Abstract
Introduction
Many large databases in the United States and Europe have shown a significant reduction in the lifespan (about a decade) of patients with type 2 diabetes (T2D), primarily due to cardiovascular complications and renal disease. Consequently, both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have revised the guidelines for managing and initiating therapy in patients with type 2 diabetes. The new guidelines preferentially guide clinicians to initiate therapies that will reduce the overall risk of cardiovascular mortality and/or need for renal dialysis or transplant. If any of these elements are present in patients with T2D, the providers are encouraged to initiate either sodium‐glucose cotransporter‐2 (SGLT2) inhibitors or glucagon‐like peptide (GLP) analogs, because these classes of drugs have demonstrated clear benefits to patients with cardiovascular disease and/or associated renal disease. Glycemic control continues to be an important metric in the management of type 2 diabetes. Many new molecules are being evaluated to manage type 2 diabetes, including glucagon‐like peptide/glucose‐dependent insulinotropic (GLP‐1/GIP) dual agonists, glucagon receptor antibodies, glucokinase activators, oral GLP analogs, and more.
Similar to T2D, the majority of the patients with type 1 diabetes (T1D) do not achieve a target level of glycated hemoglobin (HbA1c) of <7%, as recommended by the ADA and EASD. In addition, more than two‐thirds of T1D patients are overweight or obese, which was not the case many decades ago. As a result of increased weight, patients experience symptoms of T2D, in addition to T1D (due to insulin resistance), sometimes referred to as “double diabetes.” Many adjunctive therapies are being evaluated for improving T1D management, which are likely to improve glycemic control without weight gain (in fact, they may be associated with weight loss), lower blood pressure, and possibly decrease hypoglycemia. These medications include SGLT2 and SGLT1/SGLT2 inhibitors, glucagon receptor antibodies, coformulations of insulin with pramlintide, etc.
In this article, we aim to give readers an overview of the direction of new therapies for diabetes and potential developments in the next 5–10 years. It is impossible to cover all the medications under investigation in this article. We will purposely not go into the details of new insulin analogs (weekly basal insulin and ultra‐fast‐acting insulin analogs), lysosome‐directed insulin delivery systems, and biosimilar insulin products, as we expect those topics to be covered in the article on new insulins.
Key Articles Reviewed for the Article
Aharon‐Hananel G, Raz I
Chang HY, Singh S, Mansour O, Baksh S, Alexander GC
Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL
Frias JP
He YL, Haynes W, Meyers CD, Amer A, Zhang Y, Mahling P, Mendonza AE, Ma S, Chutkow W, Bachman E
Henry RR, Strange P, Zhou R, Pettus J, Shi L, Zhuplatov SB, Mansfield T, Klein D, Katz A
Herrington WG, Preiss D, Haynes R, von Eynatten M, Staplin N, Hauske SJ, George JT, Green JB, Landray MJ, Baigent C, Wanner C
Ito D, Inoue K, Sumita T, Hamaguchi K, Kaneko K, Yanagisawa M, Inukai K, Inoue I, Noda M, Shimada A
Kakuda H, Kobayashi J, Sakurai M, Takekoshi N
Akturk HK, Rewers A, Garg SK
Danne T, Cariou B, Buse JB, Garg SK, Rosenstock J, Banks P, Kushner JA, McGuire DK, Peters AL, Sawhney S, Strumph P
Mathieu C1, Dandona P, Gillard P, Senior P, Hasslacher C, Araki E, Lind M, Bain SC, Jabbour S, Arya N, Hansen L, Thorén F, Langkilde AM, on behalf of DEPICT‐2 Investigators
McCrimmon RJ, Henry RR
Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A
Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, Sahoo J
Yamashima M, Miyaaki H, Miuma S, Shibata H, Sasaki R, Haraguchi M, Fukushima M, Nakao K
Danne T, Garg S, Peters AL, Buse JB, Mathieu C, Pettus JH, Alexander CM, Battelino T, Ampudia‐Blasco FJ, Bode BW, Cariou B, Close KL, Dandona P, Dutta S, Ferrannini E, Fourlanos S, Grunberger G, Heller SR, Henry RR, Kurian MJ, Kushner JA, Oron T, Parkin CG, Pieber TR, Rodbard HW, Schatz D, Skyler JS, Tamborlane WV, Yokote K, Phillip M
Goldenberg RM, Gilbert JD, Hramiak IM, Woo VC, Zinman B
Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, Pedersen KB, Saugstrup T, Meier JJ; for the PIONEER 4 investigators
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A
Mathieu C, Del Prato S, Botros FT, Thieu VT, Pavo I, Jia N, Haupt A, Karanikas CA, García‐Pérez LE
RISE Consortium
Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, Thrasher J, Woo V, Philis‐Tsimikas A
Aroda VR, González‐Galvez G, Grøn R, Halladin N, Haluzík M, Jermendy G, Kok A, Őrsy P, Sabbah M, Sesti G, Silver R
Blonde L, Anderson JE, Chava P, Dendy JA
Lingvay I, Handelsman Y, Linjawi S, Vilsbøll T, Halladin N, Ranc K, Liebl A
Horie I, Haraguchi A, Sako A, Akeshima J, Niri T, Shigeno R, Ito A, Nozaki A, Natsuda S, Akazawa S, Mori Y, Ando T, Kawakami A, Abiru N
Hassanein MM, Sahay R, Hafidh K, Djaballah K, Li H, Azar S, Shehadeh N, Hanif W
Maiorino MI, Chiodini P, Bellastella G, Scappaticcio L, Longo M, Giugliano D, Esposito K
Han KA, Chon S, Chung CH, Lim S, Lee KW, Baik S, Jung CH, Kim DS, Park KS, Yoon KH, Lee IK, Cha BS, Sakatani T, Park S, Lee MK
Yang W, Ma J, Li Y, Li Y, Zhou Z, Kim JH, Zhao J, Ptaszynska A
Mkrtumyan A, Romantsova T, Vorobiev S, Volkova A, Vorokhobina N, Tarasov S, Putilovskiy M, Andrianova E, Epstein O
Rickels MR, DuBose SN, Toschi E, Beck RW, Verdejo AS, Wolpert H, Cummins MJ, Newswanger B, Riddell MC; T1D Exchange Mini‐Dose Glucagon Exercise Study Group
Riddle MC, Nahra R, Han J, Castle J, Hanavan K, Hompesch M, Huffman D, Strange P, Öhman P
An evaluation of the efficacy and safety of Tofogliflozin for the treatment of type II diabetes
Aharon‐Hananel G1,2, Raz I1,3
1Diabetes Medical Center, Tel Aviv, Israel; 2Endocrine Institute, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; 3Hadassah Hebrew University Hospital, Jerusalem, Israel
Background
Data amassed from recent studies have brought changes to the gold standard of care for diabetes treatment. In patients with T2D and established cardiovascular disease or those at high risk for cardiovascular (CV) disease, the use of an SGLT2 inhibitor with established benefits for cardiovascular outcome should be considered for those who have already made lifestyle changes and received metformin therapy.
Methods
The most selective SGLT2 inhibitor available is Tofogliflozin, which has been approved for the treatment of T2D in Japan.
Results
This review presents a summary of the data currently available regarding Tofogliflozin versus other SGLT2 inhibitors, primarily the three SGLT2 inhibitors with published CV outcomes: Empagliflozin, Canagliflozin, and Dapagliflozin.
Conclusions
Tofogliflozin's higher selectivity profile increases the positive effects on CV outcomes and death as well as reducing its side effects. However, there is very little clinical data on Tofogliflozin from either clinical or real‐world studies, while the other main 3 SGLT2 inhibitors do have reasonable amounts of such data, thus calling for caution and underscoring the need for further research.
Association between sodium‐glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes
Chang HY1,2, Singh S3, Mansour O1,4, Baksh S1,4, Alexander GC1,4,5
1Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 2Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 3Department of Family Medicine and Community Health, University of Massachusetts Medical School, Worcester MA; 4Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 5Division of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD
Background
Results of previous clinical trials have suggested that canagliflozin, a (SGLT2) inhibitor for the treatment of type 2 diabetes, may be associated with increased risk for lower extremity amputation. To quantify the association between the use of oral medication for type 2 diabetes and five outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer), a new study was carried out among a large cohort of commercially insured individuals in the United States.
Methods
A population‐based, retrospective, new‐user design cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals. Patients with at least one of the following antidiabetic medications were considered for inclusion: SGLT2 inhibitors, dipeptidyl peptidase 4 (DPP‐4) inhibitors, or GLP‐1 agonists (the three newer agents) and sulfonylureas, metformin hydrochloride, and thiazolidinediones (three older agents). Those included were divided into four exposure groups: new use of SGLT2 inhibitors alone, DPP‐4 inhibitors alone, GLP‐1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones). Propensity score weighting was used to balance baseline differences among groups. The four sets of sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP‐4) inhibitors and glucagon‐like peptide 1 (GLP‐1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation.
Results
Foot and leg amputation were defined according to the International Classification of Diseases, ninth revision and Current Procedural Terminology codes. Among 2.0 million potentially eligible individuals, 953,906 (516,046 women, 437,860 men; mean age 51.8±10.9 years) were included in the final analyses. Of these, 39,869 (4.2%) were new users of SGLT2 inhibitors, 105,023 (11.0%) were new users of DPP‐4 inhibitors, and 39,120 (4.1%) were new users of GLP‐1 agonists. Median observation time ranged from 99 days for new users of GLP‐1 agonists to 127 days for metformin, sulfonylureas, and thiazolidinediones users. Crude incident rates ranged from 4.90 per 10,000 person‐years for patients being treated with metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10,000 person‐years for new users of SGLT2 inhibitors. Following propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, results showed a nonstatistically significant increased risk of amputation associated with new use of SGLT2 inhibitors compared with DPP‐4 inhibitors (adjusted hazard ratio 1.50 [95% CI 0.85–2.67]) and GLP‐1 agonists (adjusted hazard ratio 1.47 [95% CI, 0.64–3.36]). The association between new use of SGLT2 inhibitors and amputation compared was statistically significant compared with sulfonylureas, metformin, and thiazolidinediones (adjusted hazard ratio 2.12 [95% CI, 1.19–3.77]). These results persisted in sensitivity analyses.
Conclusions
The use of SGLT2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies should be completed, with extended follow‐up and larger sample sizes.
Effects of the SGLT2 inhibitor dapagliflozin on glomerular and tubular injury markers
Dekkers CCJ1, Petrykiv S2, Laverman GD3, Cherney DZ4,5, Gansevoort RT1, Heerspink HJL1
1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 3Department of Nephrology, Ziekenhuisgroep Twente, Almelo and Hengelo, The Netherlands; 4Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Canada; 5Department of Physiology and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
Background
The mechanisms by which SGLT2 inhibitors lower albuminuria are incompletely understood.
This study aimed to describe the effect of the SGLT‐2 inhibitor dapagliflozin on glomerular and tubular injury and inflammatory markers. Additionally, in an attempt to gain insight regarding the mechanisms responsible for the lowering of albuminuria with dapagliflozin therapy, the secondary aim was to assess whether changes in albuminuria or estimated glomerular filtration rate (eGFR) during dapagliflozin therapy correlated with kidney injury markers.
Methods
This was a post‐hoc analysis of a prospective, randomized, double‐blind, placebo‐controlled crossover clinical trial to assess the effects of the SGLT2 inhibitor dapagliflozin on glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM‐1, NGAL, and LFABP), and inflammatory markers (urinary MCP‐1 and IL‐6).
Results
Dapagliflozin decreased albuminuria by 43.9% (95% CI 30.3%–54.8%) and eGFR by 5.1 (2.0–8.1) mL/min/1.73 m2 compared with placebo but did not alter glomerular charge or size selectivity index compared with placebo. Urinary KIM‐1 excretion was reduced by 22.6% (0.3%–39.8%; P=0.05) and IL‐6 excretion by 23.5% (1.4%–40.6%; P=0.04) compared with placebo. No changes were noted in NGAL, LFABP, and MCP‐1. Changes in albuminuria correlated with changes in eGFR (r=0.36; P=0.05) and KIM‐1 (r=0.39; P=0.05) during treatment with dapagliflozin.
Conclusions
The albuminuria‐lowering effect of 6 weeks of treatment using dapagliflozin may be due to decreased intraglomerular pressure or reduced tubular cell injury.
