Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy
2019; Cell Press; Volume: 29; Issue: 3 Linguagem: Inglês
10.1016/j.cmet.2019.02.007
ISSN1932-7420
AutoresEsther Latres, Daniel A. Finan, J L Greenstein, Aaron J. Kowalski, Timothy J. Kieffer,
Tópico(s)Diabetes and associated disorders
ResumoIncredible strides have been made since the discovery of insulin almost 100 years ago. Insulin formulations have improved dramatically, glucose levels can be measured continuously, and recently first-generation biomechanical "artificial pancreas" systems have been approved by regulators around the globe. However, still only a small fraction of patients with diabetes achieve glycemic goals. Replacement of insulin-producing cells via transplantation shows significant promise, but is limited in application due to supply constraints (cadaver-based) and the need for chronic immunosuppression. Over the past decade, significant progress has been made to address these barriers to widespread implementation of a cell therapy. Can glucose levels in people with diabetes be normalized with artificial pancreas systems or via cell replacement approaches? Here we review the road ahead, including the challenges and opportunities of both approaches. Incredible strides have been made since the discovery of insulin almost 100 years ago. Insulin formulations have improved dramatically, glucose levels can be measured continuously, and recently first-generation biomechanical "artificial pancreas" systems have been approved by regulators around the globe. However, still only a small fraction of patients with diabetes achieve glycemic goals. Replacement of insulin-producing cells via transplantation shows significant promise, but is limited in application due to supply constraints (cadaver-based) and the need for chronic immunosuppression. Over the past decade, significant progress has been made to address these barriers to widespread implementation of a cell therapy. Can glucose levels in people with diabetes be normalized with artificial pancreas systems or via cell replacement approaches? Here we review the road ahead, including the challenges and opportunities of both approaches. The discovery of insulin in 1921 and the awarding of the Nobel Prize in Physiology and Medicine to Frederick Banting and John Macleod of the University of Toronto was a triumph of science and medicine. Type 1 diabetes, a disease that was universally fatal for millennia, was "cured," saving thousands of lives. Unfortunately, it became quickly clear that while insulin saved the lives of those with type 1 diabetes, the delivery of purified animal insulin via subcutaneous injections was crude and non-physiologic. The exquisite glucose balance driven by the islet could not be replicated with subcutaneous delivery and with no means to measure blood glucose levels. The imbalance manifested itself in the development of hyperglycemia-driven micro- and macrovascular complications over time. Furthermore, a dangerous acute complication—hypoglycemia—was and still is common due to delayed insulin action. Significant improvements in insulin delivery have been made, but as Frederick Banting noted in his Nobel lecture, "insulin is not a cure for diabetes; it is a treatment." In a recent assessment of health care expenditures in the United States, diabetes was the most expensive disease at costs of >$100 billion in a single year (Dieleman et al., 2016Dieleman J.L. Baral R. Birger M. Bui A.L. Bulchis A. Chapin A. Hamavid H. Horst C. Johnson E.K. Joseph J. et al.US spending on personal health care and public health, 1996-2013.JAMA. 2016; 316: 2627-2646Crossref PubMed Scopus (204) Google Scholar), while the American Diabetes Association estimated the total economic costs of diabetes in the United States in 2017 alone to be $327 billion (American Diabetes Association, 2018cAmerican Diabetes AssociationEconomic costs of diabetes in the U.S. in 2017.Diabetes Care. 2018; 41: 917-928Crossref PubMed Scopus (18) Google Scholar). Diabetes affects >400 million people worldwide (International Diabetes Federation, 2017International Diabetes Federation (2017). IDF Diabetes Atlas, Eighth Edition, https://www.idf.org/diabetesatlas.Google Scholar) and is characterized by dysregulated glucose metabolism as a result of insufficient production or effectiveness of the pancreatic hormone insulin. Insulin is required