New Medications for the Treatment of Diabetes

Abstract

Diabetes Technology & TherapeuticsVol. 18, No. S1 Original ArticlesFree AccessNew Medications for the Treatment of DiabetesSatish K. Garg, Sarit Polsky, Ashleigh Downs, and Viral N. ShahSatish K. GargSearch for more papers by this author, Sarit PolskySearch for more papers by this author, Ashleigh DownsSearch for more papers by this author, and Viral N. ShahSearch for more papers by this authorPublished Online:2 Feb 2016https://doi.org/10.1089/dia.2016.2511AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionThere has been an increase in interest in finding new ways to manage diabetes. Additional therapeutic choices for type 2 diabetes and adjunctive treatment options for type 1 diabetes are being explored daily. A new popular therapy that involves SGLT cotransporter inhibitors that do not require insulin presence especially in type 2 diabetes are becoming a choice for treatment more so as it also helps in weight loss. It specifically lowers postprandial glucose excursions. In this article, we are going to review abstracts related to newer and investigational agents that are being used in the management of diabetes. We reviewed over 600 articles of manuscripts/abstracts indexed from July 1, 2014, to June 30, 2015 (PubMed), and chose the following to highlight new therapeutic choices for diabetes management. We purposely did not include much on newer insulin choices as this has been discussed in another article.Key Articles Reviewed for this ArticleIncretin-based drugs and the risk of congestive heart failureYu OH1,2, Filion KB1,3,4, Azoulay L1,5, Patenaude V1, Majdan A2, Suissa S1,3,4Diabetes Care 2015;38: 277–84Therapies for inter-relating diabetes and obesity—GLP-1 and obesityIepsen EW1, Torekov SS1, Holst JJ2Expert Opin Pharmacother 2014;15: 2487–500GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPKBeiroa D1,2, Imbernon M1,2, Gallego R3, Senra A1, Herranz D4, Villarroya F2,5, Serrano M4, Fernø J6, Salvador J2,7, Escalada J2,7, Dieguez C1,2, Lopez M1,2, Frühbeck G2,7, Nogueiras R1,2Diabetes 2014;63: 3346–58Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trialØstoft SH1–3, Bagger JI1–3, Hansen T3,4, Pedersen O3, Faber J5,6, Holst JJ2,3, Knop FK1–3, Vilsbøll T6Diabetes Care 2014;37: 1797–805Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetesGough SC1, Bode B2, Woo V3, Rodbard HW4, Linjawi S5, Poulsen P6, Damgaard LH6, Buse JB7; NN9068-3697 (DUAL-I) Trial InvestigatorsLancet Diabetes Endocrinol 2014;2: 885–93Prandial insulin versus glucagon-like peptide-1 added to basal insulin: comparative effectiveness in the community practice settingDigenio A1, Karve S2, Candrilli SD2, Dalal M3Postgrad Med 2014;126: 49–59Aerosolized GLP-1 for treatment of diabetes mellitus and irritable bowel syndromeSiekmeier R1, Hofmann T2, Scheuch G3, Pokorski M4Exp Med Biol 2015;849: 23–38Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetesDe Nicola L1, Gabbai FB2, Liberti ME1, Sagliocca A1, Conte G1, Minutolo R1Am J Kidney Dis 2014;64: 16–24Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathyŠkrtić M, Cherney DZCurr Opin Nephrol Hypertens 2015;24: 96–103Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetesSands AT1, Zambrowicz BP1, Rosenstock J2, Lapuerta P1, Bode BW3, Garg SK4, Buse JB5, Banks P1, Heptulla R6, Rendell M7, Cefalu WT8, Strumph P1Diabetes Care 2015;38: 1181–88Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibitionPeters AL1, Buschur EO2, Buse JB3, Cohan P4, Diner JC3, Hirsch IB5Diabetes Care 2015;38: 1687–93SGLT2 inhibitors may predispose to ketoacidosisTaylor SI1,2, Blau JE1, Rother KI1J Clin Endocrinol Metab 2015;100: 2849–52Transdermal delivery of insulin via microneedlesNarayan RJJ Biomed Nanotechnol 2014;10: 2244–60Assessment for ease of use and preference of a new prefilled insulin pen (FlexTouch Degludec U100/U200) versus the SoloSTAR insulin pen by patients with diabetes and healthcare professionalsPfützner A1, Forst T2, Niemeyer M3, Bailey T4Expert Opin Drug Deliv 2014;11: 1381–89Standardized modulation of the injection site allows for insulin dose reduction without deterioration of metabolic controlPfützner A1, Dissel S2, Forkel C3, Grenningloh M3, Bitton