Fixed‐dose combination of ertugliflozin and metformin hydrochloride for the treatment of type 2 diabetes
Frias JP
Department of Clinical Research, National Research Institute, Los Angeles, CA
Background
The current standard of care for the management of T2D involves a combination of antihyperglycemic agents to achieve safe, rapid glycemic control. Ideally, the agents used should have mechanisms of actions that are complementary and that improve glycemic control without unacceptable increase in body weight or hypoglycemia.
Methods
Segluromet (ertugliflozin and metformin hydrochloride) is a recently approved fixed‐dose combination tablet containing the SGLT2 inhibitor ertugliflozin and metformin. This review summarizes key characteristics of ertugliflozin and metformin along with the efficacy and safety results from the coadministration of these agents in the ertugliflozin clinical development program. Ertugliflozin/metformin prescribing information in addition to published clinical trials obtained through a PubMed search were used as information sources for completion of the review.
Results
SGLT2 inhibitors are effective alone and in combination with other antihyperglycemic agents. Their use produces favorable effects on both glycemia control and “extra‐glycemic” parameters such as body weight and blood pressure. Because of this, SGLT2 inhibitors are exemplary therapeutic agents for appropriate patients with T2D.
Conclusion
The fixed‐dose combination of ertugliflozin with metformin is an effective and convenient therapeutic combination that may improve medication adherence and persistence.
The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes
He YL1, Haynes W1,2, Meyers CD1,3, Amer A4, Zhang Y5, Mahling P6, Mendonza AE1, Ma S1, Chutkow W7, Bachman E1,8
1Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA; 2Novo Nordisk Research Centre Oxford, UK; 3Chief Medical Office, Anji Pharmaceuticals, Cambridge, MA; 4CMO and Patient Safety, Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Early Development Biostatistics, Biostatistics and Pharmacometrics, Novartis Institutes for BioMedical Research, East Hanover, NJ; 6DEV B&SS, CM/Global Health, Novartis Institutes for BioMedical Research, Cambridge, MA; 7Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA; 8Vertex Pharmaceuticals, Boston, MA
Background
An unmet need exists for a safer and more effective obesity treatment. Licogliflozin is a dual inhibitor of SGLT1/2 and holds promise as such a treatment. This study examined the effects of licogliflozin on body weight, incretin hormones, and metabolic parameters in patients with type 2 diabetes mellitus (T2DM) and/or obesity.
Methods
Patients with obesity (n=88; BMI 35–50 kg/m2) were enrolled in a 12‐week study using licogliflozin, 150 mg, once daily. Patients with T2DM were enrolled into a two‐part study of licogliflozin consisting of a single‐dose crossover study (n=12; 2.5–300 mg) and a 14‐day dosing study (n=30; 15 mg once daily). Effects on body weight, effects on glucose, safety, and tolerability were primary endpoints. Secondary endpoints included urinary glucose excretion and pharmacokinetics. Exploratory endpoints evaluated the effects of each licogliflozin treatment on incretin hormones (total GLP‐1, PYY3–36, and GIP), insulin, and glucagon.
Results
In the 12‐week study of patients with obesity, treatment with licogliflozin 150 mg once daily significantly reduced body weight (5.7%) versus placebo (P<0.001). The treatment also resulted in significantly reduced postprandial glucose excursion (21%; P<0.001), reduced insulin levels (80%; P<0.001), and increased glucagon (59%; P<0.001). In patients with T2DM, a single morning dose (300 mg) of licogliflozin prior to an oral glucose tolerance test (OGTT) resulted in markedly reduced glucose excursion (−93%, P<0.001; incremental AUC0–4h) and suppressed insulin by 90% (P<0.01; incremental AUC0–4h). In patients with T2DM, licogliflozin 15 mg once daily for 14 days reduced 24‐hour average glucose levels by 26% (41 mg/dL; P<0.001) and increased urinary glucose excretion to 100 g (P<0.001). This treatment regimen also resulted in a 54% increase in total GLP‐1 (P<0.001) and a 67% increase in PYY3–36 (P<0.05) post OGTT versus placebo, while significantly reducing GIP levels (−53%; P<0.001). Treatment with licogliflozin was safe and well tolerated overall. Diarrhea (increased incidence of loose stool) was the most common adverse event across all studies (90% with licogliflozin vs 25% with placebo), while lower rates of flatulence, abdominal pain, and abdominal distension (25%–43% with licogliflozin vs 9%–11% with placebo) were among the other gastrointestinal events reported in the 12‐week study.
Conclusion
In the current study, licogliflozin treatment (1–84 days) led to significant decreases in weight and favorable changes in several metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.
Effects of dapagliflozin on 24‐hour glycemic control in patients with type 2 diabetes: a randomized controlled trial
Henry RR1,2, Strange P3, Zhou R4, Pettus J1,2, Shi L3, Zhuplatov SB5, Mansfield T5, Klein D4, Katz A5
1Division of Endocrinology and Metabolism, University of California San Diego School of Medicine, San Diego, CA; 2Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA; 3Integrated Medical Development, LLC, Princeton Junction, NJ; 4Medpace, Inc. Cincinnati, OH; 5AstraZeneca, Fort Washington, PA
Background
HbA1c and other measures of short‐term glycemia do not fully capture daily patterns in plasma glucose dynamics and are poor predictors of hypoglycemia. However, continuous glucose monitoring (CGM), can provide information about glucose dynamics not available from static glucose measurements. This study assessed 24‐hour glycemic profiles in patients with T2D started on dapagliflozin treatment using CGM.
Methods
This randomized double‐blind placebo‐controlled multicenter parallel‐design study was conducted at 35 centers in the United States. The 4‐week study compared dapagliflozin (10 mg/d; n=50) with placebo (n=50) in adult patients with T2D that was uncontrolled (HbA1c 7.5%–10.5%) on either a stable dose of metformin monotherapy (≥1,500 mg/day) or a stable dose of insulin (≥30 U/d with or without as many as two oral antidiabetes drugs). Twenty‐four‐hour glycemic profiles were measured using CGM for 7 days prior to treatment and during week 4 of treatment. The primary outcome was change from baseline in 24‐hour mean glucose at week 4.
Results
The 24‐hour mean glucose decreased 18.2 mg/dL (from 177.9 to 160.7 mg/dL) with dapagliflozin and increased 5.8 mg/dL (from 182.6 to 187.5) with placebo (P<0.001). Compared with baseline, the proportion of time spent within target glucose range (70–180 mg/dL) increased significantly with dapagliflozin versus placebo (69.6% vs 52.9%; P<0.001). Mean percentage of time spent in the hypoglycemic range (<70 mg/dL) increased slightly (0.3%), driven by those on background insulin therapy. Postprandial glucose decreased and overall glucose variability was significantly decreased with dapagliflozin. Few events of symptomatic hypoglycemia occurred, and the most common adverse event was urinary tract infection (6% in each treatment arm).
Conclusion
Dapagliflozin, when compared with placebo, improved measures of glycemic control and variability as assessed by CGM. More marked glycemic improvements were observed in the group on background metformin than in those receiving basal insulin.
The potential for improving cardio‐renal outcomes by sodium‐glucose co‐transporter‐2 inhibition in people with chronic kidney disease: a rationale for the EMPA‐KIDNEY study
Herrington WG1,2, Preiss D1,2, Haynes R1,2, von Eynatten M3, Staplin N1,2,4, Hauske SJ3, George JT3, Green JB5, Landray MJ1,2,4, Baigent C1,2, Wanner C6
1Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, University of Oxford, Oxford, UK; 2Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; 3Boehringer Ingelheim International, Ingelheim, Germany; 4Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK; 5Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; 6Würzburg University Clinic, Würzburg, Germany
Background
Diabetes is a common cause of chronic kidney disease, but worldwide, nondiabetic causes account for a higher overall proportion of chronic kidney disease cases. Chronic kidney disease is often progressive and can contribute to other health problems including CV disease. Treating kidney disease through inhibition of the renin–angiotensin system decreases the risk of progression, and treatments that lower blood pressure (BP) or low‐density lipoprotein (LDL) cholesterol reduce CV risk in this population. However, despite such interventions, considerable risks for kidney and CV complications remain.
Methods
Recent, large placebo‐controlled outcome trials have demonstrated that SGLT2 inhibitors lessen the risk of CV disease (including CV death and hospitalization for heart failure) in people with T2D who are at high risk of atherosclerotic disease, and these effects were largely independent of decreases in BP, body weight, and rate of hyperglycemia.
Results
In the kidney, increased sodium delivery to the macula densa mediated by SGLT2 inhibition has the ability to decrease intraglomerular pressure, which may explain why SGLT2 inhibitors lessen albuminuria and apparently slow decline in kidney function for people with diabetes. In trials completed to date, it appears that these benefits are maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and they do not appear to be dependent on ambient hyperglycemia.
Conclusion
A rationale exists for studying the cardio‐renal effects of SGLT2 inhibition in people at risk of CV disease and hyperfiltration (i.e., those with significantly reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.
Long‐term effects of ipragliflozin on diabetic nephropathy and blood pressure in patients with type 2 diabetes: 104‐week follow‐up of an open‐label study
Ito D1,2, Inoue K1, Sumita T1,2, Hamaguchi K3, Kaneko K3, Yanagisawa M4, Inukai K5, Inoue I1, Noda M1, Shimada A1
1Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan; 2Department of Internal Medicine, Ogawa Red Cross Hospital, Saitama, Japan; 3Department of Nursing, Ogawa Red Cross Hospital, Saitama, Japan; 4Satsuki Medical Clinic, Saitama, Japan; 5Department of Diabetes and Endocrinology, Higashiyamato Hospital, Tokyo, Japan
Background
A previous assessed the efficacy of the SGLT2 inhibitor ipragliflozin on diabetic nephropathy in patients with T2D and demonstrated that it significantly improved diabetic nephropathy and also reduced HbA1c level and body weight. In the current study post‐trial monitoring was used to determine whether these blood glucose and body weight reductions or the favorable effects on diabetic nephropathy continued in the long term (104 weeks) after commencing ipragliflozin treatment.
Methods
First, a 50 mg dose of ipragliflozin was administered to 50 patients with T2D, without changing other treatments, during a 24‐week interventional trial period. These patients then returned to hospital‐based diabetes care tailored to their clinical needs during the post‐trial monitoring period. Participants' clinical data was monitored for 104 weeks in each hospital, and the results were analyzed on an intention‐to‐treat basis.
Results
Data showed that improvements in both glycemic control and body weight gained by ipragliflozin treatment during the 24‐week interventional trial period were maintained for 104 weeks. The eGFR was restored to a level near baseline level at 104 weeks, despite a transient decrease during the intervention period. Notably, in patients with diabetic nephropathy, the median urinary albumin‐to‐creatinine ratio decreased significantly from 119.2 mg/gCr (98.9–201.8) at baseline to 36.9 (19.7–204.7) mg/gCr at 104 weeks. eGFR showed no decrease, remaining stable for 104 weeks. However, the significant positive correlation between urinary albumin‐to‐creatinine ratio and BP that was observed at 24 weeks disappeared after the intervention therapy was discontinued.
Conclusion
Important changes such as the well‐controlled HbA1c as well as body weight reductions were maintained through 104 weeks of post‐trial follow‐up. Moreover, ipragliflozin significantly reduced urinary albumin excretion in patients with diabetic nephropathy without decreasing eGFR.
Residual effect of sodium glucose cotransporter 2 inhibitor, tofogliflozin, on body weight after washout in Japanese men with type 2 diabetes
Kakuda H1, Kobayashi J2, Sakurai M3, Takekoshi N4
1Kakuda Clinic, Kahoku, Ishikawa, Japan; 2Department of General Medicine, Kanazawa Medical University, Ishikawa, Japan; 3Department of Hygiene, Kanazawa Medical University, Ishikawa, Japan; 4Kanazawa Medical University, Ishikawa, Japan
Background
This study examined the potential mechanism underlying body weight reduction by tofogliflozin, an SGLT2 inhibitor, during treatment and after subsequent washout.
Methods
During a 16‐week trial, 10 adult, male Japanese patients with T2D (average age 66.3 years) were given tofogliflozin (20 mg/day) orally for 8 weeks, followed by a subsequent 8‐week washout period.
