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10-28-2017 | Hypoglycemia | Review | Article

Reporting Severe Hypoglycemia in Type 1 Diabetes: Facts and Pitfalls

Journal: Current Diabetes Reports

Authors: Ulrik Pedersen-Bjergaard, Birger Thorsteinsson

Publisher: Springer US

Abstract

Purpose of Review

To describe potential factors influencing reporting of severe hypoglycemia in adult patients with type 1 diabetes and to analyze their effect on reported rates of severe hypoglycemia.

Recent Findings

Reported rates of severe hypoglycemia defined as need for third party assistance vary between 0.3–3.0 events per patient-year in unselected cohorts, corresponding to a yearly prevalence range of 10–53%. When defined as need for parenteral therapy with glucose or glucagon or need for admission to an emergency unit or hospitalization, incidence and prevalence rates of severe hypoglycemia are 0.02–0.5 events per patient-year and 1–29%, respectively. When subjects with recurrent severe hypoglycemia in the past or suffering from impaired hypoglycemia awareness are excluded from participation in studies, lower rates are reported. Studies applying anonymous reporting or reporting by partners report higher rates of severe hypoglycemia.

Summary

There is a large variation between studies reporting incidence and prevalence of severe hypoglycemia in patients with type 1 diabetes, mainly explained by definition of severity, methods of reporting, and patient selection. These findings call for consensus about hypoglycemia definition and reporting in future research.
Literature
1.
Cryer PE. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes. 1994;43:1378–89.CrossRefPubMed
2.
Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57:3169–76.CrossRefPubMedPubMedCentral
3.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab. 2013;98:1845–59.CrossRefPubMed
4.
Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabetic Med. 1990;7:711–7.CrossRefPubMed
5.
Whipple AO. The surgical therapy of hyperinsulinism. J Int Chir. 1938;3:237–76.
6.
• Pedersen-Bjergaard U, Kristensen PL, Beck-Nielsen H, Nørgaard K, Perrild H, Christiansen JS, et al. Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. Lancet Diabetes Endocrinol. 2014;2:553–61. The first 2-year cross-over insulin trial in type 1 diabetes patients with recurrent severe hypoglycaemia, making extraction of crucial individual treatment effects possible. CrossRefPubMed
7.
Goldgewicht C, Slama G, Papoz L, Tchobroutsky G. Hypoglycaemic reactions in 172 type 1 (insulin-dependent) diabetic patients. Diabetologia. 1983;24:95–9.CrossRefPubMed
8.
Casparie AF, Elving LD. Severe hypoglycemia in diabetic patients: frequency, causes, prevention. Diabetes Care. 1985;8:141–5.CrossRefPubMed
9.
Mühlhauser I, Berger M, Sonnenberg G, Koch J, Jörgens V, Schernthaner G, et al. Incidence and management of severe hypoglycemia in 434 adults with insulin-dependent diabetes mellitus. Diabetes Care. 1985;8:268–73.CrossRefPubMed
10.
Ward CM, Stewart AW, Cutfield RG. Hypoglyceamia in insulin dependent diaebtic patients attending an outpatients’ clinic. N Z Med J. 1990;103:339–41.PubMed
11.
Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabetic Med. 1991;8:217–22.CrossRefPubMed
12.
Mühlhauser I, Heinemann L, Fritsche E, von Lennep K, Berger M. Hypoglycemia symptoms and frequency of severe hypoglycemia in patients treated with human and animal insulin preparations. Diabetes Care. 1991;14:745–9.CrossRefPubMed
13.
MacLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabetic Med. 1993;10:238–45.CrossRefPubMed
14.
EURODIAB IDDM Complications Study Group. Microvascular and acute complications in IDDM patients: the EURODIAB IDDM complications study. Diabetologia. 1994;37:278–85.CrossRef
15.
Bott S, Bott U, Berger M, Mühlhauser I. Intensified insulin therapy and risk of severe hypoglycaemia. Diabetologia. 1997;40:926–32.CrossRefPubMed
16.
Mühlhauser I, Overmann H, Bender R, Bott U, Berger M. Risk factors of severe hypoglycaemia in adult patients with type 1 diabetes—a prospective population based study. Diabetologia. 1998;41:1274–82.CrossRefPubMed
17.
ter Braak EWMT, Appelman AMMF, van de Laak MF, Stolk RP, van Haeften TW, Erkelens DW. Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia. Diabetes Care. 2000;23:1467–71.CrossRefPubMed
18.
Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B. Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus. Lancet. 2001;357:1248–53.CrossRefPubMed
19.
Jørgensen HV, Pedersen-Bjergaard U, Rasmussen AK, Borch-Johnsen K. The impact of severe hypoglycemia and impaired awareness of hypoglycemia on relatives of patients with type 1 diabetes. Diabetes Care. 2003;26:1106–9.CrossRefPubMed
20.
Bragd J, Adamson U, Lins P-E, Wredling R, Oskarson P. A repeated cross-sectional survey of severe hypoglycaemia in 178 type 1 diabetes mellitus patients performed in 1984 and 1988. Diabetic Med. 2003;20:216–9.CrossRefPubMed
21.
Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B. Prediction of severe hypoglycaemia by angiotensin-converting enzyme activity and genotype in type 1 diabetes. Diabetologia. 2003;46:89–96.CrossRefPubMed
22.
Pedersen-Bjergaard U, Pramming S, Thorsteinsson B. Recall of severe hypoglycaemia and self-estimated state of awareness in type 1 diabetes. Diabetes Metab Res Rev. 2003;19:232–40.CrossRefPubMed
23.
Pedersen-Bjergaard U, Pramming S, Heller SR, Wallace T, Rasmussen ÅK, Jørgensen HV, et al. Severe hypoglycaemia in 1076 patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev. 2004;20:479–86.CrossRefPubMed
24.
Leckie AM, Graham MK, Grant JB, Ritchie PJ, Frier BM. Frequency, severity, and morbidity of hypoglycemia occurring in the workplace in people with insulin-treated diabetes. Diabetes Care. 2005;28:1333–8.CrossRefPubMed
25.
Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, et al. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabetic Med. 2005;22:749–55.CrossRefPubMed
26.
UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7.CrossRef
27.
Hermanns N, Kulzer B, Kubiak T, Krichbaum M, Haak T. The effect of an education programme (HyPOS) to treat hypoglycaemia problems in pateints with type 1 diabetes. Diabetes Metab Res Rev. 2007;23:528–38.CrossRefPubMed
28.
Hirai FE, Moss SE, Klein BEK, Klein R. Severe hypoglycemia and smoking in a long-term type 1 diabetic population. Wisconsin epidemiologic study of diabetic retinopathy. Diabetes Care. 2007;30:1437–41.CrossRefPubMed
29.
Nielsen LR, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER. Hypoglycemia in pregnant women with type 1 diabetes: predictors and role of metabolic control. Diabetes Care. 2008;31:9–14.CrossRefPubMed
30.
Hermanns N, Kulzer B, Krichbaum M, Kubiak T, Haak T. Long-term effect of an education program (HyPOS) on the incidence of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 2010;33:e36.CrossRefPubMed
31.
Færch L, Pedersen-Bjergaard U, Thorsteinsson B. High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes. Scand J Clin Lab Invest. 2011;71:620–4.CrossRefPubMed
32.
Kristensen PL, Hansen LS, Jespersen MJ, Pedersen-Bjergaard U, Beck-Nielsen H, Christiansen JS, et al. Insulin analogues and severe hypoglycaemia in type 1 diabetes. Diabetes Res Clin Pract. 2012;96:17–23.CrossRefPubMed
33.
Hermanns N, Kulzer B, Ehrmann D, Bergis-Jurgan N, Haak T. The effect of a diabetes education programme (PRIMAS) for people with type 1 diabetes: results of a randomized trial. Diabetes Res Clin Pract. 2013;102:149–57.CrossRefPubMed
34.
Little SA, Walkinshaw E, Leelarathna L, Tan HK, Chapple O, Lubina-Solomon A, et al. Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 x 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes Care. 2014;37:2114–22.CrossRefPubMed