G4, Nagar R4, Forst T2Curr Med Res Opin 2014;30: 2001–8Subcutaneous injection of hyaluronidase with recombinant human insulin compared with insulin lispro in type 1 diabetesGarg SK1, Buse JB2, Skyler JS3, Vaughn DE4, Muchmore DB4Diabetes Obes Metab 2014;16: 1065–69Glucose-lowering effect of insulin degludec is independent of subcutaneous injection regionNosek L1, Coester HV1, Roepstorff C2, Thomsen HF3, Kristensen NR2, Haahr H2, Heise T1Clin Drug Investig 2014;34: 673–79Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target noninferiority trialDavies MJ1, Gross JL2, Ono Y3, Sasaki T4, Bantwal G5, Gall MA6, Niemeyer M6, Seino H7; BEGIN BB T1 Study GroupDiabetes Obes Metab 2014;16: 922–30Insulin degludec/insulin aspart combination for the treatment of type 1 and type 2 diabetesDardano A, Bianchi C, Del Prato S, Miccoli RVasc Health Risk Manag 2014;10: 465–75A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: VICTOZA ADD-ON)Mathieu C1, Rodbard HW2, Cariou B3, Handelsman Y4, Philis-Tsimikas A5, Ocampo Francisco AM6, Rana A7, Zinman B8; BEGIN: VICTOZA ADD-ON (NN1250-3948) study groupDiabetes Obes Metab 2014;16: 636–44Insulin lispro low mixture twice daily versus basal insulin glargine once daily and prandial insulin lispro once daily in patients with type 2 diabetes requiring insulin intensification: a randomized phase IV trialTinahones FJ1, Gross JL2, Onaca A3, Cleall S4, Rodríguez A5Diabetes Obes Metab 2014;16: 963–70New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1)Riddle MC1, Bolli GB2, Ziemen M3, Muehlen-Bartmer I3, Bizet F4, Home PD5, EDITION 1 Study InvestigatorsDiabetes Care 2014;37: 2755–62New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2)Yki-Järvinen H1, Bergenstal R2, Ziemen M3, Wardecki M4, Muehlen-Bartmer I3, Boelle E5, Riddle MC6, on behalf of the EDITION 2 Study InvestigatorsDiabetes Care 2014;37: 3235–43Basal insulin glargine and microvascular outcomes in dysglycemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trialGilbert RE1,2, Mann JF3, Hanefeld M4, Spinas G5, Bosch J6, Yusuf S6,7, Gerstein HC6,7 ORIGIN trial investigatorsDiabetologia 2014;57: 1325–31Cost implications of the use of basal insulin glargine in people with early dysglycemia: the ORIGIN trialLamy A1–4, Tong W1,2, Jung H1, Gafni A4,5, Singh K6,7, Tyrwhitt J1, Yusuf S1,4,8, Gerstein HC1,8; ORIGIN InvestigatorsJ Diabetes Complications 2014;28: 553–58Comparison of the effects of slowly and rapidly absorbed carbohydrates on postprandial glucose metabolism in type 2 diabetes mellitus patients: a randomized trialAng M, Linn TAm J Clin Nutr 2014;100: 1059–68Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trialJakubowicz D1, Froy O2, Ahrén B3, Boaz M4, Landau Z1, Bar-Dayan Y1, Ganz T1, Barnea M2, Wainstein J1Diabetologia 2014;57: 1807–11Positive association of free triiodothyronine with pancreatic β-cell function in people with prediabetesOda T, Taneichi H, Takahashi K, Togashi H, Hangai M, Nakagawa R, Ono M, Matsui M, Sasai T, Nagasawa K, Honma H, Kajiwara T, Takahashi Y, Takebe N, Ishigaki Y, Satoh JDiabet Med 2015;32: 213–19Artemisia dracunculus L. extract ameliorates insulin sensitivity by attenuating inflammatory signalling in human skeletal muscle cultureVandanmagsar B1, Haynie KR1, Wicks SE1, Bermudez EM1, Mendoza TM1, Ribnicky D2, Cefalu WT3, Mynatt RL1Diabetes Obes Metab 2014;16: 728–38IncretinsIncretin-based drugs and the risk of congestive heart failureYu OH1,2, Filion KB1,3,4, Azoulay L1,5, Patenaude V1, Majdan A2, Suissa S1,3,41Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.2Division of Endocrinology, Jewish General Hospital, Montreal, Quebec, Canada.3Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada.4Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada.5Department of Oncology, McGill University, Montreal, Quebec, CanadaDiabetes Care 2015;38: 277–84ObjectiveThis study aims to establish if the use of incretin-based drugs, including GLP-1 analogs and dipeptidyl peptidase-4 inhibitors, is associated with an increased risk of congestive heart failure (CHF) among patients with type 2 diabetes.MethodsThe U.K. Clinical Practice Research Datalink, linked to the Hospital Episode Statistics database, was used to conduct a