Results
Significant reductions were measured in blood glucose, HbA1c, uric acid, body weight, and waist circumference, and an increase in high‐molecular‐weight (HMW) adiponectin at 8 weeks was found. At 16 weeks, these markers were assessed again, and unlike HbA1c and uric acid, body weight and HMW adiponectin did not return to baseline levels. To clarify the potential underlying mechanism responsible for the body weight reduction during treatment with tofogliflozin (8 weeks) and after washout (at 16 weeks), we evaluated the correlations between changes in body weight and changes in waist circumference (or HMW adiponectin) from baseline (0 week). The changes in body weight between 0 weeks versus 8 weeks were not significantly correlated with those in waist circumference or HMW adiponectin. Changes in body weight between 0 and 16 weeks, however, did exhibit a significant correlation to the changes in waist circumference and HMW adiponectin.
Conclusion
The decrease in body weight caused by tofogliflozin may be due to several factors in addition to fat reduction at 8 weeks, but the decrease is most likely due to fat reduction alone after a subsequent 8 weeks of washout.
SGLT2 inhibitors continue to show promising results in patients with T2D, in addition to their beneficial effects on CV morbidity and mortality, heart failure, and renal disease. Due to the potential benefits of these drugs for patients with T2D, there are many new molecules in this family that are being evaluated for potential approval by regulatory agencies. These new molecules include tofogliflozin, ertugliflozin, and ipragliflozin, which have been evaluated in several phase 2 and phase 3 studies. Multiple cardiovascular outcome trials using these drugs in patients with T2D have shown a significant decrease in cardiovascular mortality. Benefits in renal protection are related to decreased intraglomerular pressure or reduced tubular cell injury. Other benefits include weight loss, lower blood pressure, and improvement in kidney function and heart failure. More recent studies have also demonstrated improved time in range (TIR) on CGM. Potential side effects for this class of drugs includes genitourinary infections (especially in women) and increased risk of limb amputation.
SGLT inhibition: a possible adjunctive treatment for type 1 diabetes
Akturk HK1,2, Rewers A1, Garg SK1,2
1Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO; 2University of Colorado, School of Medicine, Aurora, CO
Objective
SGLT2 inhibitors have been approved by the U.S. Food and Drug Administration and are used to improving glycemic control in the treatment of T2D. However, as validated in many phase 1–3 studies, SGLT2 inhibitors also have potential adjunctive use beyond glycemic control in adult patients with T1D treated with insulin therapy alone. This study was conducted to identify and assess recent trials of SGLT1 and SGLT2 inhibitor use in patients with T1D.
Methods
A review of the literature demonstrated that there is a potential adjunctive role for the use SGLT inhibitors along with insulin for improving glycemic control in T1D.
Results
Two trials, the inTandem3 (a phase 3 study evaluating the safety of sotagliflozin in patients with T1D who have inadequate glycemic control with insulin therapy alone) and the DEPICT‐1 (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes), demonstrated significant benefits of SGLT inhibitors in adult patients with T1D. The SGLT inhibitors could become the first oral medication approved for adjunctive use in the treatment of T1D.
Conclusion
Diabetic ketoacidosis is still a concern with SGLT inhibitors, but taking into account the additional benefits beyond glucose control that these medications offer, with proper counseling and education, they might allow a more patients to achieve target glucose control without weight gain or increased risk of hypoglycemia.
Improved time in range and glycemic variability with sotagliflozin in combination with insulin in adults with type 1 diabetes: a pooled analysis of 24‐week continuous glucose monitoring data from the inTandem program
Danne T1, Cariou B2, Buse JB3, Garg SK4, Rosenstock J5, Banks P6, Kushner JA7, McGuire DK8, Peters AL9, Sawhney S6, Strumph P6
1Department of Diabetes, Endocrinology, and Clinical Research, Children's and Youth Hospital Auf der Bult, Hannover Medical School, Hannover, Germany; 2L'institut du thorax, Department of Endocrinology, CHU Nantes, Nantes, France; 3Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC; 4Department of Medicine and Pediatrics, Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO; 5Dallas Diabetes Research Center at Medical City, Dallas, TX; 6Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 7Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX; 8Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX; 9Keck School of Medicine of the University of Southern California, Los Angeles, CA
Objective
A pooled cohort study was conducted to investigate the effects of the dual SGLT1 and SGLT2 inhibitor sotagliflozin in combination with insulin on glucose time in range (TIR) and glucose excursions, postprandial glucose (PPG), and other glycemic metrics in adult patients with T1D using masked continuous glucose monitoring (CGM).
Methods
The inTandem1 and inTandem2 are double‐blind randomized trials that evaluated sotagliflozin versus placebo in adults with T1D treated with optimized insulin. Data from the two trials were pooled so that a subset of participants from each trial could be used for analyses of masked CGM data. The pooled cohort included patients randomized to receive placebo (n=93), sotagliflozin 200 mg (n=89), or sotagliflozin 400 mg (n=96). Change in glucose TIR from baseline to week 24 (3.9–10.0 mmol/L [70–180 mg/dL]) was the primary outcome. Secondary endpoints were time below and above target range as well as 2‐hour PPG level assessed after a standardized mixed meal.
Results
Mean percentage of glucose TIR/percentage time spent at <3.9 mmol/L (<70 mg/dL) during week 24 was 51.6%/5.9%, 57.8%/5.5%, and 64.2%/5.5% with placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. These values corresponded to a placebo‐adjusted change from a baseline of +5.4%/ −0.3% (P=0.026; +1.3/ −0.1 h/day) for sotagliflozin 200 mg and +11.7%/ −0.1% (P<0.001; +2.8/ −0.02 h/day) for sotagliflozin 400 mg. Placebo‐adjusted PPG reductions were 1.9±0.7 mmol/L (35±13 mg/dL; P=0.004) and 2.8±0.7 mmol/L (50±13 mg/dL; P<0.001) with sotagliflozin 200 and 400 mg, respectively.
Conclusion
The analyses showed that sotagliflozin combined with optimized insulin significantly increased glucose TIR in patients with T1D without increasing time spent at <3.9 mmol/L and also reduced PPG, thereby improving glycemic control.
Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT‐2 Study): 24‐week results from a randomized controlled trial
Mathieu C1, Dandona P2, Gillard P1, Senior P3, Hasslacher C4, Araki E5, Lind M6,7, Bain SC8, Jabbour S9, Arya N10, Hansen L11, Thorén F12, Langkilde AM1,2; on behalf of DEPICT‐2 Investigators
1Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium; 2Department of Medicine, State University of New York at Buffalo, Buffalo, NY; 3Division of Endocrinology, University of Alberta, Edmonton, Canada; 4Diabetesinstitut Heidelberg, Heidelberg, Germany; 5Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; 6Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 7Department of Medicine, NU Hospital Group, Uddevalla, Sweden; 8Diabetes Research Unit, Swansea University, Swansea, Wales, U.K; 9Division of Endocrinology, Diabetes and Metabolic Diseases, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA; 10AstraZeneca, Gaithersburg, MD; 11MedImmune, Gaithersburg, MD; 12AstraZeneca, Gothenburg, Sweden
Objective
DEPICT‐2 was a 24‐week, randomized, parallel‐controlled, double‐blind, phase 3 clinical study (ClinicalTrials.gov, NCT02460978) evaluating the safety and efficacy of dapagliflozin 5 mg and 10 mg as adjunct therapy to adjustable insulin in adult patients with inadequately controlled type 1 diabetes (HbA1c 7.5–10.5%).
Methods
The study was conducted at 148 sites around the world. Following an 8‐week lead‐in period to optimize diabetes management, participants were randomized 1:1:1 to dapagliflozin 5 mg (n=271), dapagliflozin 10 mg (n=270), or placebo (n=272) plus insulin. Investigators used self‐monitored glucose readings, local guidance, and individual circumstances to adjust each participant's insulin dosage.
Results
Baseline characteristics were balanced between treatment groups. At week 24, dapagliflozin significantly decreased HbA1c (primary outcome; difference vs placebo: dapagliflozin 5 mg −0.37% [95% CI −0.49, −0.26], dapagliflozin 10 mg −0.42% [ −0.53, −0.30]); total daily insulin dose (−10.78% [ −13.73, −7.72] and −11.08% [ −14.04, −8.02], respectively); and body weight (−3.21% [ −3.96, −2.45] and −3.74% [ −4.49, −2.99], respectively) (P<0.0001 for all). Measures versus placebo were significantly improved for mean interstitial glucose, amplitude of glucose excursion, and percentage of readings within target glycemic range (>70 to ≤180 mg/dL). Compared with placebo, a larger proportion of patients taking dapagliflozin experienced a reduction in HbA1c ≥0.5% without severe hypoglycemia. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. Adjudicated definite diabetic ketoacidosis (DKA) events were more likely to occur in participants receiving dapagliflozin than with placebo (2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively).
Conclusion
In patients with T1D, dapagliflozin was well tolerated when used as adjunct therapy to adjustable insulin and improved glycemic control without increasing hypoglycemia versus placebo; however, patients did experience more DKA events.
SGLT inhibitor adjunct therapy in type 1 diabetes
McCrimmon RJ1, Henry RR2
1School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK; 2Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA
Background
Noninsulin adjunct therapies have been proposed as a means of increasing glycemic control and reducing risk of hypoglycemia in individuals with T1D. However, there is little evidence to support this approach, and few pharmacological agents have been proven effective enough to become part of routine clinical care.
Methods
Recent short‐term phase 2 trials and 24‐week phase 3 trials provide initial support for the use of sodium‐glucose cotransporter (SGLT) inhibitors in treatment of T1D.
Results
Two international, multicenter, randomized, controlled clinical trials, DEPICT‐1 and inTandem3, have reported that SGLT inhibition with dapagliflozin and sotagliflozin, respectively, offered additional benefits—namely, a 5–6 mmol/mol (0.4–0.5%) reduction in HbA1c along with weight loss and decrease in total daily insulin requirements. The reduction in HbA1c does not come with a significantly increased risk of hypoglycemia but does carry an increased risk of DKA and mycotic infections. These results suggest that SGLT inhibition will have a place in the management of T1D.
Conclusion
Longer‐term clinical trials (≥52 weeks) and observational cohort studies must be completed to determine any additional benefits or adverse effects are associated with this adjunct therapy and to describe which group of patients might benefit most from this approach. The use of SGLT inhibitors in routine T1D care will also require specific educational materials for both patients and healthcare professionals to ensure patient safety and to minimize risk.
The need for adjunctive therapies for T1D has been an unachievable goal to date (pramlintide has almost no use at this time). With few type 1 patients reaching glycemic targets, on top of the fact that particularly in the United States we see the same amount of obesity as we do in the general population, it seems that the SGLT2 inhibitors (or a combined SGLT2/SGLT1 inhibitor) would be a reasonable option to complement standard insulin therapy. These agents clearly do lower HbA1c and weight, albeit modestly, and treatment satisfaction scores are high. Three large studies treating more than 3,000 patients with T1D concluded last year: DEPICT (dapagliflozin in type 1 diabetes), inTandem (sotagliflozin), and EASE (empagliflozin). All three programs used different dosages and demonstrated reductions in HbA1c of about 0.5% without significant weight gain (in fact, weight loss was observed in all three trials) as well as reductions in blood pressure. Most studies have demonstrated a reduction in hypoglycemic episodes, including severe hypoglycemia, or were hypoglycemic neutral. All three trials also showed a slight increase in genitourinary infections, as observed in studies of individuals with T2D, and an increased risk of euglycemic diabetic ketoacidosis (DKA, discussed below). Sotagliflozin and dapagliflozin were approved by the European Medicines Agency for patients with BMI >27 kg/m2 and insulin doses exceeding 0.5 U/kg/day at initiation as adjunctive treatment for patients with T1D. A different SGLT2 inhibitor (ipragliflozin) has been approved in Japan for adjunctive therapy with T1D, but is not available in the United States or Western Europe at this time.
Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E‐LIFT Trial)
Kuchay MS1, Krishan S2, Mishra SK3, Farooqui KJ3, Singh MK4, Wasir JS3, Bansal B3, Kaur P3, Jevalikar G3, Gill HK3, Choudhary NS5, Mithal A3
1Division of Endocrinology and Diabetes, 2Department of Radiology, 3Division of Endocrinology and Diabetes, 4Department of Clinical Research and Studies, and 5Institute of Digestive and Hepatobiliary Sciences, Medanta–The Medicity Hospital, Gurugram, Haryana, India
This manuscript is also discussed in the article on NAFLD/NASH and Diabetes, page S‐174.
Objective
SGLT2 inhibitors have been shown to decrease liver fat in rodent models, but data are scarce regarding the effect of SGLT2 inhibitors on human liver fat. This study employed MRI‐derived proton density fat fraction (MRI‐PDFF) to examine the effect of empagliflozin (an SGLT2 inhibitor) on liver fat in patients with T2D and nonalcoholic fatty liver disease (NAFLD).
Methods
The study was conducted in 50 patients with T2D and NAFLD. Participants were randomly assigned to either the control group (standard treatment without empagliflozin) or empagliflozin group (standard treatment for T2D plus empagliflozin 10 mg daily) for 20 weeks. Change in liver fat was measured using MRI‐PDFF. Change in alanine transaminase (ALT), aspartate transaminase (AST), and gamma‐glutamyl transferase (GGT) levels were secondary outcomes.
Results
When included in the standard treatment for T2D, empagliflozin was significantly better at reducing liver fat (mean MRI‐PDFF difference between the empagliflozin and control groups −4.0%; P<0.0001). In addition, significant reduction was found in the end‐of‐treatment MRI‐PDFF for the empagliflozin group compared with baseline (16.2% to 11.3%; P<0.0001), although a nonsignificant change was found in the control group (16.4% to 15.5%; P=0.057). Change in serum ALT level was significant (P=0.005), but changes in AST and GGT levels were nonsignificant (P=0.212 P=0.057 respectively).
Conclusion
When included in the standard treatment for T2D, empagliflozin reduces liver fat and improves ALT levels in patients with T2D and NAFLD.
SGLT2 inhibitors in non‐alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review
Raj H1, Durgia H1, Palui R1, Kamalanathan S1, Selvarajan S2, Kar SS3, Sahoo J4
1Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India; 2Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India; 3Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India; 4Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
Background
Non‐alcoholic fatty liver disease (NAFLD) is a common comorbidity with T2D and an emerging worldwide health issue. Lifestyle changes, including a hypocaloric diet and exercise, are the focus of current treatments for NAFLD, and pioglitazone and vitamin E are sometimes recommended, but the existing treatment options are insufficient. Pioglitazone is recommended only for diabetes patients with non‐alcoholic steatohepatitis confirmed via biopsy. The frequent coexistence of NAFLD and T2D, the combined negative health consequences, and inadequate therapeutic options makes it necessary to search for newer alternative treatments. The objective of this systematic review was to assess the effect of SGLT2 inhibitors on liver enzymes in patients with T2D and NAFLD.
Methods
We searched for relevant articles on PubMed/MEDLINE, Cochrane Library, Google Scholar, and Clinicaltrials.gov. Human studies conducted in patients with T2D and NAFLD being treated with SGLT2 inhibitors for at least 12 weeks were included in the systematic review. Of the 55 articles screened, data was taken from eight (four randomized controlled trials and four observational studies) and used to complete a narrative synthesis. In these studies, a total of 214 patients were treated with SGLT2 inhibitors (94 in randomized controlled trials; 120 in observational studies).
Results
The primary outcome measure was change in serum alanine aminotransferase level. Seven of the eight included studies reported a significant decrease in levels of serum alanine aminotransferase, and most revealed reduced serum levels of other liver enzymes (e.g., aspartate aminotransferase and gamma glutamyl transferase). Five of the studies reported changes in hepatic fat content, with all five reporting a significant reduction in those treated with SGLT2 inhibitors. Similarly, among the three studies evaluating a change in hepatic fibrosis indices, two reported a significant improvement in liver fibrosis. There was also improvement in obesity, insulin resistance, glycaemia, and lipid parameters in patients taking SGLT2 inhibitors. Approximately 17% (30/176) of the subjects taking SGLT2 inhibitors developed adverse events, more than 40% (10/23) of which were genitourinary tract infections.
Conclusion
In the eight selected studies, SGLT2 inhibitors were found to improve serum levels of liver enzymes, liver fibrosis indices, and liver fat without significant side effects in T2D patients with NAFLD. Additional positive effects were seen for obesity, glycemic parameters, insulin resistance, and dyslipidemia. However, the evidence for these conclusions is low to moderate quality. Additional, more robust studies are required to better understand the action of SGLT2 inhibitors in treating T2D with NAFLD.
The long‐term efficacy of sodium glucose co‐transporter 2 inhibitor in patients with non‐alcoholic fatty liver disease
Yamashima M, Miyaaki H, Miuma S, Shibata H, Sasaki R, Haraguchi M, Fukushima M, Nakao K
Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
Objective
Sodium glucose cotransporter 2 inhibitor (SGLT2i) is the recommended therapeutic for patients with T2D and has been reported to improve liver function results in patients with NAFLD. However, the long‐term effects of SGLT2i on liver function and body weight in these patients are not fully understood. This study investigated the long‐term effects of SGLT2i in NAFLD patients.
Methods
A retrospective observational study was carried out in 22 diabetic patients with NAFLD. Participants' body weight, liver enzyme levels, metabolism, and glucose levels were measured at 12 months (n=22) and 24 months (n=15) after starting SGLT2i treatment. Transient elastography and acoustic radiation force impulse elastography were employed to assess changes in controlled attenuation parameter (CAP) and liver stiffness in 20 of the 22 study participants prior to the start of treatment and again at 1 year.
Results
At 12 and 24 months after SGLT2i treatment, body weight, AST, and ALT levels were significantly lower compared with pretreatment levels. Reductions in ALT levels at 12 and 24 months after SGLT2i treatment were significantly correlated with the initial ALT level (r=0.813, P=0.001 and r=0.867, P=0.0001, respectively). CAP and velocity of shear wave (V s) values were also found to be reduced at 12 months (CAP 315.1±43.4 db/mL →293.1±27.2 db/mL; P=0.027; Vs 1.87±0.8 m/s →1.48±0.6 m/s; P=0.011).
Conclusion
SGLT2i in NAFLD patients treatment resulted in improved liver function test results and reduced body weight over a period of 12–24 months. This improvement was greater in patients with higher ALT values at baseline than in those with lower values.
Due to their mechanism of action, SGLT2 inhibitors have consistently demonstrated that they enable patients with type 2 diabetes to lose weight. The weight loss can amount to about 3%–5% of body weight in the first year. This weight loss is closely associated with changes in liver fat content (see the last article in this yearbook for discussion of this issue). The above three studies highlight the reduction in liver fat in type 2 diabetes patients with comorbid non‐alcoholic fatty liver disease (NAFLD). Long‐term studies using these drugs in patients with NAFLD are needed to evaluate the impact on disease progression to nonalcoholic steatohepatitis and/or need for liver transplant.
International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium‐glucose cotransporter (SGLT) inhibitors
Danne T1, Garg S2, Peters AL3, Buse JB4, Mathieu C5, Pettus JH6, Alexander CM7, Battelino T8, Ampudia‐Blasco FJ9, Bode BW10, Cariou B11, Close KL12, Dandona P13, Dutta S14, Ferrannini E15, Fourlanos S16, Grunberger G17, Heller SR18, Henry RR6, Kurian MJ19, Kushner JA20, Oron T21,22, Parkin CG23, Pieber TR24, Rodbard HW25, Schatz D26, Skyler JS27, Tamborlane WV28, Yokote K29, Phillip M21,22
1Diabetes Centre for Children and Adolescents, Kinder‐ und Jugendkrankenhaus Auf der Bult, Hannover, Germany; 2University of Colorado Denver and Barbara Davis Center for Diabetes, Aurora, CO; 3Keck School of Medicine of the University of Southern California, Los Angeles, CA; 4University of North Carolina School of Medicine, Chapel Hill, NC; 5Department of Endocrinology, UZ Gasthuisberg, KU Leuven, Leuven, Belgium; 6Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, CA; 7Alexander Associates LLC, Gwynedd Valley, PA; 8Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, and Faculty of Medicine, University of Ljubljana, Slovenia; 9Clinic University Hospital of Valencia, Valencia, Spain; 10Atlanta Diabetes Associates, Atlanta, GA; 11Clinique d'endocrinologie, L'institut du thorax, CHU Nantes, CIC 1413 INSERM, Nantes, France; 12The diaTribe Foundation, San Francisco, CA; 13Division of Endocrinology, Diabetes and Metabolism, University at Buffalo, The State University of New York, Buffalo, NY; 14JDRF International, New York, NY; 15National Research Council (CNR) Institute of Clinical Physiology, Pisa, Italy; 16Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Australia; 17Grunberger Diabetes Institute, Bloomfield Hills, MI; 18Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, UK; 19Close Concerns, San Francisco, CA; 20McNair Interests, Houston, TX; 21Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel; 22Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 23CG Parkin Communications, Inc., Boulder City, NV; 24Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 25Endocrine and Metabolic Consultants, Rockville, MD; 26Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL; 27Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL; 28Department of Pediatrics, Yale School of Medicine, New Haven, CT; 29Department of Diabetes, Metabolism and Endocrinology, Chiba University Graduate School of Medicine, Chiba, Japan
Background
SGLT inhibitors are new oral antidiabetes medications that effectively reduce HbA1c and glycemic variability, blood pressure, and body weight without increasing the risk of hypoglycemia in people with T1D.
Methods
Despite these promising outcomes, however, some recent studies have demonstrated increases in the absolute risk of DKA, especially in patients with T1D. Some cases presented with mild hyperglycemia or near‐normal blood glucose levels, which makes the recognition and diagnosis of DKA more difficult, potentially causing delays in treatment.
Results
Both the U.S. Food and Drug Administration and European regulatory agencies are currently reviewing several SGLT inhibitors as potential adjuncts to insulin therapy in individuals with T1D. Strategies to lessen risk of DKA associated with these SGLT inhibitors must be developed and disseminated to the medical community to ensure the safety of this treatment in patients with T1D.
Conclusion
This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with T1D.
Sodium‐glucose co‐transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: the STOP DKA Protocol
Goldenberg RM1, Gilbert JD2, Hramiak IM3, Woo VC4, Zinman B5
1LMC Diabetes and Endocrinology, Concord, Ontario, Canada; 2Division of Endocrinology and Metabolism, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; 3Division of Endocrinology and Metabolism, St Joseph's Health Care London, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; 4Section of Endocrinology and Metabolism, Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada; 5Lunenfeld–Tanenbaum Research Institute, Mt Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Background
Recent phase 3 clinical trials have evaluated the impact of adding SGLT inhibitors to the arsenal of treatments used for T1D.
Methods
In these trials, the oral noninsulin antihyperglycemic medications dapagliflozin and empagliflozin (SGLT2 inhibitors) and sotagliflozin (a dual SGLT1 and SGLT2 inhibitor) were shown to improve glycemic control, reduce body weight, and extend TIR without increasing rates of hypoglycemia in patients with T1D.
Results
Diabetic ketoacidosis (DKA) is a complication of T1D, the risk of which increases when SGLT inhibitors are used.
Conclusion
The STOP DKA Protocol provides a risk mitigation strategy and was developed to minimize this risk of DKA while still allowing T1D patients the multiple benefits of treatment with SGLT inhibitors.
All SGLT inhibitors have consistently demonstrated a higher risk of DKA in patients with T1D when these drugs are used as adjunctive treatment. It is important to keep in mind that the background risk of DKA in patients with T1D is about 5% (data from T1DExchange and from Western Europe), and that risk has been increasing in the past decade. There is no doubt that in all three of the trials (DEPICT, inTandem, and EASE) the risk of DKA was 2‐ to 4‐fold higher when compared with the placebo arm. DKA is a serious disorder carrying a high degree of morbidity and mortality. Unfortunately, the DKA is not frequently associated with significant hyperglycemia, making it less likely to be recognized (commonly referred to as euglycemic DKA). If these drugs are to be used successfully in patients with T1D, strategies must be identified to reduce the risk of DKA when these drugs are used as adjunctive therapy. Different strategies for reducing the risk of DKA have been published recently (STICH protocol, STOP‐DKA, and international guidelines to reduce DKA risk). When these protocols are followed, it is likely that the background risk of DKA in patients with T1D that are not using SGLT inhibitors can be reduced. Additional methods to reduce DKA risk that are currently under development include interactive smartphone applications that guide patients on how to manage DKA, continuous measurement of ketone levels in the manner of continuous glucose monitoring, etc. Since these drugs have already been approved in Europe and Japan, proper education of providers who initiate these therapies, hospitalists, and emergency department physicians should be implemented so that they can recognize euglycemic DKA and administer necessary treatment in early stages.
Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double‐blind, phase 3a trial
Pratley R1, Amod A2, Hoff ST3, Kadowaki T4, Lingvay I5, Nauck M6, Pedersen KB3, Saugstrup T3, Meier JJ6; for the PIONEER 4 investigators
1AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, FL; 2Life Chatsmed Garden Hospital and Nelson R Mandela School of Medicine, Durban, South Africa; 3Novo Nordisk A/S, Søborg, Denmark; 4Department of Diabetes and Metabolic Diseases and Department of Prevention of Diabetes and Lifestyle‐Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Metabolism and Nutrition, Mizonokuchi Hospital, Teikyo University, Kanagawa, Japan; 5University of Texas Southwestern Medical Center at Dallas, Dallas, TX; 6Diabetes Division, Department of Medicine I, St Josef‐Hospital, Ruhr‐University Bochum, Bochum, Germany
Background
GLP‐1 receptor agonists are used in the effective treatment of T2D, as they work to reduce patients' weight and lower HbA1c levels; however, they are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP‐1 agonist, was compared with the subcutaneously injected GLP‐1 agonist liraglutide and with placebo in patients with T2D.
Methods
A randomized, double‐blind, double‐dummy, phase 3a trial, was conducted. Patients with T2D were recruited from 100 sites in 12 countries. Criteria for eligibility included age of 18 years or older, HbA1c of 7.0%–9.5% (53–80.3 mmol/mol), and treatment with a stable dose of metformin (≥1,500 mg or maximum tolerated) with or without a SGLT2 inhibitor. Subjects were stratified based on background glucose‐lowering medication and country of origin and randomly assigned (2:2:1) using an interactive web‐response system to once‐daily oral semaglutide (dose escalated to 14 mg), once‐daily subcutaneous liraglutide (dose escalated to 1.8 mg), or placebo for 52 weeks. Treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (all participants assumed to be on study drug without rescue medication) were identified as estimands in all randomly assigned participants; with treatment policy being the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and noninferiority [margin: 0.4%] and superiority vs subcutaneous liraglutide). The secondary endpoint was change in body weight from baseline to week 26 (oral semaglutide superiority vs placebo and liraglutide). Safety was evaluated in all subjects who received at least one dose of the study drug.
Results
Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened for participation. A total of 711 of those screened were eligible and were randomized to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). Forty‐eight percent (341) of the eligible participants were female, and 56±10 years was the mean age. All participants were given at least one dose of study drug. Ninety‐seven percent (277/285) of the participants in the oral semaglutide group, 96% (274/284) in the liraglutide group, and 94% (134/142) in the placebo group completed the full 52‐week trial period. HbA1c exhibited a mean change from baseline to week 26 of −1.2% (SE 0.1) with oral semaglutide, −1.1% (SE 0.1) with subcutaneous liraglutide, and −0.2% (SE 0.1) with placebo. Oral semaglutide was noninferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] −0.1% [95% CI −0.3 to 0.0]; P<0.0001) and superior to placebo (ETD −1.1%, −1.2 to −0.9; P<0.0001) using the treatment policy estimand. By the trial product estimand, oral semaglutide produced significantly larger decreases in HbA1c at 26 weeks than either subcutaneous liraglutide (ETD −0.2% [95% CI −0.3 to −0.1]; P=0.0056) and placebo (ETD −1.2%, −1.4 to −1.0; P<0.0001). Oral semaglutide resulted in greater weight loss at 26 weeks (−4.4 kg [SE 0.2]) than did liraglutide (−3.1 kg [SE 0.2]; ETD −1.2 kg [95% CI −1.9 to −0.6]; P=0.0003) or placebo (−0.5 kg [SE 0.3]; ETD −3.8 kg, −4.7 to −3.0; P<0.0001) (treatment policy). Using the trial product estimand, 26‐week weight loss was significantly greater with oral semaglutide than with subcutaneous liraglutide (−1.5 kg [95% CI −2.2 to −0.9]; P<0.0001) or placebo (ETD −4.0 kg,−4.8 to −3.2; P<0.0001). Treatment with oral semaglutide resulted in a higher frequency of adverse events (n=229 [80%]) than did treatment with placebo (n=95 [67%]). The same was true for subcutaneous liraglutide (n=211 [74%]).
Conclusion
Oral semaglutide was noninferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c at week 26 and was superior in decreasing bodyweight versus both liraglutide and placebo at week 26. Oral semaglutide had similar safety and tolerability to subcutaneous liraglutide. Oral semaglutide could possibly lead to earlier initiation of GLP‐1 receptor agonist therapy in the diabetes treatment continuum of care.
Efficacy and safety of LY3298176, a novel dual GIP and GLP‐1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo‐controlled and active comparator‐controlled phase 2 trial
Frias JP1, Nauck MA2, Van J3, Kutner ME4, Cui X5, Benson C5, Urva S5, Gimeno RE5, Milicevic Z6, Robins D5, Haupt A5
1National Research Institute, Los Angeles, CA; 2Diabetes Center Bochum‐Hattingen, St Josef Hospital, Ruhr‐University Bochum, Bochum, Germany; 3Diabetes Research Center, Tustin, CA; 4Suncoast Research Group, LLC, Miami, FL; 5Eli Lilly and Company, Indianapolis, IN; 6Eli Lilly and Company, Vienna, Austria
Background
LY3298176 is a novel dual GIP and GLP‐1 receptor agonist that is being developed for the treatment of type 2 diabetes. This study investigated the safety and effectiveness of GLP‐1 and GIP receptor co‐stimulation with LY3298176 compared with placebo or selective stimulation of GLP‐1 receptors using dulaglutide in patients with poorly controlled T2D.
Methods
In this 26‐week, double‐blind, randomized, phase 2 study, individuals with T2D were stratified by baseline glycated HbA1c (HbA1c), metformin use, and BMI and randomly assigned (1:1:1:1:1:1) to receive once‐weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1.5 mg), or placebo for the term of the study. Eligible participants met the following criteria: age 18–75 years; T2D for at least 6 months (HbA1c 7.0%–10.5%, inclusive), not sufficiently controlled with diet and exercise alone or with stable metformin therapy; and BMI of 23–50 kg/m2. The primary efficacy outcome was change in HbA1c from baseline to week 26 in the modified intention‐to‐treat (mITT) population (all patients who were administered at least one dose of study drug and had at least one outcome measured postbaseline). Secondary endpoints, measured in the mITT on treatment dataset, were change in HbA1c from baseline to week 12; change in mean bodyweight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; proportion of patients reaching the HbA1c target (≤6.5% and <7.0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% decrease in bodyweight from baseline to 26 weeks.
Results
Between May 24, 2017, and March 28, 2018, a total of 555 patients were recruited and assessed for eligibility; 318 were randomized to one of the six treatment groups. Two participants did not receive treatment; therefore, the modified intention‐to‐treat and safety populations totaled 316. Of these, 258 (81.7%) participants completed the full 26 weeks of treatment, and 283 (89.6%) completed the entire study. At baseline, mean age was 57±9 years, BMI was 32.6±5.9 kg/m2, and duration from diagnosis of diabetes was 9±6 years. HbA1c was 8.1±1.0%. Men comprised 53% of subjects; 47% were women. The effect of LY3298176 on change in HbA1c at week 26 was dose‐dependent and did not plateau; mean changes from baseline were −1.06% for 1 mg of LY3298176, −1.73% for 5 mg, −1.89% for 10 mg, and −1.94% for 15 mg, compared with −0.06% for placebo (posterior mean differences [80% credible set] vs placebo: −1.00% [−1.22 to −0.79] for 1 mg, −1.67% [ −1.88 to −1.46] for 5 mg, −1.83% [ −2.04 to −1.61] for 10 mg, and −1.89% [−2.11 to −1.67] for 15 mg). The posterior mean differences (80% credible set) for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0.15% (−0.08 to 0.38) for 1 mg, −0.52% (−0.72 to −0.31) for 5 mg, −0.67% (−0.89 to −0.46) for 10 mg, and −0.73% (−0.95 to −0.52) for 15 mg compared with dulaglutide (−1.21%). Among patients treated with LY3298176, 33%–90% achieved the 26‐week HbA1c target of less than 7.0% (vs 52% with dulaglutide and 12% with placebo); 15%–82% reached the HbA1c target of at least 6.5% (vs 39% with dulaglutide and 2% with placebo). Changes in fasting plasma glucose with LY3298176 ranged from −0.4 mmol/L to −3.4 mmol/L, versus 0.9 mmol/L for placebo and −1.2 mmol/L for dulaglutide. Mean body weight change ranged from −0.9 kg to −11.3 kg for LY3298176, compared with −0.4 kg for placebo and −2.7 kg for dulaglutide. Among those treated with LY3298176 14%–71% achieved the 26‐week weight loss goal of at least 5% versus 22% with dulaglutide and 0% with placebo, and 6%–39% reached the weight loss goal of at least 10%, versus 9% with dulaglutide and 0% with placebo. Waist circumference change ranged from −2.1 cm to −10.2 cm for LY3298176 versus −1.3 cm for placebo and −2.5 cm for dulaglutide. Changes in total cholesterol ranged from 0.2 mmol/L to −0.3 mmol/L for LY3298176 versus 0.3 mmol/L for placebo and −0.2 mmol/L for dulaglutide. Changes in HDL or LDL cholesterol did not differ between the LY3298176 and placebo groups. Triglyceride concentration changes ranged from 0 mmol/L to −0.8 mmol/L for LY3298176 versus 0.3 mmol/L for placebo and −0.3 mmol/L for dulaglutide. The 12‐week outcomes were similar to those at 26 weeks for all secondary outcomes. A total of twenty‐three adverse events were recorded among 13 (4%) of 316 participants across the six treatment groups, with gastrointestinal events (nausea, diarrhea, and vomiting) being the most common. The incidence of gastrointestinal events was dose‐related (23.1% for 1 mg LY3298176, 32.7% for 5 mg LY3298176, 51.0% for 10 mg LY3298176, and 66.0% for 15 mg LY3298176, 42.6% for dulaglutide; 9.8% for placebo); most events were transient and of mild to moderate intensity. The second most common adverse event was decrease in appetite (3.8% for 1 mg LY3298176, 20.0% for 5 mg LY3298176, 25.5% for 10 mg LY3298176, 18.9% for 15 mg LY3298176, 5.6% for dulaglutide, 2.0% for placebo). No reports of severe hypoglycemia were made. One patient in the placebo group died from lung adenocarcinoma stage IV, which was unrelated to study treatment.
Conclusion
The dual GIP and GLP‐1 receptor agonist LY3298176 was significantly more efficacious with respect to glucose control and weight loss than was dulaglutide, with an acceptable safety and tolerability profile. Combined GIP and GLP‐1 receptor stimulation might offer a new therapeutic option in the treatment of T2D.
Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme
Mathieu C1, Del Prato S2, Botros FT3, Thieu VT3, Pavo I4, Jia N3, Haupt A3, Karanikas CA3, García‐Pérez LE3
1Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium; 2Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 3Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN; 4Eli Lilly Regional Operations, Vienna, Austria
Objective
GLP‐1 receptor agonists lower blood glucose in patients with T2D, in part by glucose‐dependent stimulation of insulin secretion. This study investigated whether beta‐cell function (as measured by homeostatic model assessment of beta‐cell function [HOMA2‐%B]) at baseline affects the glycemic response to dulaglutide.
Methods
Dulaglutide‐treated patients from AWARD‐1, AWARD‐3, and AWARD‐6 clinical studies were categorized based on their HOMA2‐%B tertiles. Changes in glycemic measures resulting from once‐weekly dulaglutide were evaluated in each HOMA2‐%B tertile.
Results
Patients with low HOMA2‐%B had higher baseline HbA1c, higher fasting and postprandial blood glucose levels, and longer duration of diabetes (P<0.001, all) (mean low, middle, and high tertiles with dulaglutide 1.5 mg: HOMAB‐2%B 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, and 7.3%, respectively). At 26 weeks, the lowest tertile with dulaglutide exhibited larger reductions in HbA1c versus the highest tertile with dulaglutide 1.5 mg (mean; −1.55% vs −0.98% [−16.94 vs −10.71 mmol/mol]). Differences between low and high tertiles faded when adjusted for baseline HbA1c (LSM; −1.00 vs −1.18% [ −10.93 vs −12.90 mmol/mol]). Observed decreases in fasting blood glucose and observed increases in fasting C‐peptide were greater in the low tertile. All three tertiles had similar increases in HOMA2‐%B.
Conclusion
Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta‐cell function.
GLP‐1 analogs have been available for clinical use for the past decade. The first GLP analog was exenatide, which required injection 2–3 times per day to achieve optimal prandial glucose control because of the drug's bioavailability profile. Daily injections of GLP analogs like liraglutide, or weekly injections of GLP analogs such as dulaglutide or semaglutide, have demonstrated similar or better glycemic control and improved cardiovascular outcomes. More recently, an oral tablet formulation of semaglutide was introduced, which demonstrated success in phase 3 clinical trials. The glucose‐reducing effect was maintained (similar to the injectable GLP analogs) and additional cardiovascular benefits were observed (PIONEER trials).
It is difficult to cover all the GLP analogs in development, but one novel drug, tirzepatide (LY3298176, a GLP/GIP dual agonist), has shown improved glycemic control and significant weight loss effects. Additionally, this drug is being evaluated in patients with NAFLD and as an anti‐obesity medication. Multiple clinical trials with different GLP analogs have demonstrated cardiovascular safety and thus are recommended as first‐line drugs for patients with T2D. Their use in T1D (ADJUNCT 1 and 2 trials) demonstrated slight improvement in glucose control, significant reduction in insulin dose, and weight loss. However, subjects treated with liraglutide had an increased number of severe hypoglycemic episodes and DKA, and the sponsor elected not to file for the supplemental new drug application for adjunctive use in patients with T1D.
Impact of insulin and metformin versus metformin alone on beta‐cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes
RISE Consortium
Objective
The incidence of pediatric type 2 diabetes is increasing, with beta‐cell dysfunction key in its pathogenesis. The RISE Pediatric Medication Study compared two approaches for treating pediatric diabetes, glargine followed by metformin and metformin alone, for ability to preserve or improve beta‐cell function in youth with impaired glucose tolerance (IGT) or recently diagnosed T2D during and after withdrawal of therapy.
Methods
Ninety‐one pubertal, overweight/obese 10‐ to 19‐year‐old youth with IGT (60%) or recently diagnosed (<6 months) T2D (40%) were randomly assigned to one of two treatment plans: (a) 3 months of insulin glargine with a target glucose of 4.4–5.0 mmol/L followed by 9 months of metformin or (b) 12 months of metformin alone. Beta‐cell function (insulin sensitivity paired with beta‐cell responses) was evaluated using hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months after end of treatment).
Results
No significant differences were observed in beta‐cell function, BMI percentile, HbA1c, fasting glucose, or oral glucose tolerance test 2‐hour glucose results between treatment groups at baseline, 12 months, or 15 months. In both treatment groups, clamp‐measured beta‐cell function was significantly lower at 12 months and 15 months than it was at baseline. HbA1c fell transiently at 6 months in both groups. Between 6 and 9 months, BMI was highest in the glargine, followed by metformin, compared with the metformin‐alone group. A very few participants (5%) discontinued the interventions, and both treatments were well tolerated.
Conclusion
In youth with IGT or recently diagnosed T2D, neither 3 months of glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta‐cell function. Research into alternate treatments to preserve beta‐cell function in youth are needed.
This is an extremely important study documenting how aggressive dysglycemia and diabetes is among the pediatric population. As we learn more about the pathobiology, one has to wonder why this is different than what we see in adults, how can this be stopped, and are these findings similar in other countries around the world? These questions need to be a priority with our research funding.
Semaglutide once weekly as add‐on to SGLT2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo‐controlled trial
Zinman B1, Bhosekar V2, Busch R3, Holst I4, Ludvik B5, Thielke D4, Thrasher J6, Woo V7, Philis‐Tsimikas A8
1Mount Sinai Hospital, Toronto, ON, Canada; 2Novo Nordisk, Bengaluru, India; 3Albany Medical Center Division of Community Endocrinology, Albany, NY; 4Novo Nordisk A/S, Søborg, Denmark; 51st Medical Department and Karl Landsteiner Institute for Obesity and Metabolic Disorders, Rudolfstiftung Hospital, Vienna, Austria; 6Medical Investigations, Inc, Little Rock, AR; 7University of Manitoba, Winnipeg, MB, Canada; 8Scripps Whittier Diabetes Institute, San Diego, CA
Background
Semaglutide is a once‐weekly GLP‐1 analogue for treatment of T2D. Few clinical trials have reported on the concomitant use of GLP‐1 receptor agonists with SGLT2 inhibitors. The focus of this study was to investigate the safety and effectiveness of semaglutide when added to SGLT2 inhibitor therapy in patients with inadequately controlled T2D.
Methods
The SUSTAIN 9 double‐blind, parallel‐group trial was conducted at 61 centers in six countries (Austria, Canada, Japan, Norway, Russia, and the United States) in adult patients with T2D and HbA1c 7.0%–10.0% (53–86 mmol/mol) despite ≥90 days of treatment with an SGLT2 inhibitor. Participants were randomly assigned (1:1) to receive subcutaneous semaglutide (1.0 mg) or volume‐matched placebo once weekly for 30 weeks, following a dose‐escalation period of 4 weeks with 0.25 mg semaglutide or placebo and 4 weeks with 0.5 mg semaglutide or placebo. Existing antidiabetic treatment, including the use of an SGLT2 inhibitor, were continued during the trial. Rescue medication, defined as intensification of background antidiabetic treatment or the initiation of new glucose‐lowering medications, could be administered to patients meeting specific criteria at the discretion of the investigator. Change in HbA1c from baseline at week 30 was the primary outcome and was assessed in the full analysis set (all patients randomly allocated to any treatment) using on‐treatment data collected before any rescue medication began. The confirmatory secondary outcome was change in bodyweight from baseline to week 30. The safety analysis set (all patients who received at least one dose of treatment) was used to assess the safety of semaglutide.
Results
Between March 15, and Dec 4, 2017, a total of 302 participants were enrolled and randomly assigned to receive semaglutide 1.0 mg or placebo (full analysis set) Of these, 301 received at least one treatment dose (safety analysis set). One patient was assigned to semaglutide but was not treated for unknown reasons. A large proportion (97.4%; 294/302) of participants completed the trial, and 88.4% (267/302) completed treatment. Baseline characteristics were generally comparable between groups. In addition to randomized medication and SGLT2 inhibitor, 216 (71.5%) patients were taking metformin and 39 (12.9%) were taking sulphonylurea. Patients given semaglutide had greater reductions in HbA1c (ETD −1.42% [95% CI −1.61 to −1.24]; −15.55 mmol/mol [−17.54 to −13.56]) and body weight (−3.81 kg [ −4.70 to −2.93]) versus those randomized to placebo (both P<0.0001). A total of 356 adverse events were reported by 104 (69.3%) patients in the semaglutide group, and 247 adverse events were reported by 91 (60.3%) patients in the placebo group. Gastrointestinal adverse events were most common and were reported in 56 (37.3%) patients in the semaglutide group and 20 (13.2%) in the placebo group. Serious adverse events occurred in seven (4.7%) patients in the semaglutide group and six (4.0%) in the placebo group. Four patients on semaglutide (2.7%) reported severe or blood glucose–confirmed hypoglycemic events. Sixteen patients, 13 of whom were in the semaglutide group, stopped ceased early due to some type of adverse event. There were no deaths during the trial.
Conclusion
Adding semaglutide to SGLT2 inhibitor therapy significantly improves glycemic control and reduces bodyweight in patients with inadequately controlled T2D and is generally well tolerated by these patients.
Durability of insulin degludec plus liraglutide versus insulin glargine U100 as initial injectable therapy in type 2 diabetes (DUAL VIII): a multicentre, open‐label, phase 3b, randomised controlled trial
Aroda VR1, González‐Galvez G2, Grøn R3, Halladin N3, Haluzík M4, Jermendy G5, Kok A6, Őrsy P3, Sabbah M7, Sesti G8, Silver R9
1Brigham and Women's Hospital, Boston, MA and MedStar Health Research Institute, Hyattsville, MD; 2Jalisco Institute of Research in Diabetes and Obesity SC, Guadalajara, Jalisco, Mexico; 3Novo Nordisk A/S, Søborg, Denmark; 4Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic; 5Bajcsy‐Zsilinszky Hospital, Budapest, Hungary; 6Union and Clinton Hospitals in Alberton, Gauteng, South Africa; 7Hadassah University Hospital, Jerusalem, Israel; 8Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; 9Southern New Hampshire Diabetes and Endocrinology, Nashua, NH
Background
Durable glycemic control holds the possibility of reducing disease burden and improving long‐term outcomes in patients with T2D. The DUAL VIII study investigated the long‐term glycemic control of insulin degludec plus liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) in patients with T2D using a visit schedule that mirrored routine clinical practice.
Methods
A 104‐week international, multicenter, open‐label, phase 3b randomized controlled trial was conducted in adult insulin‐naive patients (≥18 years of age). Individuals whose HbA1c levels were 7.0% to 11.0% (53–97 mmol/mol), with BMI of 20 kg/m2 or higher, and on stable doses of oral antidiabetic drugs, were recruited from outpatient clinics and randomly assigned (1:1), using a simple sequential allocation randomization schedule (block size of four), to IDegLira or IGlar U100, with each treatment as an add‐on to existing therapy. Personnel involved in defining the analysis sets, along with the internal safety committee and the independent external committee, were masked until the database was released for statistical analysis. Patient participants and all remaining investigators were not masked. Patients were provided prefilled pens for subcutaneous injection: in the IDegLira group, they received degludec 100 units/mL plus liraglutide 3.6 mg/mL in a 3 mL PDS290 pen; in the IGlar U100 group, they received IGlar U100 solution in a 3 mL Solostar pen. Both treatments were given once daily (at any time); consistency regarding time of day was recommended. The primary endpoint was time from randomization to need for treatment intensification, defined as HbA1c level ≥7.0% (53 mmol/mol) at two consecutive clinic visits, including week 26. Once patients met this criterion, the trial product was permanently discontinued, but patients were not withdrawn from the study; instead, they remained on follow‐up for the entire treatment and follow‐up period. The primary analysis was in the intention‐to‐treat population.
Results
Participant screening was carried out from Jan 8, 2016, to Oct 3, 2018. A total of 1,345 patients were screened, of which 1,012 (75.2%) were eligible and randomly assigned to either IDegLira (n=506) or IGlar U100 (n=506). Ninety‐six percent (484/506) of subjects in the IDegLira group and 95% (481/506) in the IGlar U100 group completed the trial. Baseline characteristics were similar between groups and reflective of patients eligible for basal insulin intensification (10 years of overall mean diabetes; HbA1c 8.5% [69 mmol/mol]; fasting plasma glucose 10 mmol/L). Those in the IDegLira group experienced significantly longer time on the test treatment until intensification was required than those in the IGlar U100 group (median >2 years vs about 1 year). Fewer individuals from the IDegLira group required treatment intensification over the 104‐week study period compared with the IGlar U100 group (189/506 [37%] vs 335/506 [66%] respectively). The preplanned sensitivity analyses of the primary endpoint were in agreement with the primary analysis (hazard ratio 0.45 [95% CI 0.38–0.54]) in the proportional hazards regression model, and the generalized log‐rank test was also in favor of IDegLira (P<0.0001). No new or unexpected safety and tolerability issues were identified and no treatment‐related deaths occurred.
Conclusion
In patients with uncontrolled T2D on oral antidiabetic drugs, initial injectable therapy with IDegLira resulted in fewer patients reaching the treatment intensification criterion during 104 weeks than did IGlar U100, and the use of IDegLira resulted in longer duration of the treatment effect.
Rationale for a titratable fixed‐ratio co‐formulation of a basal insulin analog and a glucagon‐like peptide 1 receptor agonist in patients with type 2 diabetes
Blonde L1, Anderson JE2, Chava P3, Dendy JA3
1Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA; 2The Frist Clinic, Nashville, TN; 3Ochsner Medical Center, Department of Endocrinology, New Orleans, LA
Objective
Reaching and maintaining recommended target glycemic levels, including those for HbA1c, is key to improving outcomes in patients with T2D. Both fasting plasma glucose and postprandial glucose contribute to overall HbA1c; therefore, targeting both is vital for sustaining glycemic control.
Methods
This review examines the complementary action mechanisms of GLP‐1 receptor agonists and basal insulin, both of which enhance glucose‐stimulated insulin release and suppress glucagon secretion. In addition, GLP‐1 receptor agonists slow gastric emptying and increase satiety, which contributes to reduced food intake.
Results
Adding a GLP‐1 receptor agonist to basal insulin analog therapy has been correlated with improved overall glycemic control, at a comparable risk of hypoglycemia and without weight gain. Titratable fixed‐ratio co‐formulations of basal insulin and a GLP‐1 receptor agonist have been shown to improve glycemic control, and offer less complex dosing schedules, which might increase treatment adherence. Slow titration of fixed‐ratio co‐formulations has been shown to reduce the frequency and severity of adverse gastrointestinal events often seen with the use of a separate GLP‐1 receptor agonist. Titratable fixed‐ratio coformulations also reduce patients' insulin‐associated weight gain and carry a similar risk of hypoglycemia compared with use of basal insulin alone.
Conclusion
The efficacy and safety of titratable fixed‐ratio coformulations have been demonstrated for insulin degludec/liraglutide and insulin glargine/lixisenatide in the DUAL and LixiLan trials, respectively, in both insulin‐naive and insulin‐experienced patients. Titratable fixed‐ratio co‐formulations present an attractive option for treatment in many patients with T2D.
Efficacy and safety of ideglira in older patients with type 2 diabetes
Lingvay I1, Handelsman Y2, Linjawi S3, Vilsbøll T4, Halladin N5, Ranc K5, Liebl A6
1UT Southwestern Medical Center, Dallas, TX; 2Metabolic Institute of America, Tarzana, CA; 3Coffs Endocrine and Diabetes Services, Coffs Harbour, New South Wales, Australia; 4Steno Diabetes Center Copenhagen, Gentofte, Denmark; 5Novo Nordisk A/S, Sobørg, Denmark; 6Centre for Diabetes and Metabolism, Fachklinik Bad Heilbrunn, Bad Heilbrunn, Germany
Objective
The efficacy and safety of insulin degludec/Liraglutide (IDegLira) in older patients has not yet been reported. This analysis aimed to evaluate the efficacy and safety of IDegLira in patients aged ≥65 years.
Methods
A post hoc analysis compared results of from the DUAL II, III, and V trials in patients aged ≥65 versus those <65 years. These were 26‐week, phase 3, randomized, two‐arm parallel, treat‐to‐target trials in patients already using injectable glucose‐lowering agents. In this study, 311 individuals aged <65 and 87 patients aged ≥65 years from DUAL II, 326 patients <65 years and 112 patients ≥65 years from DUAL III, and 412 patients <65 years and 145 patients ≥65 years from DUAL V were evaluated. Participants in the DUAL trials were randomly assigned to treatment plans: IDegLira or insulin degludec (DUAL II), IDegLira or unchanged GLP‐1RA (DUAL III), or IDegLira or IGlar U100 (DUAL V).
Results
In patients ≥65 years, HbA1c decreased to more with IDegLira than with other treatment (ETD −1.0% [95% CI −1.5, −0.6], −0.8% [95% CI −1.0, −0.5], and −0.9% [95% CI −1.3, −0.6] for DUAL II, V, and III, respectively; all P<0.001). These mirrored results of patients <65 years of age. Hypoglycemia rates were lower with IDegLira compared with basal insulin and higher versus unchanged GLP‐1RA (estimated rate ratios, 0.5 [95% CI 0.2, 1.6], P=0.242; 0.3 [95% CI 0.1, 0.5] P<0.001, and 11.8 [95% CI 3.3, 42.8] P<0.001 for DUAL II, V, and III, respectively).
Conclusion
Adding IDegLira can improve glycemic control in patients aged ≥65 years already using basal insulin or GLP‐1RA, and it is well tolerated overall.
Predictive factors of efficacy of combination therapy with basal insulin and liraglutide in type 2 diabetes when switched from longstanding basal‐bolus insulin: association between the responses of beta‐ and alpha‐cells to GLP‐1 stimulation and the glycaemic control at 6 months after switching therapy
Horie I1, Haraguchi A2, Sako A2, Akeshima J2, Niri T2, Shigeno R2, Ito A2, Nozaki A2, Natsuda S2, Akazawa S2, Mori Y2, Ando T2, Kawakami A2, Abiru N2
1Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan; 2Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan
Objective
Glycemic control was evaluated for patients treated with combination therapy using basal insulin and liraglutide, as were factors predictive of efficacy in patients with T2D when switched from longstanding basal‐bolus insulin therapy.
Methods
The study included 41 patients who switched from basal‐bolus insulin therapy (>3 years) to basal insulin/Liraglutide combination therapy. Glycemic control was evaluated 6 months after switching therapies and the results were used to split the patients into two groups: good responders (HbA1c <7.0% or 1.0% decrease) and poor responders (all participants who did not meet first criteria). The glucose‐dependent insulin/glucagon responses without/with liraglutide were evaluated using a 75‐g OGTT, which was performed twice—before administration of liraglutide (1st‐OGTT) and 2‐days after (2nd‐OGTT).
Results
Twenty‐eight patients (68.3%) reached the target HbA1c and were identified as good responders. No differences win baseline characteristics, including insulin/glucagon responses, were found between the two groups during 1st‐OGTT. During 2nd‐OGTT paradoxical hyperglucagonemia was significantly improved in both groups, but only good responders achieved significant increases in insulin secretory response. Logistic regression analyses revealed that improvement in insulin response during 2nd‐OGTT versus 1st‐OGTT is associated with the good responder group.
Conclusion
Enhancement of glucose‐dependent insulin response under treatment with liraglutide is a potential predictor of long‐term glycemic control after switching the therapies.
Safety of lixisenatide versus sulfonylurea added to basal insulin treatment in people with type 2 diabetes mellitus who elect to fast during Ramadan (LixiRam): an international, randomized, open‐label trial
Hassanein MM1, Sahay R2, Hafidh K3, Djaballah K4, Li H5, Azar S6, Shehadeh N7, Hanif W8
1Dubai Hospital, Dubai, United Arab Emirates; 2Osmania Medical College, Hyderabad, India; 3Rashid Hospital, Dubai, United Arab Emirates; 4Sanofi, Paris, France; 5Sanofi‐Aventis (China), Chaoyang District, Beijing, China; 6American University of Beirut Medical Center, Beirut, Lebanon; 7Rambam Medical Center, Haifa, Israel; 8University Hospital Birmingham & Institute of Translational Medicine, Edgbaston, Birmingham, UK
Objective
The effects of adding lixisenatide rather than sulfonylurea (SU) to basal insulin (BI) versus continuing with SU+BI was assessed in individuals with T2DM who intended to fast during Ramadan 2017.
Methods
LixiRam (NCT02941367) was a phase 4, randomized, open‐label, 12‐ to 22‐week study in patients with T2DM that was insufficiently controlled with SU+BI ±1 oral anti‐diabetic. The primary endpoint was percentage of patients with ≥1 documented symptomatic hypoglycemia event (plasma glucose ≤70 mg/dL); and any hypoglycemia during Ramadan fasting was also an endpoint.
Results
Compared with SU+BI, a smaller percentage of patients using lixisenatide+BI had ≥1 documented symptomatic hypoglycemia event (intent‐to‐treat visit 4) during Ramadan fasting (3.3%, 3/91 with lixisenatide+BI vs SU+BI 8.9%, 8/90 with SU+BI; OR 0.34 [95% CI 0.09, 1.35]; proportion difference −0.06 [95% CI −0.13, 0.01]). The difference was statistically significant for the “any hypoglycemia” category (lixisenatide+BI 4.3%, 4/92; SU+BI 17.4%, 16/92; OR 0.22 [95% CI 0.07, 0.68]; proportion difference −0.13 [95% CI −0.22, −0.04]; intent‐to‐treat). No new treatment‐emergent adverse events occurred.
Conclusion
Compared with SU+BI, lixisenatide+BI resulted in lower rates of any hypoglycemia in patients with T2DM during Ramadan fasting. This indicates that lixisenatide+BI therapy might be a suitable treatment option for T2DM during fasting.
The good companions: insulin and glucagon‐like peptide‐1 receptor agonist in type 2 diabetes: a systematic review and meta‐analysis of randomized controlled trials
Maiorino MI1, Chiodini P2, Bellastella G1, Scappaticcio L1, Longo M1, Giugliano D1, Esposito K3
1Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy; 2Medical Statistics Unit, University of Campania “Luigi Vanvitelli,” Naples, Italy; 3Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy
Introduction
An updated systematic review was completed using meta‐analysis of randomized controlled trials (RCTs) to assess the metabolic effects of combination therapy (insulin and GLP‐1RA [combo]) in comparison with other injectable therapy.
Methods
PubMed, Cochrane Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov were searched for RCTs investigating changes in HbA1c (primary endpoint), proportion of patients at HbA1c target <7%, hypoglycemia, and weight change (secondary endpoints). In all, 36 RCTs involving 14,636 patients were included.
Results
When evaluated against comparator therapies (overall analysis), the insulin and GLP‐1RA combo led to a significant reduction in HbA1c (−0.49% [95% CI −0.61%, −0.38%]; P<0.001), with more patients at HbA1c target level (relative risk, RR, 1.77 [95% CI, 1.56, 2.01]; P<0.001), similar occurrence of hypoglycemic events (RR 1.03 [95% CI, 0.88, 1.19]; P=0.728), and achieving a reduction in body weight (−2.5 kg [95% CI −3.1, −1.8 kg]; P<0.001), with high heterogeneity in each analysis. The quality of the evidence was low for three of the considered outcomes. Compared with intensified insulin regimens (basal‐plus/basal‐bolus) the combo produced similar glycemic control with reduction of both hypoglycemia, and body weight.
Conclusion
Combination therapy using GLP‐1RA and insulin could be a valuable treatment strategy to improve glycemic control in the management of T2D.
The use of GLP‐1 RAs has become an important option for the treatment of T2D. The ADA/EASD Standards of Care now recommend these agents prior to insulin when additional glycemic control is required. The study by Horie makes one wonder if these agents should be initiated even sooner for those without atherosclerotic cardiovascular disease (when they have been clearly proven to reduce cardiovascular events and thus they should be used even sooner), since, anecdotally, clinicians have noted a heterogeneous response without everyone having a good glycemic effect. Not surprisingly, we can now conclude this is related to current endogenous insulin secretion. The Maiorino study also concluded the advantages of using basal insulin with GLP1‐RAs compared with traditional basal bolus therapy (less hypoglycemia and weight loss). Furthermore, while the results of the Hassanein study were not surprising, it is good to have evidence that basal insulin with lixisenatide is well tolerated and gives less hypoglycemia than basal insulin with a sulfonylurea during Ramadan. Mostly, the number of studies with GLP‐1 RAs to improve blood glucose control continues to grow, and these drugs should be a more significant component of our therapy for T2D. Unfortunately, cost is often the major reason why these agents cannot be utilized.
Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: a randomized controlled trial
Han KA1, Chon S2, Chung CH3, Lim S4, Lee KW5, Baik S6, Jung CH7, Kim DS8, Park KS9, Yoon KH10, Lee IK11, Cha BS12, Sakatani T13, Park S14, Lee MK15
1Nowon Eulji Medical Center, Eulji University, Seoul, Korea; 2Kyung Hee University Hospital, Seoul, Korea; 3Yonsei University Wonju Severance Christian Hospital, Gangwon, Korea; 4Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Korea; 5Ajou University Hospital, Suwon‐si, Korea; 6Korea University Guro Hospital, Seoul, Korea; 7Department of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8Department of Endocrinology and Metabolism, Hanyang University Hospital, Seoul, Korea; 9Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 10Department of Endocrinology and Metabolism, Seoul St. Mary's Hospital, Catholic University Medical College, Seoul, Korea; 11Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea; 12Department of Internal Medicine, Yonsei University Severance Hospital, Seoul, Korea; 13Biostatistics Group, Japan‐Asia Data Science, Development, Astellas Pharma Inc., Tokyo, Japan; 14Clinical Research Team, Development Department, Astellas Pharma Korea, Inc., Seoul, Korea; 15Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Objective
The safety and efficacy of ipragliflozin versus placebo as add‐on therapy to metformin and sitagliptin was evaluated in Korean patients with T2DM.