for regulating the rate at which cells are able to uptake and metabolize glucose and is thus critical for determining how cells store and utilize fuels. In type 1 diabetes, there is a profound loss of the insulin-producing beta cells involving an autoimmune response, and the resulting insulin deficiency leads to the telltale signs of diabetes: elevated blood glucose levels, fatigue, polyuria, and increased thirst. In type 2 diabetes, insulin levels may be normal, or even elevated, but insulin resistance in peripheral tissues leads to inadequate insulin action, resulting in hyperglycemia. In all patients with type 1 diabetes (7%–12% of all diabetes in high-income countries; International Diabetes Federation, 2017International Diabetes Federation (2017). IDF Diabetes Atlas, Eighth Edition, https://www.idf.org/diabetesatlas.Google Scholar) and those with late-stage type 2 diabetes, insulin replacement is required for survival. While lifesaving, the conventional form of insulin therapy involving subcutaneous insulin injections is crude and typically does not prevent debilitating complications that result from elevated blood glucose levels, including damage to the microvasculature causing retinopathy, nephropathy, and neuropathy, as well as macrovascular disease. Thus, better forms of insulin replacement are desperately needed. Patient accessibility to insulin therapy is also a global issue. Even though we are approaching 100 years since the discovery of insulin (Banting et al., 1922Banting F.G. Best C.H. Collip J.B. Campbell W.R. Fletcher A.A. Pancreatic extracts in the treatment of diabetes mellitus.Can. Med. Assoc. J. 1922; 12: 141-146PubMed Google Scholar), the main cause of mortality for a child with type 1 diabetes remains a lack of access to insulin. In some areas of the world, the life expectancy of a child with type 1 diabetes is still as low as 1 year after diagnosis (Beran et al., 2018Beran D. Hirsch I.B. Yudkin J.S. Why are we failing to address the issue of access to insulin? A national and global perspective.Diabetes Care. 2018; 41: 1125-1131Crossref PubMed Scopus (1) Google Scholar), whereas where insulin is available, life expectancy approaches that of the general population. In a healthy adult of 75 kg with a blood volume of 5 L, the blood contains ∼5 g glucose, equivalent to about a teaspoon of sugar, equating to an average blood glucose level of 5.5 mmol/L (100 mg/dL). Maintaining a minimal amount of glucose in the blood is critical to meet energy demands of the brain. Despite fluctuating intake and use of glucose, blood glucose levels are tightly regulated within a few mM by the precisely coordinated release of hormones produced in the pancreatic islets of Langerhans (Figure 1). Beta cells, the most abundant cell type in the islets, are highly sensitive to glucose concentrations and have a tremendous capacity to rapidly secrete insulin in a glucose-dependent manner. Typically, beta cells release only a few percent of their insulin content in response to a meal or stimulus, and stores are rapidly replenished, so the reserves can easily accommodate the daily demands to facilitate glucose disposal. Beta cells are constantly sensing blood glucose levels and are highly specialized to secrete insulin in response to increasing glucose concentrations. Glucose is transported into beta cells and is then phosphorylated for its metabolism through glycolysis and oxidation. The generation of ATP by glycolysis, the Krebs cycle, and the respiratory chain closes ATP-sensitive K+ channels (KATP), allowing sodium (Na+) entry, producing membrane depolarization, and opening voltage-dependent T-type calcium (Ca2+) channels. Together with calcium mobilized from intracellular stores, this Ca2+ increase leads to fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin into the circulation. This KATP-dependent mechanism is gradually augmented in a KATP channel-independent manner, producing biphasic insulin secretion (Komatsu et al., 2013Komatsu M. Takei M. Ishii H. Sato Y. Glucose-stimulated insulin secretion: a newer perspective.J. Diabetes Investig. 2013; 4: 511-516Crossref PubMed Scopus (61) Google Scholar, Rorsman et al., 2014Rorsman P. Ramracheya R. Rorsman N.J. Zhang Q. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion.Diabetologia. 