35.
Elliott J, Jacques RM, Kruger J, Campbell MJ, Amiel SA, Mansell P, et al. Substantial reductions in the number of diabetic ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to reduced costs after structured education in adults with type 1 diabetes. Diabetic Med. 2014;31:847–53.CrossRefPubMedPubMedCentral
36.
Li J, Yang D, Yan J, Huang B, Zhang Y, Weng J. For the Guangdong type 1 diabetes translational study group. Secondary diabetic ketoacidosis and severe hypoglycaemia in patients with established type 1 diabetes mellitus in China: a multicentre registration study. Diabetes Metab Res Rev. 2014;30:497–504.CrossRefPubMed
37.
Östenson CG, Geelhoed-Duijvestijn P, Lahtela J, Weitgasser R, Jensen MM, Pedersen-Bjergaard U. Self-reported non-severe hypoglycaemic events in Europe. Diabetic Med. 2014;31:92–101.CrossRefPubMed
38.
Peene B, D’Hooge D, Vandebrouck T, Mathieu C. Patient-reported frequency, awareness and patient-physician communication of hypoglycaemia in Belgium. Acta Clin Belgica. 2014;69:439–45.CrossRef
39.
Hendrieckx C, Halliday JA, Bowden JP, Colman PG, Cohen N, Jenkins A, et al. Severe hypoglycaemia and its association with psychological well-being in Australian adults with type 1 diabetes attending specialist tertiary clinics. Diabetes Res Clin Pract. 2014;103:430–6.CrossRefPubMed
40.
Dømgaard M, Bagger M, Rhee NA, Burton CM, Thorsteinsson B. Individual and societal consequences of hypoglycemia: a cross-sectional survey. Postgrad Med. 2015;127:438–45.CrossRefPubMed
41.
Frier BM, Jensen MM, Chubb BD. Hypoglycaemia in adults with insulin-treated diabetes in the UK: self-reported frequency and effects. Diabetic Med. 2015;33:1125–32.CrossRefPubMedPubMedCentral
42.
Giorda CB, Ozzello A, Gentile S, Aglialoro A, Chiambretti A, Baccetti F, et al. HYPOS-1 study group of AMD. Incidence and risk factors for severe and symptomatic hypoglycemia in type 1 diabetes. Results of the HYPOS-1 study. Acta Diabetol. 2015;52:845–53.CrossRefPubMed
43.
• Pedersen-Bjergaard U, Færch L, Allingbjerg M-L, Agesen R, Thorsteinsson B. The influence of new European Union driver’s license legislation on reporting of severe hypoglycemia by patients with type 1 diabetes. Diabetes Care. 2015;38:29–33. This study demonstrates that driver’s license legislation counteracts reporting of severe hypoglycaemia, thereby possibly impairing general traffic safety and threating patient-physician relationship. CrossRefPubMed
44.
Cariou B, Fontaine P, Eschwege E, Lièvre M, Gouet D, Huet D, et al. Frequency and predictors of confirmed hypoglycaemia in type 1 and insulin-treated type 2 diabetes mellitus patients in a real-life setting: results from the DIALOG study. Diabetes Metab. 2015;41:116–25.CrossRefPubMed
45.
Potter J, Clarke P, Gale EAM, Dave SH, Tattersall RB. Insulin-induced hypoglycaemia in an accident and emergency department: the tip of an iceberg? BMJ. 1982;285:1180–2.CrossRefPubMedPubMedCentral
46.
Basdevant A, Costagliola D, Lanöe JL, Goldgewicht C, Triomphe A, Metz F, et al. The risk of diabetic control: a comparison of hospital versus general practice supervision. Diabetologia. 1982;22:309–14.CrossRefPubMed
47.
Lüddeke H-J, Sreenan S, Aczel S, Maxeiner S, Yenigun M, Kozlovski P, et al. PREDICTIVETM—a global, prospective observational study to evaluate insulin detemir treatment in types 1 and 2 diabetes: baseline characteristics and predictors of hypoglycaemia from the European cohort. Diabetes Obes Metab. 2007;9:428–34.CrossRefPubMed
48.
Marre M, Pinget M, Gin H, Thivolet C, Hanaire H, Robert J-J, et al. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain: 52-week data from the PREDICTIVETM study in a cohort of French patients with type 1 or type 2 diabetes. Diabetes & Metabolism. 2009;35:469–75.CrossRef
49.
Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, et al. For the DARTS/MEMO collaboration. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes. Diabetes Care. 2003;26:1176–80.CrossRefPubMed
50.
Sämann A, Mühlhauser I, Bender R, Kloos C, Müller UA. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia. 2005;48:1965–70.CrossRefPubMed
51.
Sämann A, Lehmann T, Heller T, Müller N, Hartmann P, Wolf GB, et al. A retrospective study on the incidence and risk factors of severe hypoglycemia in primary care. Family Pract. 2013;30:290–3.CrossRef
52.
Weinstock RS, Xing D, Maahs DM, Michels A, Rickels MR, Peters AL, et al. For the T1D exchange clinic network. Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D exchange clinic registry. J Clin Endocrinol Metab. 2013;98:3411–9.CrossRefPubMed
53.
DCCT Research Group. Diabetes Controls and Complications Trial Research Group. The 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;329:977–86.CrossRef
54.
Zinman B, Ross S, Campos RV, Strack T. The Canadian lispro study group. Effectiveness of human ultralente versus NPH insulin in providing basal insulin replacement for an insulin lispro multiple daily injection regimen. Diabetes Care. 1999;22:603–8.CrossRefPubMed
55.
Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. For the U.S. study group of insulin glargine in type 1 diabetes. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care. 2000;23:639–43.CrossRefPubMed
56.
Vague P, Selam J-L, Skeie S, de Leeuw I, Elte JWF, Haahr H, et al. Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care. 2003;26:590–6.CrossRefPubMed
57.
Standl E, Lang H, Roberts A. The 12-month efficacy and safety of insulin detemir and NPH insulin in basal-bolus therapy for the treatment of type 1 diabetes. Diabetes Technol Ther. 2004;6:579–88.CrossRefPubMed
58.
Porcelatti F, Rossetti P, Pampanelli S, Fanelli CG, Torlone E, Scionti L, et al. Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with type 1 diabetes mellitus given meal-time lispro insulin. Diabetic Med. 2004;21:1213–20.CrossRef
59.
Russell-Jones D, Simpson R, Hylleberg B, Draeger E, Bolinder J. Effects of QD insulin detemir or neutral protamine Hagedorn on blood glucose control in patients with type 1 diabetes mellitus using a basal-bolus regimen. Clin Ther. 2002;26:724–36.CrossRef
60.
de Leeuw I, Vague P, Selam J-L, Skeie S, Lang H, Draeger E, et al. Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin. Diabetes Obes Metab. 2005;7:73–82.CrossRefPubMed
61.
Fulcher GR, Gilbert RE, Yue DK. Glargine is superior to neutral protamine Hagedorn for improving glycated haemoglobin and fasting blood glucose levels during intensive insulin therapy. Intern Med J. 2005;35:536–42.CrossRefPubMed
62.
Pieber TR, Treichel H-C, Hompesch B, Philotheou A, Mordhorst L, Gall M-A, et al. Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy. Diabetic Med. 2007;24:635–42.CrossRefPubMed
63.
Bartley PC, Bogoev M, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir compared to neutral protamine Hagedorn insulin in patients with type 1 diabetes using a treat-to-target basal–bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. Diabetic Med. 2008;25:442–9.CrossRefPubMedPubMedCentral
64.
Heller S, Koenen C, Bode B. Comparison of insulin detemir and insulin glargine in a basal–bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: a 52-week, multinational, randomized, open-label, parallel-group, treat-to-target noninferiority trial. Clin Ther. 2009;31:2086–97.CrossRefPubMed
65.
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN basal-bolus type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1489–97.CrossRefPubMed
66.
Gale EAM for the UK Trial Group. A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with type 1 diabetes on intensified insulin therapy. Diabetic Med. 2000;17:209–14.CrossRef
67.
Ferguson SC, Strachan MWJ, Janes JM, Frier BM. Severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia: a comparative study of insulin lispro and regular human insulin. Diabetes Metab Res Rev. 2001;17:285–91.CrossRefPubMed
68.
Bulsara MK, Holman CDJ, Davis EA, Jones TW. Evaluating risk factors associated with severe hypoglycaemia in epidemiology studies—what methods should we use? Diabetic Med. 2004;21:914–9.CrossRefPubMed
69.
Henriksen MM, Færch L, Thorsteinsson B, Pedersen-Bjergaard U. Long-term prediction of severe hypoglycemia in type 1 diabetes: is it really possible? J Diabetes Sci Technol. 2016;10:1230–5.CrossRefPubMedPubMedCentral
70.
Gold AE, MacLeod KH, Frier BM. Frequency of severe hypoglycaemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994;17:697–703.CrossRefPubMed
71.
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. Diabetes Care. 1995;18:517–22.CrossRefPubMed
72.
Høi-Hansen T, Pedersen-Bjergaard U, Thorsteinsson B. Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice. J Diabetes Complicat. 2010;24:392–7.CrossRefPubMed
73.
The DCCT Research Group. The Diabetes Controls and Complications Trial (DCCT): design and methodologic considerations for the feasibility phase. Diabetes. 1986;35:530–45.CrossRef
74.
The DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Controls and Complications Trial. Am J Med. 1991;90:450–9.CrossRef
75.
Hirsch IB, Bode B, Courreges J-P, Dykiel P, Franek E, Hermansen K, et al. Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes. Diabetes Care. 2012;35:2174–81.CrossRefPubMedPubMedCentral
76.
Mathieu C, Hollander P, Miranda-Palma B, Cooper J, Franek E, Russell-Jones D, et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab. 2013;98:1154–62.CrossRefPubMedPubMedCentral
77.
Bode BW, Buse JB, Fisher M, Garg SK, Marre M, Merker L, et al. Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN® basal-bolus type 1): 2-year results of a randomized clinical trial. Diabetic Med. 2013;30:1293–7.CrossRefPubMedPubMedCentral
78.
Davies MJ, Gross JL, Ono Y, Sasaki T, Bantwal G, Gall MA, et al. Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial. Diabetes Obes Metab. 2014;16:922–30.CrossRefPubMedPubMedCentral
79.
Heller S, Chapman J, McCloud J, Ward J. Unreliability of reports of hypoglycaemia by diabetic patients. BMJ. 1995;310:440.CrossRefPubMedPubMedCentral
80.
Worth R, Home PD, Johnston DG, Andersen J, Ashworth L, Burrin JM, et al. Intensive attention improves glycaemic control in insulin-dependent diabetes without further advantage from home blood glucose monitoring: results from a controlled trial. BMJ. 1982;285:1233–40.CrossRefPubMedPubMedCentral
81.
•• The International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2016;60:3–6. The most recent update on proposed glucose levels when reporting hypoglycaemia in clinical trials. CrossRef
82.
Elliott L, Fidler C, Ditchfield A, Stissing T. Hypoglycemia event rates: a comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. Diabetes Ther. 2016;7:45–60.CrossRefPubMedPubMedCentral
83.
Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab. 2014;16:193–205.CrossRefPubMed
84.
Food and Drug Administration. Guidance for industry, U.S. Department of Health and Human Services. Guidance for industry, Diabetes mellitus: Developing drugs and therapeutic biologics for treatment and prevention. 2008, March 3. https://​www.​fda.​gov/​ucm/​groups/​fdagov-public/​@fdagov-drugs-gen/​documents/​document/​ucm071624.​pdf. Assessed 3 March 2017.
85.
European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012, May 14. http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Scientific_​guideline/​2012/​06/​WC500129256.​pdf. Assessed 3 March 2017.

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