Methods
A 24‐week, double‐blind, placebo‐controlled, multicenter, phase 3 study was carried out from 2015 to 2017 in Korea. Participants were randomly assigned to receive either ipragliflozin 50 mg/day or placebo once daily as an add‐on to metformin and sitagliptin therapy. The primary endpoint was change in HbA1c from baseline to end of treatment (EOT).
Results
Of the 143 patients who were randomized, 139 were included in the efficacy analyses (ipragliflozin, 73; placebo, 66). Baseline mean (SD) HbA1c values were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo add‐on. The associated mean (SD) changes from baseline to 24 weeks were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favor of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; P<0.0001). Compared with placebo‐treated patients, a higher percentage of ipragliflozin‐treated patients reached HbA1c target levels of <7.0% (44.4% vs 12.1%) and <6.5% (12.5% vs 1.5%) at EOT (P<0.05 for both). Fasting plasma glucose, fasting serum insulin, body weight, and HOMA of insulin resistance all showed significant decreases, in favor of ipragliflozin, at EOT (adjusted mean difference −1.64 mmol/L, −1.50 muU/mL, −1.72 kg, and −0.99, respectively; P<0.05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). There were no previously unreported safety concerns.
Conclusion
As an add‐on to metformin and sitagliptin, ipragliflozin, significantly improved glycemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.
Dapagliflozin as add‐on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial
Yang W1, Ma J2, Li Y3, Li Y4, Zhou Z5, Kim JH6, Zhao J7, Ptaszynska A8
1Department of Endocrinology, China–Japan Friendship Hospital, Beijing, China; 2Department of Endocrinology, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China; 3Department of Endocrinology, Huashan Hospital Fudan University, Shanghai, China; 4Department of Endocrinology, The Affiliated Hospital, Sun Yat‐Sen University, Guangzhou, China; 5Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China; 6Department of Endocrinology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 7CVMD GMed, AstraZeneca, Gaithersburg, MD; 8Innovative Medicines Development, Cardiovascular, Bristol‐Myers Squibb, Princeton, NJ
Background
The safety and efficacy of dapagliflozin as add‐on to insulin, with or without oral antihyperglycemic drugs (OADs), was assessed in Asian patients with inadequately controlled T2DM.
Methods
A 24‐week phase 3 double‐blind placebo‐controlled study was conducted in adult patients with HbA1c ≥7.5% to ≤10.5%, BMI ≤45 kg/m2, and using insulin doses ≥20 IU daily. Participants were randomized to dapagliflozin 10 mg (n=139) or placebo (n=133). Changes in HbA1c (primary outcome), fasting plasma glucose (FPG), body weight, total daily dose of insulin (TDDI), and seated systolic BP (exploratory outcome) were evaluated at 24 weeks.
Results
Baseline characteristics were similar in both groups. HbA1c was significantly improved with dapagliflozin treatment (mean [95% CI] 0.03% [−0.11, 0.17] for placebo vs −0.87% [ −1.00, −0.74] for dapagliflozin; between‐group difference −0.90% [ −1.09, −0.71], P<0.0001). FPG, body weight, TDDI, and seated systolic BP were also significantly improved with dapagliflozin versus placebo. The frequency of adverse events in the dapagliflozin and placebo groups was 80.5% and 71.2%, respectively; very few patients discontinued due to AEs (dapagliflozin, 2.2%; placebo, 4.2%). Hypoglycemia occurred at a similar rate with dapagliflozin and placebo (23.7% and 22.6%, respectively; no major events). The rates of urinary tract and genital infections was low, and no deaths were reported among participants.
Conclusion
Dapagliflozin as add‐on to insulin treatment with or without OADs resulted in significant improvement of glycemic control as well as reduced body weight and blood pressure in Asian patients. Dapagliflozin was well tolerated, with a similar frequency of hypoglycemia as seen with placebo. These results support the use of dapagliflozin as an add‐on to insulin in this population, with or without OADs.
It is good to see that both new and old SGLT2 inhibitors are effective for glycemic control with different medications (including insulin) and with different populations. There is no reason to think that the cardiac and renal benefits would be different in these populations too.
Efficacy and safety of Subetta add‐on therapy in type 1 diabetes mellitus: the results of a multicenter, double‐blind, placebo‐controlled, randomized clinical trial
Mkrtumyan A1, Romantsova T2, Vorobiev S3, Volkova A4, Vorokhobina N5, Tarasov S6, Putilovskiy M6, Andrianova E6, Epstein O7
1Moscow Clinical Scientific and Practical Center named after A.S. Loginov, Moscow, Russian Federation; 2Sechenov First Moscow State Medical University, Moscow, Russian Federation; 3Rostov State Medical University, Rostov‐on‐Don, Russian Federation; 4Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Russian Federation; 5Elizavetinskaya Municipal Hospital, Saint Petersburg, Russian Federation; 6OOO “NPF” Materia Medica Holding, Moscow, Russian Federation; 7The Institute of General Pathology and Pathophysiology, Moscow, Russian Federation
Background
Subetta is an oral drug derived through technological treatment of antibodies to insulin receptor beta‐subunit and endothelial NO synthase, which has previously been shown to activate insulin signaling pathway. A multicenter, double‐blind, placebo‐controlled, randomized clinical trial was performed to evaluate the effectiveness of Subetta as an add‐on to insulin therapy in patients with T1DM.
Methods
Patients with poor glycemic control using basal‐bolus insulin therapy were included in an intention‐to‐treat analysis of Subetta as an add‐on therapy. A total of 144 participants were randomized to receive Subetta or placebo (n=72 in both groups). Data for HbA1c and FPG levels, basal and prandial insulin doses, and number of hypoglycemia episodes confirmed by patient blood glucose self‐monitoring were recorded for 36 weeks.
Results
Participant baseline characteristics were similar between the two groups. HbA1c mean change was −0.59±0.99% (95% CI −0.84 to −0.37) after 36 weeks in Subetta (vs. −0.20±1.14% [95% CI −0.44 to 0.11] in placebo; P=0.028). For overall hypoglycemia events, the rate was 7.9 per patient year (95% CI 7.1–8.6) in the Subetta group and 7.6 per patient year (95% CI 6.9–8.4) in the placebo group (P=0.63). For both groups, basal and total insulin doses were not changed at the end of 36 weeks.
Conclusion
Subetta add‐on therapy was found to increase insulin activity and improve glycemic control, therefore proving its benefit for patients with T1DM.
Subetta is an oral polyclonal antibody mixture that exerts its effect by stimulating the beta‐subunit of insulin receptors as well as endothelial nitric oxide synthase. By activating insulin receptors, Subetta exerts its antihyperglycemic effect primarily by stimulating the uptake of glucose by muscle cells. Compared with the SGLT2 inhibitors, this agent has had minimal visibility but may be an important adjunctive therapy in the future for T1D. Since this agent also has a beneficial effect on endothelial dysfunction, one cannot help but wonder how this may have a positive impact on cardiovascular events.
Mini‐dose glucagon as a novel approach to prevent exercise‐induced hypoglycemia in type 1 diabetes
Rickels MR, DuBose SN, Toschi E, Beck RW, Verdejo AS, Wolpert H, Cummins MJ,
Newswanger B, Riddell MC; T1D Exchange Mini‐Dose Glucagon Exercise Study Group
Objective
People with T1D who participate in aerobic exercise often experience a decrease in blood glucose concentration that can result in hypoglycemia. Current methods to prevent exercise‐induced hypoglycemia typically include reducing insulin dosage or ingesting carbohydrates, but both of these strategies can still result in hypoglycemia or hyperglycemia. We sought to determine whether subcutaneous administration of mini‐dose glucagon (MDG) prior to exercise could prevent subsequent lowering of blood glucose and to compare the glycemic response to MDG with current approaches for mitigating exercise‐associated hypoglycemia.
Methods
A four‐session, randomized crossover trial was carried out in 15 adults with T1D using continuous subcutaneous insulin infusion who participated in fasted morning exercise at approximately 55% VO2max for 45 minutes under one of the following conditions: no intervention (control), 50% basal insulin reduction, 40‐g oral glucose tablets, or 150‐μg subcutaneous glucagon (MDG).
Results
During aerobic exercise and early postexercise recovery, plasma glucose increased slightly with MDG, while a decrease was observed in the control and insulin reduction groups, and a greater increase occurred with glucose tablets (P<0.001). Insulin levels were not different among sessions; however, glucagon increased with MDG administration (P<0.001). Six participants experienced hypoglycemia (plasma glucose <70 mg/dL) during control, five subjects experienced it during insulin reduction, and none with glucose tablets or MDG. In addition, five subjects experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one reported it with MDG.
Conclusion
MDG may be more effective than insulin reduction for the prevention of exercise‐induced hypoglycemia and may result in less postintervention hyperglycemia than is observed with ingestion of carbohydrates.
Control of postprandial hyperglycemia in type 1 diabetes by 24‐hour fixed‐dose coadministration of pramlintide and regular human insulin: a randomized, two‐way crossover study
Riddle MC1, Nahra R2, Han J3, Castle J1, Hanavan K1, Hompesch M4, Huffman D5, Strange P6, Öhman P2
1Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland, OR; 2AstraZeneca, Gaithersburg, MD; 3Pharmapace, Inc., San Diego, CA; 4ProSciento, Chula Vista, CA; 5University Diabetes and Endocrine Consultants, Chattanooga, TN; 6Integrated Medical Development, LLC, Princeton Junction, NJ
Objective
Healthy pancreatic beta cells secrete a fixed ratio of insulin and amylin hormones. Both of these hormones are lacking in patients with T1D, and it is difficult to control postprandial glucose using insulin therapy alone. This study tested the pharmacodynamic effects of the amylin analog pramlintide and insulin combination delivered in a fixed ratio over a 24‐hour period.
Methods
A randomized, single‐masked, two‐way crossover, 24‐hour inpatient study was conducted in patients with T1D. Participants were stabilized on insulin pump therapy with insulin lispro before prior to commencement of the study in which separate infusion pumps administered regular human insulin with pramlintide or placebo in a fixed ratio of 9 μg/unit. Meal content and timing along with patient‐specific insulin doses were the same in each treatment. Change in mean glucose measured by CGM was the primary outcome. Laboratory‐measured glucose, insulin, glucagon, and triglyceride profiles were also compared.
Results
Due to a marked reduction of postprandial increments, mean CGM‐measured 24‐hour glucose was lower with pramlintide than with placebo (8.5 vs 9.7 mmol/L, respectively; P=0.012). Glycemic variability was reduced with pramlintide versus placebo as well, and postprandial glucagon and triglyceride levels also decreased. Gastrointestinal side effects were more found to be more frequent when using pramlintide. No major hypoglycemic events occurred with either pramlintide or placebo.
Conclusion
In patients with t1D, coadministration of fixed‐ratio pramlintide and regular human insulin for 24 hours improved both postprandial hyperglycemia and glycemic variability. Longer studies including dose titration under daily conditions will be necessary to determine whether this regimen could provide long‐term improvement in glycemic control.
New delivery methods to improve delivery of older drugs are always desirable. Mini‐dose glucagon administered subcutaneously to prevent exercise‐induced hypoglycemia is quite sensible, and now with the introduction of nasal glucagon perhaps there can be a major reduction in this frequent problem. Glucagon needs to be considered an important therapeutic option other than simply treating severe hypoglycemia, which is why there is so much interest in the bihormonal pancreas with insulin and glucagon. Similarly, the use of a fixed‐dose of pramlintide has been shown to be effective and likewise could potentially be used in a bihormonal artificial pancreas system. For this latter option, different ratios of insulin and pramlintide may be required depending on the patient, but hopefully this area of research will also move forward.
Summary and Conclusion
Adjunctive therapies for type 1 diabetes and combination therapies for type 2 diabetes continue to expand. The type 1 studies show steady progress, but as of now we are still waiting for the perfectly safe therapy. Even if the SGLT2 inhibitors were available to all patients with type 1 diabetes, many would not be good candidates for them. New uses of glucagon and pramlintide seem promising. Use of combination therapies in type 2 diabetes is now a standard of care. While many of these reports have assessed how effectively these various combinations work together, it must be emphasized that those with preexisting atherosclerotic cardiovascular disease and renal disease would be best served with agents (GLP1 receptor agonists and SGLT2 inhibitors) proven to reduce further advancement of each comorbidity. Surveys have shown low usage of these agents when the evidence has clearly proven their benefit, meaning one of our goals as clinicians is to better utilize these drugs in appropriate patients.
Footnotes
Author Disclosure Statement
No competing financial interests exist.