Pharmacotherapy in Type 1 Diabetes

Abstract

Key Messages•Basal-bolus insulin regimens (e.g. multiple daily injections or continuous subcutaneous insulin infusion) are the insulin regimens of choice for all adults with type 1 diabetes.•Insulin regimens should be tailored to the individual’s treatment goals, lifestyle, diet, age, general health, motivation, hypoglycemia awareness status and ability for self-management.•All individuals with type 1 diabetes should be counseled about the risk, prevention and treatment of insulin-induced hypoglycemia. •Basal-bolus insulin regimens (e.g. multiple daily injections or continuous subcutaneous insulin infusion) are the insulin regimens of choice for all adults with type 1 diabetes.•Insulin regimens should be tailored to the individual’s treatment goals, lifestyle, diet, age, general health, motivation, hypoglycemia awareness status and ability for self-management.•All individuals with type 1 diabetes should be counseled about the risk, prevention and treatment of insulin-induced hypoglycemia. Insulin is lifesaving pharmacological therapy for people with type 1 diabetes. Insulin preparations are primarily produced by recombinant DNA technology and are formulated either as structurally identical to human insulin or as a modification of human insulin (insulin analogues) to alter pharmacokinetics. Human insulin and insulin analogues are preferred and used by most adults with type 1 diabetes; however, preparations of animal-sourced insulin are still accessible in Canada (1Health Canada website. www.hc-sc.gc.ca. Accessed February 28, 2013.Google Scholar). Insulin preparations are classified according to their duration of action and are further differentiated by their time of onset and peak actions (Table 1). Premixed insulin preparations are available and are not generally suitable for intensive treatment in patients with type 1 diabetes in whom frequent adjustments of insulin are required.Table 1Types of insulinInsulin type (trade name)OnsetPeakDurationBolus (prandial) insulins Rapid-acting insulin analogues (clear)Insulin aspart (NovoRapid®)10–15 min1–1.5 h3–5 hInsulin glulisine (Apidra®)10–15 min1–1.5 h3–5 hInsulin lispro (Humalog®)10–15 min1–2 h3.5–4.75 h Short-acting insulins (clear)Humulin®-R30 min2–3 h6.5 hNovolin® ge TorontoBasal insulins Intermediate-acting (cloudy)Humulin®-N1–3 h5–8 hUp to 18 hNovolin® ge NPH Long-acting insulin analogues (clear)Insulin detemir (Levemir®)90 minNot applicableUp to 24 h (glargine 24 h, detemir 16–24 h)Insulin glargine (Lantus®)Premixed insulins Premixed regular insulin–NPH (cloudy)Humulin® 30/70Novolin® ge 30/70, 40/60, 50/50A single vial or cartridge contains a fixed ratio of insulin (% of rapid-acting or short-acting insulin to % of intermediate-acting insulin) Premixed insulin analogues (cloudy)Biphasic insulin aspart (NovoMix® 30)Insulin lispro/lispro protamine (Humalog® Mix25 and Mix50)Physicians should refer to the most current edition of Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada) and product monographs for detailed information. Open table in a new tab Physicians should refer to the most current edition of Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada) and product monographs for detailed information. There may be a role for adjunctive therapy in some people with type 1 diabetes to aid in achieving optimal glycemic targets. Pharmacotherapy for prevention of complications and treatment of risk factors will be addressed in other chapters. Insulin can be administered by syringe, pen or pump (continuous subcutaneous insulin infusion [CSII]). Insulin pen devices facilitate the use of multiple injections of insulin. CSII therapy is a safe and effective method of intensive insulin therapy in type 1 diabetes and has shown improvements in glucose control over NPH-based regimens and, in fewer studies, over long-acting analogue regimens with less severe hypoglycemia (2Hoogma R.P. Hammond P.J. Gomis R. et al.Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial.Diabetic Medicine. 2005; 23: 141-147Crossref Scopus (216) Google Scholar, 3Misso M.L. Egberts K.J. Page M. et al.Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus.Cochrane Database Syst Rev. 2010; 1: CD005103PubMed Google Scholar). Advancements in basal insulins may lessen the value of CSII in type 1 diabetes. CSII may provide some advantages over other methods of intensive therapy, particularly in individuals with higher baseline glycated hemoglobin (A1C) (4Pickup J. Mattock M. Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials.BMJ. 2002; 324: 705Crossref PubMed Google Scholar, 5Tsui E. Barnie A. Ross S. et al.Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection.Diabetes Care. 2001; 24: 1722-1727Crossref PubMed Scopus (117) Google Scholar, 6DeVries J.H. Snoek F.J. Kostense P.J. et al.Dutch Insulin Pump Study GroupA randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control.Diabetes Care. 2002; 25: 2074-2080Crossref PubMed Scopus (166) Google Scholar, 7Hirsch I.B. Bode B.W. Garg S. et al.Insulin Aspart CSII/MDI Comparison Study GroupContinuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII.Diabetes Care. 2005; 28: 533-538Crossref PubMed Scopus (168) Google Scholar, 8Retnakaran R. Hochman J. DeVries J.H. et al.Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline A1c.Diabetes Care. 2004; 27: 2590-2596Crossref PubMed Scopus (185) Google Scholar, 9Monami M. Lamanna C. Marchionni N. Mannucci E. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 1 diabetes: a meta-analysis.Acta Diabetologica. 2010; 47: S77-S81Crossref PubMed Scopus (78) Google Scholar) In patients using CSII, insulin aspart and insulin lispro have been shown to be superior to regular insulin by improving postprandial glycemic control and reducing hypoglycemia (10Zinman B. Tildesley H. Chiasson J.L. et al.Insulin lispro in CSII: results of a double-blind crossover study.Diabetes. 1997; 46: 440-443Crossref PubMed Scopus (275) Google Scholar, 11Bode B. Weinstein R. Bell D. et al.Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes.Diabetes Care. 2002; 25: 439-444Crossref PubMed Scopus (140) Google Scholar, 12Radermecker R.P. Scheen A.J. Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness.Diabetes Metab Res Rev. 2004; 20: 178-188Crossref PubMed Scopus (78) Google Scholar, 13Siebenhofer A. Plank J. Berghold A. et al.Meta-analysis of short-acting insulin analogues in adult patients with type 1 diabetes: continuous subcutaneous insulin infusion versus injection therapy.Diabetologia. 2004; 47: 1895-1905Crossref PubMed Scopus (45) Google Scholar). Advances in continuous glucose monitoring systems (CGMSs) may augment CSII (14O'Connell M.A. Donath S. O'Neal D.N. et al.Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial.Diabetologia. 2009; 52: 1250-1257Crossref PubMed Scopus (186) Google Scholar, 15Bergenstal R.M. Tamborlane W.V. Ahmann A. et al.Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.N Engl J Med. 2010; 4: 311-320Crossref Scopus (719) Google Scholar). For CSII and CGMS, adverse events, cost and mortality data are lacking (3Misso M.L. Egberts K.J. Page M. et al.Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus.Cochrane Database Syst Rev. 2010; 1: CD005103PubMed Google Scholar). Patients with type 1 diabetes will be initiated on insulin therapy immediately at diagnosis. This will involve both the selection of an insulin regimen and the start of education. Patients must receive initial and ongoing education that includes comprehensive information on how to care for and use insulin; prevention, recognition and treatment of hypoglycemia; sick-day management; adjustments for food intake (e.g. carbohydrate counting) and physical activity; and self-monitoring of blood glucose (SMBG). Insulin regimens should be tailored to the individual’s treatment goals, lifestyle, diet, age, general health, motivation, hypoglycemia awareness status and ability for self-management. Social and financial aspects also should be considered. After insulin initiation, some patients go through a “honeymoon period,” during which insulin requirements may decrease. This period is, however, transient (usually weeks to months), and insulin requirements will increase with time. While fixed-dose regimens (conventional therapy) once were common and still may be used in some circumstances, they are not preferred. The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that intensive treatment of type 1 diabetes significantly delays the onset and slows the progression of microvascular and macrovascular complications (16The 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 (22708) Google Scholar, 17Nathan D.M. Cleary P.A. Backlund J.Y. et al.Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4136) Google Scholar). The most successful protocols for type 1 diabetes rely on basal-bolus (basal-prandial) regimens that are used as a component of intensive diabetes therapy. Basal insulin is provided by an intermediate-acting insulin or a long-acting insulin analogue once or twice daily. Bolus insulin is provided by a short-acting insulin or a rapid-acting insulin analogue given at each meal. Such protocols attempt to duplicate normal pancreatic insulin secretion. Prandial insulin dose must take into account the carbohydrate content and glycemic index of the carbohydrate consumed, exercise around mealtime and the fact that the carbohydrate-to-insulin ratio may not be the same for each meal (breakfast, lunch and dinner). Prandial insulins also can be used for correction doses to manage hyperglycemia. Compared with regular insulin, insulin aspart, insulin glulisine or insulin lispro, in combination with adequate basal insulin, results in improved postprandial glycemic control and A1C while minimizing the occurrence of hypoglycemia (when using insulin lispro or insulin aspart) (18DeWitt D.E. Hirsch I.B. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review.JAMA. 2003; 289: 2254-2264Crossref PubMed Scopus (455) Google Scholar, 19Siebenhofer A. Plank J. Berghold A. et al.Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.Cochrane Database Syst Rev. 2006; 2: CD003287PubMed Google Scholar, 20Heller S.R. Colagiuri S. Vaaler S. et al.Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with type1 diabetes.Diabet Med. 2004; 21: 769-775Crossref PubMed Scopus (95) Google Scholar, 21Plank J. Siebenhofer A. 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Groele L. Pankowska E. Long-acting insulin analogue detemir compared with NPH insulin in type 1 diabetes.Pol Arch Med Wewn. 2011; 121: 237-245PubMed Google Scholar). Given the potential severe consequences of nocturnal hypoglycemia (discussed below), the avoidance of this complication is of critical clinical importance. Patients report increased treatment satisfaction and quality of life with use of insulin glargine compared with use of NPH in a basal-bolus insulin regimen (38Chatterjee S. Jarvis-Kay J. Rengarajan T. et al.Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes: the Glargine and Aspart Study (GLASS): a randomized cross-over study.Diabetes Res Clin Pract. 2007; 77: 215-222Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 39Ashwell S.G. Bradley C. 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Busciantella N.R. et al.Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study.Diabetes Care. 2007; 30: 2447-2452Crossref PubMed Scopus (190) Google Scholar); however, 15% to 30% of patients using insulin glargine will experience preinjection hyperglycemia, which is prevented by twice daily administration of the insulin (41Ashwell S.G. Gebbie J. Home P.D. Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.Diabet Med. 2006; 23: 879-886Crossref PubMed Scopus (93) Google Scholar). Insulin detemir has a flatter pharmacodynamic profile than NPH insulin (33Plank J. Bodenlenz M. Sinner F. et al.A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.Diabetes Care. 2005; 28: 1107-1112Crossref PubMed Scopus (261) Google Scholar). Twice-daily insulin detemir as the basal component of a basal-bolus insulin regimen has been shown to reduce nocturnal hypoglycemia compared with twice-daily NPH insulin (34De Leeuw I. Vague P. Selam J.L. 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: 73-82Crossref PubMed Scopus (180) Google Scholar, 42Home P. Bartley P. Russell-Jones D. et al.Study to Evaluate the Administration of Detemir Insulin Efficacy, Safety and Suitability (STEADINESS) Study GroupInsulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial.Diabetes Care. 2004; 27: 1081-1087Crossref PubMed Scopus (250) Google Scholar). There has been a trend toward improved A1C with both insulin detemir and insulin glargine that has reached significance in several studies (36Monami M. Marchionni N. Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis.Diabetes Obes Metab. 2009; 11: 372-378Crossref PubMed Scopus (174) Google Scholar, 38Chatterjee S. Jarvis-Kay J. Rengarajan T. et al.Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes: the Glargine and Aspart Study (GLASS): a randomized cross-over study.Diabetes Res Clin Pract. 2007; 77: 215-222Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 42Home P. Bartley P. Russell-Jones D. et al.Study to Evaluate the Administration of Detemir Insulin Efficacy, Safety and Suitability (STEADINESS) Study GroupInsulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial.Diabetes Care. 2004; 27: 1081-1087Crossref PubMed Scopus (250) Google Scholar, 43Hermansen K. Fontaine P. Kukolja K.K. et al.Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes.Diabetologia. 2004; 47: 622-629Crossref PubMed Scopus (358) Google Scholar, 44Kudva Y.C. Basu A. Jenkins G.D. et al.Randomized controlled clinical trial of glargine versus ultralente insulin in the treatment of type 1 diabetes.Diabetes Care. 2005; 28: 10-14Crossref PubMed Scopus (29) Google Scholar, 45Ashwell S.G. Amiel S.A. Bilous R.W. et al.Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with type 1 diabetes.Diabet Med. 2006; 23: 285-292Crossref PubMed Scopus (101) Google Scholar, 46Bartley P.C. 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-treat basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial.Diabet Med. 2008; 25: 442-449Crossref PubMed Scopus (128) Google Scholar). Due to concerns that alterations in the pharmacokinetics may occur, mixing detemir or glargine with other insulins in the same syringe is not recommended by the manufacturers. An ultra-long-acting insulin analogue, insulin degludec, has been shown to have comparable safety and tolerability to insulin glargine when used as a basal insulin in type 1 diabetes and less hypoglycemia (47Birkeland K.I. Home P.D. Wendisch U. et al.Insulin degludec in type 1 diabetes. A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine.Diabetes Care. 2011; 34: 661-665Crossref PubMed Scopus (151) Google Scholar). As the incidents of obesity and overweight increase in the population, including those with type 1 diabetes, there is increasing interest in the potential use of oral medications that improve insulin sensitivity for these patients. The use of metformin in type 1 diabetes reduces insulin requirements and the total cholesterol/low-density lipoprotein ratio and may lead to modest weight loss, but it does not result in improved A1C (48Vella S. Buetow L. Royle P. et al.The use of metformin in type 1 diabetes: a systematic review of efficacy.Diabetologia. 2010; 53: 809-820Crossref PubMed Scopus (163) Google Scholar). Metformin use in type 1 diabetes is off-label and potentially harmful in the setting of renal or heart failure. Insulin-induced hypoglycemia is a major obstacle for individuals trying to achieve glycemic targets. Hypoglycemia can be severe and result in confusion, coma or seizure, requiring the assistance of other individuals. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. The negative social and emotional impact of hypoglycemia may make patients reluctant to intensify therapy. The diabetes healthcare team should review the patient’s experience with hypoglycemia at each visit. This should include an estimate of cause, frequency, symptoms, recognition, severity and treatment, as well as the risk of driving mishaps with hypoglycemia. Hypoglycemia is the most common adverse effect of intensive insulin therapy in patients with type 1 diabetes. In the DCCT, 35% of patients in the conventional treatment group and 65% in the intensive group experienced at least 1 episode of severe hypoglycemia (49The Diabetes Control and Complications Trial Research GroupAdverse events and their association with treatment regimens in the Diabetes Control and Complications Trial.Diabetes Care. 1995; 18: 1415-1427Crossref PubMed Scopus (328) Google Scholar, 50The Diabetes Control and Complications Trial Research GroupHypoglycemia in the Diabetes Control and Complications Trial.Diabetes. 1997; 46: 271-286Crossref PubMed Google Scholar). In a meta-analysis of 14 trials, the median incidence of severe hypoglycemia was 4.6 and 7.9 episodes per 100 patient-years in the conventionally treated and intensively treated patients, respectively (51Egger M. Davey Smith G. Stettler C. et al.Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis.Diabet Med. 1997; 14: 919-928Crossref PubMed Scopus (116) Google Scholar). Studies have suggested that with adequate self-management education, appropriate glycemic targets, SMBG and professional support, intensive therapy may result in less hypoglycemia than reported in the DCCT (52Fanelli C.G. Epifano L. Rambotti A.M. et al.Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM.Diabetes. 1993; 42: 1683-1689Crossref PubMed Google Scholar, 53Bott S. Bott U. Berger M. et al.Intensified insulin therapy and the risk of severe hypoglycaemia.Diabetologia. 1997; 40: 926-932Crossref PubMed Scopus (183) Google Scholar, 54Ahern J. Tamborlane W.V. 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Freeman S.C. Sutton A.J. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data.BMJ. 2011; 343: d3805Crossref PubMed Scopus (440) Google Scholar). Although there are no differences in the magnitude and temporal pattern of the physiological, symptomatic and counterregulatory hormonal responses to hypoglycemia induced by regular human insulin or rapid-acting analogues (59Torlone E. Fanelli C. Rambotti A.M. et al.Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28), Pro(B29)] in IDDM.Diabetologia. 1994; 37: 713-720Crossref PubMed Scopus (150) Google Scholar, 60McCrimmon R.J. Frier B.M. Symptomatic and physiological responses to hypoglycaemia induced by human soluble insulin and the analogue lispro human insulin.Diabet Med. 1997; 14: 929-936Crossref PubMed Scopus (22) Google Scholar), the frequency of hypoglycemic events has been shown to be reduced with rapid-acting insulin analogues compared with regular insulin (18DeWitt D.E. Hirsch I.B. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review.JAMA. 2003; 289: 2254-2264Crossref PubMed Scopus (455) Google Scholar, 19Siebenhofer A. Plank J. Berghold A. et al.Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.Cochrane Database Syst Rev. 2006; 2: CD003287PubMed Google Scholar, 20Heller S.R. Colagiuri S. Vaaler S. et al.Hypoglycaemia with insulin aspa