2014; 57: 1749-1761Crossref PubMed Google Scholar, Shibasaki et al., 2004Shibasaki T. Sunaga Y. Seino S. Integration of ATP, cAMP, and Ca2+ signals in insulin granule exocytosis.Diabetes. 2004; 53: S59-S62Crossref PubMed Scopus (42) Google Scholar). Importantly, aside from glucose, the beta cell is exposed to other factors that amplify glucose-induced insulin secretion, such as additional nutrients (e.g., amino acids and free fatty acids), neuronal inputs, and the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which may account for ∼50% of postprandial insulin secretion (Creutzfeldt, 1979Creutzfeldt W. The incretin concept today.Diabetologia. 1979; 16: 75-85Crossref PubMed Google Scholar). Basal (fasting) insulin levels are typically <25 mIU/L (<174 pmol/L) and can rise 10-fold or more after a meal to promote glucose uptake and also inhibit glucose output from the liver. Insulin release from beta cells oscillates with a period of 3–6 min, which is thought to avoid downregulation of insulin receptors in target cells, and to assist the liver in extracting insulin from the blood. Importantly, as blood glucose levels fall, insulin secretion is proportionally decreased, and in the absence of further food consumption, will rapidly return to basal levels. This protects the body from hypoglycemia, as does the production of glucagon from alpha cells, which serves to promote the hepatic production of glucose to maintain blood glucose levels during fasting periods. Thus, given their opposing actions, it is primarily the ratio of insulin and glucagon that determines prevailing glucose concentrations (Unger and Cherrington, 2012Unger R.H. Cherrington A.D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover.J. Clin. Invest. 2012; 122: 4-12Crossref PubMed Scopus (316) Google Scholar). Of note, in the setting of insulin-dependent diabetes, glucagon secretion is not adequately suppressed during meals, and thus, in the face of relative hypoinsulinemia, inappropriate hepatic glucose production contributes to hyperglycemia (Cryer, 2012Cryer P.E. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes.Endocrinology. 2012; 153: 1039-1048Crossref PubMed Scopus (103) Google Scholar, Geary, 2017Geary N. Postprandial suppression of glucagon secretion: a puzzlement.Diabetes. 2017; 66: 1123-1125Crossref PubMed Scopus (1) Google Scholar). Moreover, there are often deficits in the counterregulatory responses, leaving patients with type 1 diabetes more susceptible to episodes of hypoglycemia. Adding to the complexity of diabetes therapy, beta cells release additional hormones that may complement insulin action. C-peptide is a by-product of proinsulin processing and interestingly appears to improve blood flow such that as an auxiliary therapeutic with insulin, C-peptide might prevent and ameliorate diabetic vasculopathy (Bhatt et al., 2014Bhatt M.P. Lim Y.C. Ha K.S. C-peptide replacement therapy as an emerging strategy for preventing diabetic vasculopathy.Cardiovasc. Res. 2014; 104: 234-244Crossref PubMed Scopus (13) Google Scholar, Pinger et al., 2017Pinger C.W. Entwistle K.E. Bell T.M. Liu Y. Spence D.M. C-peptide replacement therapy in type 1 diabetes: are we in the trough of disillusionment?.Mol. Biosyst. 2017; 13: 1432-1437Crossref PubMed Google Scholar). Amylin is another peptide co-secreted with insulin, and it serves to reduce gastric emptying and suppress postprandial release of the glucose-raising hormone glucagon from alpha cells, which collectively reduces blood glucose excursions. Given the loss of amylin in patients with type 1 diabetes, it is potentially a useful adjunct to insulin therapy (Denroche and Verchere, 2018Denroche H.C. Verchere C.B. IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants.J. Mol. Endocrinol. 2018; 60: R57-R75Crossref PubMed Scopus (1) Google Scholar, Hinshaw et al., 2016Hinshaw L. Schiavon M. Dadlani V. Mallad A. Dalla Man C. Bharucha A. Basu R. Geske J.R. Carter R.E. Cobelli C. et al.Effect of pramlintide on postprandial glucose fluxes in type 1 diabetes.J. Clin. Endocrinol. Metab. 2016; 101: 1954-1962Crossref PubMed Scopus (12) Google Scholar, Levetan et al., 2003Levetan C. Want L.L. Weyer C. Strobel S.A. Crean J. Wang Y. Maggs D.G. Kolterman O.G. Chandran M. Mudaliar S.R. Henry R.R. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps.Diabetes Care. 2003; 26: 1-8Crossref PubMed Scopus (0) Google Scholar, Weyer et al., 2003Weyer C. Gottlieb A. Kim D.D. Lutz K. Schwartz S. Gutierrez M. Wang Y. Ruggles J.A. Kolterman O.G. Maggs D.G. Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study.Diabetes Care. 2003; 26: 3074-3079Crossref PubMed Scopus (80) Google Scholar). The goal of exogenous insulin replacement is to mimic the dynamic patterns of normal insulin secretion, taking into account the glucose content of meals and activity levels, and adjusted based upon results of frequent blood glucose monitoring. However, replacing insulin via subcutaneous injections or infusion presents significant challenges in attempting to mimic the islet biology that is so closely tied to gut and liver physiology. The normal kinetics of insulin release and the flow of insulin first to the liver cannot occur via subcutaneous adsorption. Insulin secretion into the portal vein begins before food is even swallowed and is followed by rapid biphasic insulin release that returns to basal levels as the food is absorbed. In contrast, insulin delivered subcutaneously has significant and variable delays in entering the blood (∼1 h to peak levels) and limited liver passage. The development of rapid- and long-acting insulin analogs with improved kinetic profiles (Mathieu et al., 2017Mathieu C. Gillard P. Benhalima K. Insulin analogues in type 1 diabetes mellitus: getting better all the time.Nat. Rev. Endocrinol. 2017; 13: 385-399Crossref PubMed Scopus (26) Google Scholar) and decision support tools often in the form of apps, the emergence of new devices designed to track glucose concentrations in the body continuously (continuous glucose monitors, CGMs), and improved insulin pumps that enable basal rates of insulin to be delivered continuously and bolus amounts to be delivered on-demand have provided clinicians and patients who have access to them with better tools to treat diabetes. However, varying insulin needs still pose considerable challenges to patients. For instance, continuous glucose monitoring in patients with type 1 diabetes revealed highly variable overnight insulin requirements that were from half to 3-fold of the baseline amounts (Ruan et al., 2016Ruan Y. Thabit H. Leelarathna L. Hartnell S. Willinska M.E. Dellweg S. Benesch C. Mader J.K. Holzer M. Kojzar H. et al.[email protected] ConsortiumVariability of insulin requirements over 12 weeks of closed-loop insulin delivery in adults with type 1 diabetes.Diabetes Care. 2016; 39: 830-832Crossref PubMed Google Scholar). Inappropriately high insulin levels, combined with defective counterregulatory responses that would otherwise raise blood glucose levels, put patients at risk of coma and even death. This can be more worrisome to parents treating young children with insulin than the long-term consequences of hyperglycemia, resulting in interrupted sleep for nighttime blood glucose checking. Even in a hospital setting, children with type 1 diabetes experienced hypoglycemia (blood glucose < 3.9 mmol/L or 70 mg/dL) 10% of the nights (Buckingham et al., 2015Buckingham B.A. Raghinaru D. Cameron F. Bequette B.W. Chase H.P. Maahs D.M. Slover R. Wadwa R.P. Wilson D.M. Ly T. et al.In Home Closed Loop Study GroupPredictive low-glucose insulin suspension reduces duration of nocturnal hypoglycemia in children without increasing ketosis.Diabetes Care. 2015; 38: 1197-1204Crossref PubMed Scopus (74) Google Scholar). Thus, hypoglycemia is a major limiting factor in the glycemic management of diabetes. Blood glucose ≤70 mg/dL (3.9 mmol/L) is sufficiently low for treatment by ingestion of carbohydrate while levels ≤54 mg/dL (3.0 mmol/L) indicate serious hypoglycemia that is associated with cognitive impairment, which could progress to loss of consciousness and neurological damage if not rapidly treated. Hypoglycemia is still a major cause of morbidity and mortality in people with diabetes (Cryer, 2013Cryer P.E. Mechanisms of hypoglycemia-associated autonomic failure in diabetes.N. Engl. J. Med. 2013; 369: 362-372Crossref PubMed Scopus (167) Google Scholar). Glycemic control is fundamental to the effective management of diabetes. A prospective randomized controlled trial of intensive versus standard glycemic control in patients with type 1 diabetes demonstrated that better glycemic control is associated with significantly decreased rates of development and progression of microvascular complications (Lachin et al., 2015Lachin J.M. White N.H. Hainsworth D.P. Sun W. Cleary P.A. Nathan D.M. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research GroupEffect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC.Diabetes. 2015; 64: 631-642Crossref PubMed Scopus (93) Google Scholar, Nathan et al., 1993Nathan D.M. Genuth S. Lachin J. Cleary P. Crofford O. Davis M. Rand L. Siebert C. Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N. Engl. J. Med. 1993; 329: 977-986Crossref PubMed Scopus (19310) Google Scholar). Notably, tight glycemic control early in the disease persistently reduces microvascular complications (Holman et al., 2008Holman R.R. Paul S.K. Bethel M.A. Matthews D.R. Neil H.A. 10-year follow-up of intensive glucose control in type 2 diabetes.N. Engl. J. Med. 2008; 359: 1577-1589Crossref PubMed Scopus (3975) Google Scholar, Lachin et al., 2000Lachin J.M. Genuth S. Cleary P. Davis M.D. Nathan D.M. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research GroupRetinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy.N. Engl. J. Med. 2000; 342: 381-389Crossref PubMed Scopus (1117) Google Scholar). Thus, careful blood glucose monitoring is key to optimizing glucose control and minimizing tissue damage. The landmark Diabetes Control and Complications Trial (DCCT) demonstrated the benefit of intensive glycemic control on diabetes complications in type 1 diabetes (Nathan et al., 1993Nathan D.M. Genuth S. Lachin J. Cleary P. Crofford O. Davis M. Rand L. Siebert C. Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N. Engl. J. Med. 1993; 329: 977-986Crossref PubMed Scopus (19310) Google Scholar). Similar benefit was demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes (King et al., 1999King P. Peacock I. Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes.Br. J. Clin. Pharmacol. 1999; 48: 643-648Crossref PubMed Scopus (143) Google Scholar). Unlike the islet, which assesses glucose levels continuously and responds in real time, people with diabetes could previously only measure glucose intermittently, first via urine glucose monitoring and subsequently by capillary blood glucose testing. Now, technology permits continuous monitoring of interstitial fluid glucose levels (a proxy to blood glucose) (Cengiz and Tamborlane, 2009Cengiz E. Tamborlane W.V. A tale of two compartments: interstitial versus blood glucose monitoring.Diabetes Technol. Ther. 2009; 11: S11-S16Crossref PubMed Scopus (139) Google Scholar, Kulcu et al., 2003Kulcu E. Tamada J.A. Reach G. Potts R.O. Lesho M.J. Physiological differences between interstitial glucose and blood glucose measured in human subjects.Diabetes Care. 2003; 26: 2405-2409Crossref PubMed Scopus (0) Google Scholar). Frequent monitoring of blood glucose allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Guidelines from the American Diabetes Association recommend that "most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform self-monitoring of blood glucose prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving" (American Diabetes Association, 2018bAmerican Diabetes Association6. Glycemic targets: standards of medical care in diabetes-2018.Diabetes Care. 2018; 41: S55-S64Crossref PubMed Scopus (0) Google Scholar). For many patients, this means blood glucose testing via finger-stick 6–10 times daily. More recently, CGM has become a standard of care with benefit demonstrated in multiple populations of people with diabetes (American Diabetes Association, 2018aAmerican Diabetes Association1. Improving care and promoting health in populations: standards of medical care in diabetes-2018.Diabetes Care. 2018; 41: S7-S12Crossref PubMed Scopus (23) Google Scholar), but user burden is a significant barrier to use (Engler et al., 2018Engler R. Routh T.L. Lucisano J.Y. Adoption barriers for continuous glucose monitoring and their potential reduction with a fully implanted system: results from patient preference surveys.Clin. Diabetes. 2018; 36: 50-58Crossref PubMed Google Scholar). Another commonly used tool to assess glycemic control is hemoglobin A1c (HbA1c), which reflects average glycemia over approximately 3 months and has strong predictive value for diabetes complications (Albers et al., 2010Albers J.W. Herman W.H. Pop-Busui R. Feldman E.L. Martin C.L. Cleary P.A. Waberski B.H. Lachin J.M. Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications Research GroupEffect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study.Diabetes Care. 2010; 33: 1090-1096Crossref PubMed Scopus (186) Google Scholar, Stratton et al., 2000Stratton I.M. Adler A.I. Neil H.A. Matthews D.R. Manley S.E. Cull C.A. Hadden D. Turner R.C. Holman R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.BMJ. 2000; 321: 405-412Crossref PubMed Google Scholar). Thus, regular HbA1c testing is recommended for all patients with diabetes—at initial assessment and as part of continuing care (American Diabetes Association, 2018bAmerican Diabetes Association6. Glycemic targets: standards of medical care in diabetes-2018.Diabetes Care. 2018; 41: S55-S64Crossref PubMed Scopus (0) Google Scholar). Measurements help patients and their caregivers to assess how well glycemic targets are being reached and maintained. The normal HbA1c level is below 6.0% (42 mmol/mol) for the average adult. The guidelines from the American Diabetes Association recommend targeting <7.5% (58 mmol/mol) for children and adolescents with diabetes and <7.0% (53 mmol/mol) for adults. Achieving HbA1c targets of <7% as early in the course of the disease as possible can prevent or delay the micro- and macro-vascular complications of diabetes, although there are diminishing returns of further lowering of HbA1c from 7% to 6% (Adler et al., 2000Adler A.I. Stratton I.M. Neil H.A. Yudkin J.S. Matthews D.R. Cull C.A. Wright A.D. Turner R.C. Holman R.R. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.BMJ. 2000; 321: 412-419Crossref PubMed Google Scholar, Nathan et al., 1993Nathan D.M. Genuth S. Lachin J. Cleary P. Crofford O. Davis M. Rand L. Siebert C. Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N. Engl. J. Med. 1993; 329: 977-986Crossref PubMed Scopus (19310) Google Scholar, Nathan and DCCT/EDIC Research Group, 2014Nathan D.M. DCCT/EDIC Research GroupThe diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview.Diabetes Care. 2014; 37: 9-16Crossref PubMed Scopus (275) Google Scholar) and substantially increased risk of causing hypoglycemia (Skyler et al., 2009Skyler J.S. Bergenstal R. Bonow R.O. Buse J. 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While HbA1c levels have been firmly tied to risk for diabetes complications, the measurement does not provide sufficient information on hypoglycemia exposure, glycemic variability, and quality of life. Therefore, HbA1c levels alone do not provide sufficient information to allow people with diabetes and clinicians to make actionable changes to diabetes management strategies. CGMs allow for a more complete picture of glycemia including time in the euglycemic or target glucose range, time spent hypoglycemic, and time spent hyperglycemic. These data can be reported in standardized formats that allow for diabetes management strategies and/or comprehensive assessment of novel treatment modalities (Mullen et al., 2018Mullen D.M. Bergenstal R. Criego A. Arnold K.C. Goland R. Richter S. Time savings using a standardized glucose reporting system and ambulatory glucose profile.J. Diabetes Sci. Technol. 2018; 12: 614-621Crossref PubMed Scopus (3) Google Scholar, Schnell et al., 2017Schnell O. Barnard K. Bergenstal R. Bosi E. Garg S. Guerci B. Haak T. Hirsch I.B. Ji L. Joshi S.R. et al.Role of continuous glucose monitoring in clinical trials: recommendations on reporting.Diabetes Technol. Ther. 2017; 19: 391-399Crossref PubMed Scopus (10) Google Scholar). Leading clinical and patient organizations have prioritized and reported on the importance of additional diabetes outcomes including hypoglycemia frequency, time in target glucose ranges, risk for diabetic ketoacidosis, and patient reported outcomes (Agiostratidou et al., 2017Agiostratidou G. Anhalt H. Ball D. Blonde L. Gourgari E. Harriman K.N. Kowalski A.J. Madden P. McAuliffe-Fogarty A.H. McElwee-Malloy M. et al.Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.Diabetes Care. 2017; 40: 1622-1630Crossref PubMed Scopus (0) Google Scholar). We believe that these metrics will become commonplace in the assessment of the incremental benefit of novel therapies versus the current standard of care—i.e., future artificial pancreas systems and cell therapies. Advances in glucose monitoring and insulin delivery devices have improved outcomes for patients with diabetes (Bally et al., 2018Bally L. Thabit H. Hartnell S. Andereggen E. Ruan Y. Wilinska M.E. Evans M.L. Wertli M.M. Coll A.P. Stettler C. Hovorka R. 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