cohort study with a nested case–control analysis among patients newly prescribed antidiabetic drugs between January 1, 2007, and March 31, 2012, and no prior history of CHF. Case subjects were defined as patients hospitalized for a first CHF and matched with up to 20 control subjects on age, duration of treated diabetes, calendar year, and time since cohort entry. Conditional logistic regression was used to estimate odds ratios (ORs) with corresponding 95% CIs of incident CHF comparing current use of incretin-based drugs with current use of two or more oral antidiabetic drugs.ResultsThe cohort consisted of 57,737 patients followed for a mean 2.4 years, during which time 1,118 incident cases of hospitalized CHF were identified (incidence rate 8.1/1,000 person-years). Current use of incretin-based drugs was not associated with an increased risk of CHF (adjusted OR 0.85 [95% CI 0.62–1.16]). Secondary analyses revealed no duration–response relationship (p trend=0.39).ConclusionsIncretin-based drug use was not associated with an increased risk of CHF among patients with type 2 diabetes. Although these results are reassuring, the findings will need to be replicated in other large-scale studies.Therapies for inter-relating diabetes and obesity—GLP-1 and obesityIepsen EW1, Torekov SS1, Holst JJ21Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.2University of Copenhagen, Copenhagen, DenmarkExpert Opin Pharmacother 2014;15: 2487–500IntroductionThe extreme rise in obesity and type 2 diabetes mellitus (T2DM) is associated with increased mortality and morbidity, as well as a rise in public health-care expenses throughout the world. The necessity for effective and long-lasting pharmaceutical treatment is evident. The past performance of antiobesity drugs has been inadequate until now, and the only efficient treatment today is bariatric surgery. Research has indicated that appetite inhibiting hormones from the gut may have a therapeutic potential in obesity. The gut incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiety. Clinical trials have shown that two GLP-1 receptor agonists, exenatide and liraglutide, have a weight-lowering potential in nondiabetic obese individuals. Furthermore, they may also hold a potential in preventing diabetes as compared to other weight loss agents.Areas CoveredThis review aims to look at the background for the GLP-1-based therapies and their potential in obesity and prediabetes. Up-to-date literature on incretin-based therapies will be summarized with a special mention of their weight-lowering properties. The literature updated to August 2014 from PubMed was identified using the combinations GLP-1, GLP-1 receptor agonists, incretins, obesity, and prediabetes.ConclusionThe incretin impairment, which seems to exist in both obesity and diabetes, may link these two pathologies and underlines the potential of GLP-1-based therapies in the prevention and treatment of these diseases.GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPKBeiroa D1,2, Imbernon M1,2, Gallego R3, Senra A1, Herranz D4, Villarroya F2,5, Serrano M4, Fernø J6, Salvador J2,7, Escalada J2,7, Dieguez C1,2, Lopez M1,2, Frühbeck G2,7, Nogueiras R1,2,1Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.2CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.3Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.4Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.5Department of Biochemistry and Molecular Biology and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.6Department of Clinical Science, K.G. Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.7Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, SpainDiabetes 2014;63: 3346–58AbstractThe GLP-1 receptor (GLP-1R) is found throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas in charge of these interactions remain largely unknown. The authors observed that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is enough to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was adequately explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. The results do not eliminate the prospect that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, but the data suggests that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through a range of hypothalamic sites and that these mechanisms might be clinically relevant.Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trialØstoft SH123, Bagger JI123, Hansen T3,4, Pedersen O3, Faber J5,6, Holst JJ2,3, Knop FK123, Vilsbøll T61Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.2Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.3NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.4Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.5Department of Medicine, Herlev Hospital, University of Copenhagen, Herlev, Denmark.6Faculty of Health Sciences, University of Copenhagen, Copenhagen, DenmarkDiabetes Care 2014;37: 1797–805ObjectiveHepatocyte nuclear factor 1α (HNF1A diabetes: MODY3) is the most common form of maturity-onset diabetes of the young (MODY), and it is commonly treated with sulfonylureas, which present a high risk of hypoglycemia. The authors loooked at treating patients with HNF1A diabetes with GLP-1 receptor agonists (GLP-1RAs).Research Design and MethodsSixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23–67 years]; BMI 24.9±0.5 kg/m2 [mean ± SEM]; fasting plasma glucose [FPG] 9.9±0.9 mmol/L; HbA1c 6.4±0.2% [47±3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutide was up-titrated once weekly to 1.8 mg once daily. At baseline and at the end of each treatment period a standardized liquid meal test was performed, including a 30 min light bicycle test.ResultsFPG decreased during the treatment periods (−1.6±0.5 mmol/L liraglutide [p=0.012] and −2.8±0.7 mmol/L glimepiride [p=0.003]), with no difference between treatments (p=0.624). Postprandial plasma glucose (PG) responses (total area under the curve) were lower with both glimepiride (2,136±292 min × mmol/L) and liraglutide (2,624±340 min × mmol/L) compared with baseline (3,127±291 min × mmol/L; p<0.001, glimepiride; p=0.017, liraglutide), with no difference between treatments (p=0.121). Eighteen episodes of hypoglycemia (PG ≤3.9 mmol/L) occurred during glimepiride treatment and one during liraglutide treatment.ConclusionsIn patients with HNF1A diabetes, 6 weeks of treatment with glimepiride or liraglutide reduced FPG and postprandial glucose excursions. The glucose-lowering effect was greater with glimepiride at the expense of a higher risk of exclusively mild hypoglycemia.Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetesGough SC1, Bode B2, Woo V3, Rodbard HW4, Linjawi S5, Poulsen P6, Damgaard LH6, Buse JB7NN9068-3697 (DUAL-I) Trial Investigators1Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.2Atlanta Diabetes Associates, Atlanta, GA.3Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.4Endocrine and Metabolic Consultants, Rockville, MD.5Coffs Harbour Diabetes Clinic, Coffs Harbour, NSW, Australia.6Novo Nordisk, Søborg, Denmark.7Department of Medicine, University of North Carolina, Chapel Hill, NCLancet Diabetes Endocrinol 2014;2: 885–93BackgroundFor the treatment of type 2 diabetes, a fixed-ratio combination of the basal insulin analog insulin degludec and the glucagon-like peptide-1 (GLP-1) analog liraglutide was developed as a once-daily injection. The authors sought to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients.MethodsAdults with type 2 diabetes, HbA1c of 7–10% (inclusive), a BMI of 40 kg/m2 or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1.8 mg/day) in this phase 3, 26-week, open-label, randomized trial. IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4–5 mmol/L. Change in HbA1c after 26 weeks of treatment was the primary endpoint. The main objective was to assess the noninferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0.3%) and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%).FindingsIn all, 1,663 adults (mean age 55 years [SD 10], HbA1c 8.3% [0.9], and BMI 31.2 kg/m2 [4.8]) were randomly assigned as follows: 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1.9% (SD 1.1) to 6.4% (1.0) with IDegLira, by 1.4% (1.0) to 6.9% (1.1) with insulin degludec, and by 1.3% (1.1) to 7.0% (1.2) with liraglutide. IDegLira was noninferior to insulin degludec (estimated treatment difference −0.47%, 95% CI −0.58 to −0.36, p<0·0001) and superior to liraglutide (−0.64%, −0.75 to −0.53, p<0.0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8.8% vs. 19.7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3.6%). With respect to standard safety assessments, the authors didn't note any clinically relevant differences between treatments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycemic events per patient year was 1.8 for IDegLira, 0.2 for liraglutide, and 2.6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, 8 (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group.InterpretationIDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycemic control compared with its components given alone.Prandial insulin versus glucagon-like peptide-1 added to basal insulin: comparative effectiveness in the community practice settingDigenio A1, Karve S2, Candrilli SD2, Dalal M31Isis Pharmaceuticals, Inc., Carlsbad, CA.2RTI Health Solutions, Research Triangle Park, NC.3Sanofi US, Inc., Bridgewater, NJPostgrad Med 2014;126: 49–59BackgroundReal-world data on emerging combination approaches for type 2 diabetes mellitus (T2DM) management are limited. The aim of this study was to record the characteristics and clinical outcomes of patients with T2DM who were initiating prandial insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist while on basal insulin.MethodsThis was a retrospective analysis of an electronic medical records database of patients with T2DM managed in a community practice setting in the United States. The main outcome measures were glycated hemoglobin (HbA1c), body weight, hypoglycemia, and health-care resource utilization at baseline and at 6-month and 1-year follow-ups.ResultsA total of 33,810 patients were included in the study: 31,848 on prandial insulin and 1,962 on a GLP-1 receptor agonist. There were considerable differences at baseline between the prandial insulin and GLP-1 receptor agonist groups in the following factors, respectively (p<0.001 for each): mean age (60 vs. 56 years), mean Charlson Comorbidity Index score (1.1 vs. 0.7), mean HbA1c (8.8% vs. 8.4%), and mean body weight (99 vs. 112 kg). After matching for baseline differences, significant and similar changes from baseline were observed between the prandial insulin and the GLP-1 receptor agonist groups during follow-up at the 6 months/1 year post-index date for HbA1c (−0.45/−0.60% vs. −0.44/−0.58%, respectively; p=0.907/0.723 between groups). Body weight changes between the groups were significantly different at 6 months/1 year (+1.7/−1.7 vs. −0.9/−3.7 kg; p<0.001). Hypoglycemia incidence and health-care resource utilization were significantly greater in the prandial insulin versus GLP-1 receptor agonist group.ConclusionsThe results of this real-world analysis of patients with T2DM adding a GLP-1 receptor agonist or prandial insulin to basal insulin suggest an association between adding a GLP-1 receptor agonist with similar glycemic control, greater reduction in body weight, lower hypoglycemia incidence, and lower health-care utilization compared with adding prandial insulin.Aerosolized GLP-1 for treatment of diabetes mellitus and irritable bowel syndromeSiekmeier R1, Hofmann T2, Scheuch G3, Pokorski M41Drug Regulatory Affairs, Pharmaceutical Institute, Bonn University, Bonn, Germany.2Aumapharma LLC, Doylestown, PA.3Vectura AG, Gemünden, Germany.4Institute of Psychology, Opole University, Opole, PolandExp Med Biol 2015;849: 23–38AbstractThe prevalence of diabetes, in particular diabetes mellitus type 2, is skyrocketing throughout the world. A major number of pharmaceuticals have been developed for the treatment of diabetes mellitus type 2 after introduction of insulin into clinical therapy about 90 years ago. Like insulin, the incretin glucagon-like peptide 1 (GLP-1) needs subcutaneous administration, which makes it inconvenient for patients. However, administration of GLP-1 also plays a role in the treatment of irritable bowel syndrome (IBS). To improve patient convenience, inhaled insulin (Exubera®) was developed and approved but failed market acceptance some years ago. Recently, another inhalative insulin (Afrezza®) received market approval, and GLP-1 may serve as another candidate drug for inhalative administration. This