to have an ophthalmic examination within 6 years of diagnosis compared with those in higher-income households (net worth ≥US$100,000). Black and Latino patients were less likely to receive ophthalmic examinations within 6 years compared with white patients. • Despite having health insurance, as indicated by their inclusion in the database used, many patients do not receive recommended ophthalmic examinations within an appropriate timeframe following a diabetes diagnosis. It is especially important to realize that racial minorities and patients from less affluent families are at particular risk.

Abstract IMPORTANCE Ophthalmic screening to check for diabetic retinopathy (DR) is important to prevent vision loss in persons with diabetes. The Amer- ican Academy of Ophthalmology recommends that ophthalmic screening for DR occur begin- ning at 5 years after initial diabetes diagnosis for youths with type 1 diabetes; the American Diabetes Association recommends screening of youths with type 2 diabetes at the time of ini- tial diagnosis. To our knowledge, it is unknown to what extent youths with diabetes obtain eye examinations in accordance with these guidelines. As a healthcare community, we’re failing our diabetics. Less than half of diabetics are getting their annual eye exams. OBJECTIVE To assess the rate of obtaining oph- thalmic examinations and factors associated with receipt of eye examinations for youths with diabetes. DESIGN, SETTING, AND PARTICIPANTS This retro- spective, longitudinal cohort study examined youths 21 years or younger with newly diag- nosed diabetes enrolled in a US managed care network from January 1, 2001, through Decem- ber 31, 2014. MAIN OUTCOMES AND MEASURES Kaplan-Meier survival curves estimated the time from initial diabetes diagnosis to first eye examination by an ophthalmologist or optometrist. Multivariable Cox proportional hazards regression models identified factors associated with receiving an ophthalmic examination after initial diabetes diagnosis. RESULTS Among 5453 youths with type 1 dia- betes (median age at initial diagnosis, 11 years;

[11.4%] of the sample) had an 18% decreased hazard of undergoing an eye examination by 6 years compared with white youths (black youths: adjusted hazard ratio [HR], 0.89; 95% CI, 0.79–0.99; Latino youths: HR, 0.82; 95% CI, 0.73–0.92). As household net worth increased, youths were increasingly more likely to undergo an eye examination by 6 years after initial dia- betes diagnosis (net worth of ≥$500 000 vs <$25 000: HR, 1.50; 95% CI, 1.34–1.68).

interquartile range, 8-15 years; 2972 male [54.5%]; 4505 white [82.6%]) and 7233 youths with type 2 diabetes (median age at initial diag- nosis, 19 years; interquartile range, 16-22 years; 1196 male [16.5%]; 5052 white [69.9%]), 64.9% of patients with type 1 diabetes and 42.2% of patients with type 2 diabetes had undergone an eye examination by 6 years after initial dia- betes diagnosis. Black youths (1367 [10.8%] of the sample) had an 11% and Latino youths (1450

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EDITOR’S PICKS 7

Effect of artificial pancreas systems on glycemic control in patients with type 1 diabetes Take-home message • This meta-analysis of randomized controlled trials eval- uated the efficacy of single- and dual-hormone artificial pancreas systems compared with conventional insulin pump therapy for glucose control in adults and children with type 1 diabetes. The results show that time in target glucose range was higher with artificial pancreas systems and was highest with dual-hormone systems. • The authors concluded that, regardless of varying clinical factors, artificial pancreas systems are superior to insulin pump therapy in glucose control. Abstract BACKGROUND Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous var- ied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. METHODS We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcu- taneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3.9–10 mmol/L or 3.9–8 mmol/L, depending on the study), assessed by random-effects meta-analysis. FINDINGS We identified984 reports; after exclusions, 27 comparisons from24 studies (23 crossover and one parallel design) including a total of 585 par- ticipants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hor- mone (insulin andglucagon), two comparisons assessedboth dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hor- mone artificial pancreas systems. Time in target was 12.59% higher with artificial pancreas systems (95% CI 9.02–16.16; p<0.0001), from a weighted mean of 58.21% for conventional pump therapy (I(2)=84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19.52% [95% CI 15.12–23.91] vs 11.06% [6.94 to 15.18]; p=0.006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the compara- tor. Single-hormone studies had higher heterogeneity than dual-hormone studies (I(2) 79%vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the inter- vention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. INTERPRETATION Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and tech- nical factors. Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of out- patient randomised controlled trials. Lancet Diabetes Endocrinol 2017 May 19;[EPub Ahead of Print], A Weisman, JW Bai, M Cardinez, et al. The Lancet Diabetes & Endocrinology

COMMENT By Raza M Shah MD A s a healthcare community, we’re failing our diabetics. Less than half of diabetics are getting their annual eye exams. For primary care providers, this means they’re failing their Health Effectiveness Data and Information Set (HEDIS) quality measures. For eye care providers, we’re failing to provide the care we’ve been trained and sworn to give. For patients, we’re falling prey to one of the leading causes of vision loss in the United States. We can come up with many excuses…patients aren’t following recommendations, referrals aren’t happening soon enough, access is limited in certain areas, etc. The bot- tom line is we can do better. We have to do better. But how? Thankfully, an answer to our question is already here...Intelligent Retinal Imaging Systems (IRIS). Microsoft recently awarded their prestigious 2017 Health Innovation Award for IRIS’s diagnostic solution. By providing the only FDA-approved system, they’ve created a safe, noninvasive, quick, and accurate way to help our diabetics. Essentially, they’ve created a way to integrate the diabetic eye exam with primary care. Instantly, HEDIS measures are met, people with previously undiagnosed disease can be identified, and blindness can be prevented. Diabetic screening involves taking a non-mydriatic photo in the office and having it sent to a reading center for evaluation. Within minutes, a report can be generated, which seamlessly integrates with a practice’s electronic medical record (EMR). We already know that over 99% of patients who’ve undergone this method like it enough to recommend it to a friend or col- league. We also know that seeing your disease with your own eyes is much more likely to put everything in perspective and help ensure you take an active role in fighting your disease. As with any condition, the earlier we’re able to diagnose and treat, the better our patients will do. As our young diabetic population continues to skyrocket, we need to be able to keep up and even- tually get ahead. It not only helps our patients, but can prevent the need for later-stage, expensive treatments and surgeries that will eventually cripple the healthcare system. Does it mean patients don’t need their annual eye exam? Abso- lutely not. This does not replace the skilled examinations needed to diagnose and treat many other eye conditions. It does, how- ever, help identify the nearly 60% of diabetics who previously were not being seen or treated by eye care providers and help reduce the risk of severe vision loss by nearly 90%. We owe this to our patients.

Dr Shah is Retina Surgeon at Mid Atlantic Retina Specialists in Maryland.

CONCLUSIONS AND RELEVANCE Despite possessing health insurance, many youths with diabetes are not receiving eye examinations by 6 years after initial diagnosis to monitor for DR. These data suggest that adherence to clinical practice guidelines is particularly challenging for racial minorities and youths from less affluent families. Ophthalmic screening patterns among youths with diabetes enrolled in a large US Managed Care Network. JAMA Ophthalmol 2017 Mar 23;[EPub Ahead of Print], SY Wang, CA Andrews, TW Gardner, et al.

VOL. 1 • NO. 1 • 2017

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American Association of Clinical Endocrinologists 26th Annual Meeting & Clinical Congress 3–7 MAY 2017 • AUSTIN, TEXAS, USA

Postpartum diabetes risk, prognosis for patients with diabetic ketoacidosis, more intense treatment of dyslipidemia, and heart failure complication of type 2 diabetes, were among the many studies presented at this year’s AACE annual meeting. The PracticeUpdate Editorial Team reports. Womenwith gestational diabetes requiring insulin at higher risk of postpartumdiabetes Women with gestational diabetes who require insulin during pregnancy are at higher risk of postpartum diabetes than those who do not require insulin during pregnancy, finds a retrospective review. O kpara Ukandu Igwe, MBBS, of Lagos University Teaching Hospital, Nigeria, set out to assess factors associated with postpartum glucose testing among women with gestational diabetes mellitus and patterns of the results. Eighty-five women diagnosed with gesta- tional diabetes using a 75-g oral glucose tolerance test from 2006 to 2015 at a ter- tiary healthcare facility were studied. Information concerning screening and

testing between 6 to 12 weeks postpartum were significantly correlated. Among the mothers with gestational diabe- tes were tested, 15.3% (n = 13) suffered from impaired glucose tolerance while 7.05% (n = 6) of mothers with gestational diabetes who were diagnosed with diabetes melli- tus. Abnormal postpartum results and use of insulin therapy during pregnancy were significantly correlated. Gestational diabetes mellitus is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Women with gestational diabetes are at increased risk of recurrence and future development of type 2 diabetes mellitus, and need to be screened and followed postpartum.

sociodemographic features within 6 to 12 weeks of delivery were collected. Pat- terns of test results were assessed and analyzed. Linear and logistic regression models were employed to evaluate the correlation between maternal age, parity, body mass index, mode of treatment, and results of postpartum screening. Of the 85 women with gestational diabetes, 34 (40%) were tested during the 6- to 12- week postpartum period. Mean patient age was 36 ± 2 years. The majority of mothers (58.8%, n = 50) had delivered two to three children. A total of 65.9% (n = 56) had body mass index ≥25kg/m 2 . The majority of women who did not present for postpartum testing followed a controlled diet. Use of insulin during pregnancy and

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AACE 2017 9

Three prognostic factors of mortality identified in patients with diabetic ketoacidosis Advanced age, admission to the intensive care unit, and deteriorating kidney function signify a poorer prognosis among type 2 diabetic patients with diabetic ketoacidosis, reports a retrospective, single-center review. Z areen Kiran, MBBS, of Aga Khan University Hospital, Karachi, Pakistan, and colleagues set out to determine prognostic factors associated with increased mortality in patients with type 2 diabetes admitted with diabetic ketoacidosis). They compared mortality of these patients for the period from 2010 to 2016 (n = 279) vs that observed from 1991–1996. Medical records of 279 such patients from 2010 to 2016 were reviewed. A total of 128 patients fulfilled criteria and were included. One-hundred and eighteen patients had a history of type 2 dia- betes mellitus whereas 10 patients had no history of diabetes or diabetic ketoacidosis. Mean patient age was 56.9 ± 12.4 years, 53.1% (n = 68) were males, and 46.9% (n = 60) were females. Ten (7.8%) patients suffered from severe; 68 (53.12%) patients, mod- erate; and 50 (39.1%), mild diabetic ketoacidosis. Mean age, duration of diabetes, hemoglobin, hemoglobin A1c, random blood sugar, and body mass index did not differ statis- tically significantly between the two groups. Two patients with severe, 8 patients with moderate, and six with mild diabetic ketoacidosis died. Age and creatinine level contributed significantly to risk of mortal- ity in univariate analysis (hazard ratio 1.05 and 1.23, respectively, P < 0.05). All variables used in univariate analysis were analyzed further for an adjusted model. Advanced age and admission to the intensive care unit were independent predictors of death (hazard ratio 1.06 and 5.85, respectively, P < 0.05). More patients with type 2 diabetes (n = 128) presented with diabetic ketoacidosis during 2010 to 2016 than from 1991 to 1996 (n = 57). Markedly less mortality (12.5%) of patients with type 2 diabetes admitted with diabetic ketoacidosis was observed during 2010 to 2016 than from 1991 to 1996 (21%). Factors related to this improvement included an inpatient endo- crine consultation service composed of an endocrine consultant; endocrine fellow; diabetes nurse; training of nurses staff, interns, and residents by endocrine faculty in managing diabetic ketoac- idosis; timely institution of insulin infusion protocols designed for managing diabetic ketoacidosis; and a greater number of more patients receiving expert care. Dr Kiran concluded that advanced age, admission to the intensive care unit, and deteriorating kidney function signify a poorer prog- nosis among type 2 diabetic patients with diabetic ketoacidosis. Though the number of patients with type 2 diabetes admitted with diabetic ketoacidosis increased a considerable decrease in mortality is attributed to a number of improvements in manag- ing diabetic ketoacidosis and the development of standardized protocols.

Results of this study revealed that the majority of women with gestational diabetes were not screened postpartum, as recom- mended. The observed lack of postpartum screening is similar to results of other studies, which found that most women with ges- tational diabetes are not retested at the end of the postpartum period. The majority of subjects with postpartum diabetes mellitus had received insulin therapy. Lack of communication after patient dis- charge may have explained the lack of follow-up. Text messages and telephone calls may improve follow-up in this population. Dr Igwe concluded that women with gestational diabetes who require insulin during pregnancy are at higher risk of postpartum diabetes mellitus than those who do not require insulin. Women with gestational diabetes should follow a long-term man- agement plan from pregnancy going forward to prevent being lost during follow-up.

PracticeUpdate Editorial Team

PracticeUpdate Editorial Team

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CONFERENCE COVERAGE 10

U500 insulin screening of diabetic patients uncovers large amount of undiagnosed hypercorticolismconsistent with Cushing’s syndrome

J oseph Wolfgang Mathews, MD, of Palmetto Endocrinology, Summerville, South Caro- lina, explained, “Studies screening patients with diabetes for hypercortisolism indicate that 2–10% of patients suffer from undiagnosed Cushing’s syndrome. These authors concluded that such a low percentage prevents screening of all diabetic patients Cush- ing’s syndrome. “The Centers for Disease Control and Prevention estimate that in 2014, 29.1 million Amer- icans suffered from diabetes. So we tried to identify a more at-risk population to screen those with severe insulin resistance requiring high doses of insulin.” Patients with type 2 diabetes requiring concentrated insulin (Humulin R U500, Lilly), how- ever, suffer severe insulin resistance and hyperglycemia that result from undiagnosed and uncontrolled hypercortisolism. This was the first report on screening patients for Cushing’s syndrome using U500 insulin. “U500 insulin is used commonly in patients who require more than 200 units of insulin daily,” Dr Mathews said. “Identifying patients with hypercortisolism is important,” Dr Mathews said, “but not easy. Patients can present a wide range of phenotypes with mild symptoms easily attributed to other conditions.” He continued, “Excess cortisol contributes to dysfunction in multiple organ systems includ- ing muscle weakness and atrophy, osteoporosis, dermatologic manifestations, menstrual irregularities, insomnia, mood disturbances, recurrent infection, obesity, hypertension, dyslipidemia, and insulin resistance. These metabolic disturbances increase the risk of heart attack, stroke, and death. So we wanted to determine the prevalence of hypercor- tisolism in our patient population.” “In our community endocrine practice,” Dr Mathews said, “we screened 34 patients using concentrated U500 insulin. Twenty-one patients (62%) had a biochemical indicator of hypercortisolism consistent with Cushing’s syndrome. Of those 21 patients, 13 underwent imaging at the time of publication, and nine showed radiologically confirmed hyperplasia or adenoma. The remaining patients are anticipated to complete imaging soon.” Dr Mathews concluded that in this community practice, 50% of patients screened by using concentrated U500 insulin were found to suffer from underlying hypercortisolism con- sistent with Cushing’s syndrome. These patients likely represent a population enriched in undiagnosed Cushing’s syndrome who would benefit from testing and treatment.

Fifty percent of patients screened using concentrated U500 insulin were found to suffer from underlying hypercortisolism consistent with Cushing’s syndrome, reports a community-based, randomized screening study.

It would make sense to consider screening patients requiring U500 insulin for Cushing’s syndrome. Once such patients are identified, they can receive more targeted therapy to improve their morbidity and mortality.

“Results of our study,” he added, “demon- strated that hypercortisolism appears to be prevalent in the population of patients requiring concentrated U500 insulin. The majority of these patients appear to have an adrenal etiology of hypercortisolism.” He continued, “Based on this data, it would make sense to consider screen- ing patients requiring U500 insulin for Cushing’s syndrome. Once such patients are identified, they can receive more tar- geted therapy to improve their morbidity and mortality.” Paras Mehta, MD, of Baylor College of Medicine, Houston, Texas, highlighted the difficulty of diagnosing and manag- ing Cushing’s syndrome in a case series. Individualized treatment of Cushing’s syndrome He explained that while the diagnosis of Cushing’s syndrome is often une- quivocal, determining its etiology and managing the syndrome effectively remain a challenge.

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Dr Mehta presented three cases of Cushing’s syndrome with var- ied presentations, etiologies, and management. Case 1 A 71-year-old male with coronary artery disease presented with fatigue and weakness, Cushingoid features, insulin resistance, and hypokalemic metabolic alkalosis. Laboratory evaluation showed an elevated 24-h urinary free cortisol and ACTH level. Pituitary MRI revealed no mass. He failed 1 and 8 mg dex- amethasone suppression tests. Both whole body PET and octreotide scans, however, showed no evidence of a source of ectopic ACTH. Subsequently, the patient underwent inferior petrosal sinus sampling, results of which were consistent with a pituitary source of ACTH. Total hypophysectomy was performed for a presumed pituitary microadenoma, but pathology instead showed corticotrophic hyperplasia. At publication, the patient continued to suffer from persis- tent Cushing’s syndrome, which is managed medically with mifepristone. Recent intolerances, however, have led to con- sideration of bilateral adrenalectomy. Case 2 A 35-year-old male developed diabetes mellitus, coronary artery disease, pulmonary embolism, and osteoporosis over a 1-year period. He was noted to harbor Cushingoid features and hypokalemic metabolic alkalosis. Random cortisol and ACTH levels were very elevated. Pituitary MRI revealed a 3-mm microadenoma, yet he failed the 8 mg dexamethasone suppression test. The patient then underwent inferior petrosal sinus sampling, results of which were consistent with a pituitary etiology. Pitu- itary microadenoma was resected, and pathology confirmed ACTH-secreting adenoma. At publication, he was being mon- itored closely postoperatively and exhibited signs of adrenal insufficiency. Case 3 A 40-year-old female with history of metastatic pancreatic neuroendocrine tumor presented with altered mental status, skin hyperpigmentation, and hypokalemic metabolic alkalo- sis. Laboratory evaluation showed an elevated 24-h urinary cortisol and ACTH level. Results of high-dose dexamethasone suppression and cor- ticotropin-releasing hormone stimulation tests suggested ectopic ACTH secretion. Pituitary MRI did not reveal any sig- nificant mass. ACTH staining of previously resected ovarian metastases of pancreatic neuroendocrine tumor showed pos- itive immunoreactivity, confirming the source of ACTH. Given the lack of surgical options due to metastatic disease, she is being managed with combination octreotide, ketoconazole, and mifepristone. Dr Mehta concluded that the three cases demonstrate the diffi- culty of applying the theoretical diagnostic algorithm to determine the etiology of Cushing’s syndrome. In addition, they demonstrate that treatment for Cushing’s syndrome should be individualized.

Guidelines for treating the new cardiovascular “extreme risk” category have been validated More intense treatment and intervention for dyslipidemia has been recommended by the American Association of Clinical Endocrinologists and American College of Endocrinology, and a new “extreme risk” category has been introduced. The updated guidelines and new risk category were presented at AACE 2017. P aul Jellinger, MD, of Memorial Regional Hospital South, Hollywood, Florida, and Yehuda Handelsman, MD, of Providence Tarzana Medical Center, Tarzana, California, highlighted the patient benefits of the recently introduced clin- ical guidelines. Drs Jellinger and Handelsman underscored the application of more aggressive treatment to reduce low-density lipoprotein cholesterol (LDL-C) in: • Patients with progressive atherosclerotic cardiovascular dis- ease who have achieved an LDL under 70 mg/dL. • Those with established atherosclerotic cardiovascular disease and diabetes, stage 3 or 4 kidney chronic kidney disease, or heterozygous familial hypercholesterolemia. • Those with a history of premature cardiovascular disease Patients with the above characteristics are now categorized as being at cardiovascular “extreme risk.” Treatment goals for these patients include: • LDL cholesterol <55 mg/dL • Non-HDL cholesterol <80 mg/dL • ApoB <70 mg/dL Coronary artery calcium score and inflammatory markers are also valuable in stratifying risk. The groundbreaking guidelines also assess the following: • Adding ezetimibe and PCSK9 inhibitors in patients with car- diovascular disease who are unable to reach LDL cholesterol goals with statin therapy. • Screening for cardiovascular risk in female patients using the Reynolds Risk Score or Framingham Risk Assessment Tool. • Special guidance for the diagnosis and management of dys- lipidemia in children and adolescents as early as possible to decrease the long-term risk of adult cardiovascular events. Dr Jellinger said, “While suggestive evidence pointed in the direction of better outcomes with more aggressive LDL treat- ment, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was the first prospective trial to demonstrate that driving LDL down to 53 provided a clear, significant benefit in reducing cardiovascular outcomes in high- risk groups.” “By expanding the group of patients studied in IMPROVE-IT to other very high-risk situations, our knowledge base expanded con- siderably. The new information led to the creation of the new risk category, a broader range of disease stages, and accompanying groundbreaking treatment and intervention recommendations.”

PracticeUpdate Editorial Team

PracticeUpdate Editorial Team

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BMI, polypharmacy, lab testingmay help diagnose DKA and identify high risk of its recurrence Demographic variables, especially body mass index and polypharmacy, could potentially aid in identifying subjects at high risk of recurrent diabetic ketoacidosis. In addition, beta-hydroxybutyrate measurement adds rigor to the diagnosis of diabetic ketoacidosis, conclude two presentations on diagnosing diabetic ketoacidosis and risk factors for its recurrence. V ishal Sehgal, MD, of the University of Tennessee Health Science Center, Memphis, explained, “Diabetic variables. Multivariable logistic regression was used to determine predictors of recur- rent diabetic ketoacidosis. variables, especially body mass index and polypharmacy, could potentially aid in identifying subjects at high risk of recurrent diabetic ketoacidosis.

ketoacidosis and its recurrence continue despite near-universal availability of insulin. So we set out to describe factors associ- ated with recurrent diabetic ketoacidosis in a community hospital.” He added, “The cost of healthcare seems to rise every year with no corresponding improvement in healthcare statistics. In this context, any scientific study should focus on reducing healthcare costs, in addition to reducing the morbidity and mortality.” All patients admitted with the diagnosis of diabetic ketoacidosis from 2013 to 2015 were identified. Patients with multiple admissions were identified and compared with patients who were admitted for dia- betic ketoacidosis only once. The unadjusted association between each of the variables and diabetic ketoacidosis was determined using chi-square tests for categorical variables and t-tests for con- tinuous variables. Logistic regression was used to calculate odds ratios and 95% confidence intervals for all categorical

A total of 116 patients accounted for 349 admissions during the 33-month study period. Of the 116 patients with diabetic ketoacidosis, 58 experienced only one episode and the remainder were admit- ted multiple times. Unadjusted results suggested that patients with lower body mass index, mean body weight and higher anion gap values were more likely to suffer recurrent diabetic ketoacidosis. In multivariable analysis, how- ever, body mass index and polypharmacy were the strongest predictors of recurrent diabetic ketoacidosis. Low body mass index and polypharmacy are easily quantifiable in day-to-day clin- ical practice. The results provide simple and easily available markers of patients at high risk of recurrent diabetic ketoacidosis. If confirmed in other data sets and pop- ulations, these markers might help direct interventions toward high-risk patients to reduce their morbidity and mortality. Dr Sehgal concluded that demographic

He said, “Our study helped define two easily quantifiable markers of readmis- sion to hospital in patients with diabetic ketoacidosis. Such identification could be extrapolated to hospital readmissions for other disease pathologies as well.” He continued, “If validated in other studies, interventions may be designed to reduce hospital readmissions in this population. Such interventions could help save the healthcare system billions of dollars.” In a related study on diabetic ketoacidosis presented at the American College of Clin- ical Endocrinology’s Scientific and Clinical Congress, John M. Miles, MD, FACE, of the University of Kansas Medical Center, Kan- sas City, assessed diagnostic criteria for the disorder. Dr Miles explained that American Diabetes Association diagnostic criteria for diabetic ketoacidosis include the triad of ketonuria, hyperglycemia (glucose ≥250 mg/dL), and serum bicarbonate ≤18 mEq/L. Serum bicarbonate is not specific for dia- betic ketoacidosis, however, and American Diabetes Association recommendations on laboratory testing for diabetes state that urine ketone testing should not be used for diagnosing diabetic ketoacidosis in view of its qualitative nature and inability to detect the dominant ketone body anion in diabetic ketoacidosis, beta-hydroxybutyrate. In a prior study, these limitations led Dr Miles and coinvestigators to suggest that admission beta-hydroxybutyrate ≥3.8 mmoL/L could be used in place of these criteria to diagnose diabetic ketoacidosis. In the present study, Dr Miles’s team reviewed records from adult admissions for diabetic ketoacidosis from 2012–2016 to assess the sensitivity and specificity of the American Diabetes Association criteria, using beta-hydroxybutyrate ≥3.8 mmoL/L to define diabetic ketoacidosis. Trace or negative ketonuria was consid- ered to be inconsistent with a diagnosis of diabetic ketoacidosis, whereas small, moder- ate, or large ketones were considered to be

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consistent with diabetic ketoacidosis. Records were reviewed on 224 patients with diabetic ketoacidosis and 151 individuals with diabetes but not diabetic ketoacidosis (beta-hydroxybutyrate <3.8 mmoL/L). Among patients with diabetic ketoacido- sis, serum bicarbonate was >18 mEq/L in 17%, consistent with previous reports. Urine ketones were negative to trace in 21%, and glucose was <250 mg/dL in 4%. Urine ketones and serum bicarbonate were both negative for diabetic ketoacidosis in 7%. Among individuals who did not experience diabetic ketoacidosis, 17% harbored small to large urine ketones, 18% serum bicarbo- nate ≤18 mEq/L, and 4%, both. Thus, 35% of patients who experienced diabetic ketoac- idosis as defined by beta-hydroxybutyrate lacked one or more American Diabetic Association diagnostic laboratory criteria. Thirty-one percent who did not experi- ence diabetic ketoacidosis fulfilled criteria for diabetic ketoacidosis with respect to serum bicarbonate, ketonuria, or both. When patients with diabetes who are admitted to the hospital are characterized as suffering from diabetic ketoacidosis or not based on admission beta- hydroxybutyrate, substantial discordance with American Diabetes Association diagnostic criteria is observed. Specifically, serum bicarbonate and urine ketones were often at odds with beta-hydroxybutyrate results. This is not surprising, considering the limitations of the urine ketone test and the fact that a serum bicarbonate ≤18 mEq/L is not specific for diabetic ketoacidosis. The results argue in favor of the use of serum beta-hydroxybutyrate to diagnose diabetic ketoacidosis, at least in hospi- tals with sufficient admissions for diabetic ketoacidosis to justify test availability. Dr Miles concluded that beta-hydroxybu- tyrate measurement should not supersede clinical judgment in the care of patients with diabetic ketoacidosis, but the meas- urement does add diagnostic rigor. If validated in other studies, interventions may be designed to reduce hospital readmissions in this population. Such interventions could help save the healthcare system billions of dollars.

Heart failure deserves more scrutiny as a complication of type 2 diabetes While much attention is given to the microvascular effects of type 2 diabetes, such as diabetic retinopathy, nephropathy, neuropathy; and macrovascular consequences such as stroke, myocardial infarction, and peripheral vascular disease, heart failure is a seventh and more sinister

complication that raises mortality. T his conclusion was based on an in-depth session entitled, “Heart Failure: The Frequent, Forgotten and Often Fatal Complication of Type 2 Diabetes”. David S.H. Bell, MD, of the University of Ala- bama at Birmingham School of Medicine, has performed clinical trials on the effects of angiotensin II receptor blockers in patients with diabetes and diastolic dysfunction. He suggested that the evidence should pro- pel endocrinologists to screen symptomatic patients more rigorously and to consider treating heart failure to mitigate the poor outcomes often seen in these patients. Anti-heart failure therapies such as angiotensin- converting-enzyme inhibitors and others work similarly well in individuals with diabetes as in those without diabetes. He said, “It’s not widely realized how common this condition is. Between 40 and 45% percent of US patients with diabetes suffer heart failure vs 12% of nondiabetics. Mortality depends on the degree of glycemic control.” Dr Bell highlighted studies that examined

has been found to increase heart failure in patients with diabetes. An expert in kidney disease and diabetes as major, independent risk factors for the development of heart failure, Dr Gilbert highlighted the relation between gly- cemic control and heart failure risk. He focused on evidence of the detrimental and beneficial effects of various types of hypoglycemic drugs. Aaron I. Vinik, PhD, FCP, MACP, FACE, of Eastern Virginia Medical School, Norfolk, presented his research on autonomic neuropathy, one of the most overlooked complications of type 2 diabetes, contrib- uting to the high incidence of heart failure. Vascular damage extends to involuntary nerves that stimulate the heart and blood vessels, resulting in heart rate and vascu- lar abnormalities. Dr Vinik noted that autonomic system dysfunction is a predictor of cardiovas- cular risk and sudden death in patients with type 2 diabetes. Autonomic dysfunc- tion also occurs in prediabetes, offering opportunities for early intervention. Impor- tant technological advances in technology during the past decade allow for identi- fication of early stages of autonomic dysfunction using objective, standardized measurements.

the complex effect of diabetes and contributing factors to the three causes of the heart fail- ure, including coronary artery disease, left ventricular hyper- trophy (approximately 65% of patients with type 2 diabetes), and diabetic cardiomyopathy. Richard E. Gilbert, MD, PhD, FRCPC, of the University of Toronto, Canada, noted that anti-heart failure therapies such as angiotensin-converting- enzyme inhibitors and others work similarly well in individuals with diabetes as in thosewithout diabetes. The glucose-lowering drug dipeptidylpeptidase-4 inhibitor saxagliptin, however,

PracticeUpdate Editorial Team

PracticeUpdate Editorial Team

© Photo by Jean Whiteside/AACE 2017

VOL. 1 • NO. 1 • 2017