review analyzes the current literature investigating alternative administration of GLP-1 and GLP-1 analogs focusing on inhalation. Several formulations for inhalative administration of GLP-1 and analogs were investigated in animal studies, whereas there are only few clinical data. However, feasibility of GLP-1 inhalation has been shown and should be further investigated as such type of drug administration may serve for improvement of therapy in patients with diabetes mellitus or irritable bowel syndrome.CommentPreviously, preclinical and observational studies documented possible cardiovascular (CVD) protective effects of incretin agents. However, two large clinical trials showed no increase or decrease in CVD events with DPP-IV inhibitors. Moreover, two clinical trials reported higher incidence of heart failure with DPP-IV inhibitors and thus creating another controversy with the use of DPP-IV inhibitors. The study by Yu and colleagues examined the UK clinical practice research database to assess the risk of heart failure in real-life using these drugs. They did not find increase risk for heart failure with the use of incretin therapies. Though this data is reassuring, proper randomized clinical trials are required to elucidate the cause-and-effect relationship between heart failure and incretin therapies.Many investigators are also exploring the nonglycemic effects of incretin hormones with a hope of expanding their clinical use. Since GLP-1 analogs are associated with clinically significant weight loss, studies are evaluating weight loss effect of GLP-1 analogs. Recently, liraglutide 3 mg (Saxend®) has been approved by the Food and Drug Administration for the treatment of obesity in adults with obesity-related comorbidities. The article by Iepsen and colleagues reviewed (above) relationships between diabetes and obesity and the role of GLP-1 in treating both conditions. Another report by Beiroa et al. studied the effect of GLP-1 analogs on brown adipose tissue thermogenesis.In addition, the lack of or lower hypoglycemic episodes with GLP analogs is attractive as an option for initiating therapy in type 2 diabetes. Study by Ostoft et al. compared the effect of sulfonylurea and liraglutide for treatment of maturity onset diabetes of young (MODY). They found that glucose lowering effect was greater with glimepiride compared to liraglutide but at expense of higher rate of hypoglycemia. However, this is a small study with only a 6-week duration.Gough et al. showed efficacy of fixed dose combination of insulin and GLP-1 analogs (IDegLira). The investigators showed improved glycemic control without increasing hypoglycemia with combined drugs compared to either GLP-1 or insulin alone. Study by Digenio et al. demonstrated that the addition of GLP-1 analogs to basal insulin improved glycemic control similar to adding prandial insulin to basal insulin. However, GLP-1 analog therapy to basal insulin was associated with reduction in weight and hypoglycemia. The last article by Siekmeier et al. discussed the possibility of aerosolized GLP-1 for treatment of diabetes.SGLT InhibitorsSodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetesDe Nicola L1, Gabbai FB2, Liberti ME1, Sagliocca A1, Conte G1, Minutolo R11Nephrology Division, Second University of Naples-Med School, Naples, Italy.2Department of Medicine, Veterans Administration San Diego Healthcare System-University of California at San Diego Medical School, San Diego, CAAm J Kidney Dis 2014;64: 16–24AbstractOptimal prevention and treatment of chronic kidney disease in diabetes requires therapies that target the pathogenesis of diabetic nephropathy. Due to this, alterations of the proximal tubule and resulting changes in glomerular filtration rate have been given substantial consideration. Hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport at the onset of diabetes mellitus. The increase in proximal reabsorption leads to the following: a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate.Because glomerular hyperfiltration is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. For this high-risk patient population, the introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives.