Earn 3 CPD : THERAPY IN TYPE 2 DIABETES Points online

This article was made possible by an unrestricted educational grant from Sanofi, which had no control over content. Insulins: Basal or premix insulin in type 2 diabetes management

When and how to introduce insulin

KEY MESSAGES

• Premixes/admixes of regular and NPH/lente insulin in the same syringe should never be used in type 1 1 diabetes patients or in type 2 diabetes of long duration targeting an HbA1c level of less than 7%. • Analogue premixes are the most popular insulins worldwide, but they also result in inadequate pran- dial insulin delivery and excess inter-prandial supply.

• Premixes therefore increase the risk of hypoglycaemia, while achieving similar HbA1c levels as other Professor Geremia Bolli insulin strategies.2,3 Department of Medicine, Endocrinology and Metabolism • With regard to the basal insulins, and – one is not superior to the University of Perugia, Italy other; but they are different and require different dosage regimens. • Ultra-long-acting insulins are on the horizon – such as , glargine U300 (concentrated insulin glargine) and LY2605541 (pegylated ). • Where NPH insulin is used as the basal insulin, explore opportunities to optimise therapy by (i) reduc- ing risk of nocturnal hypoglycaemia with self-monitoring protocols and a bedtime snack (ii) splitting the dose every six hours and, in patients with lower BMIs, not up-titrating too aggressively.

Poor control of type 2 diabetes and blood insights, was undertaken with older oral levels occurs over time due to drugs (, progressive loss of β-cell function. “The and , along with lifestyle meas- UKPDS study,4 which has provided key ures), yet I am unsure as to whether we

Figure 1. Glucose homeostasis

MAY 2014 1 INSULINS: INSULIN THERAPY IN TYPE 2 DIABETES

can prevent progressive deterioration with “Premixes do not exist in nature, nor do the new oral agents,” Professor Bolli said. they meet real insulin needs,” he said. “However, what is true then is true today: In a recent evaluation of the glycaemic at the time of diagnosis of type 2 diabetes, profiles of premixed aspart 30/70 versus the hidden history of developing diabetes human 30/70 insulin as administered by 300 has resulted in significant loss of pancre- type 1 and type 2 diabetes patients to achieve

atic β-cell function. This means that we HbA1c levels of 8%, the extent of hypogly- should be aggressive in terms of treating caemia late morning and late at night was

type 2 diabetes at the time of diagnosis.” evident.3 Major hypoglycaemic episodes Referring to the recent ADA/EASD guide- were fewer with the analogue premix lines for treating type 2 diabetes,5 Professor (BIAsp30), but the overall risk of hypogly- Bolli pointed out that the addition of insulin caemia did not differ significantly between to metformin at stage 2 of intensifying type the human and analogue premix. The risk of 2 diabetes treatment would be the focus of hypoglycaemia in type 2 diabetes on these his presentation. therapies is summarised in Table 1. In contrast, the INITIATE study7 of two How do we start and progress BIAsp30 insulin doses versus insulin glargine with insulin treatment? showed that the premix could achieve better

The major focus of insulin therapy is to treat HbA1c levels than the basal insulin. “This, the dysfunctional glucose control and restore however, occurred at a cost of significantly insulin function to physiological normality6 more hypoglycaemic events than with (Figure 1). “Glucose homeostasis in normal glargine,” Professor Bolli pointed out. “The hidden subjects is characterised by sharp insulin history of type spikes with a return to basal insulin levels in Evaluating insulin initiation pulses between meals (average plasma basal strategies 2 diabetes insulin levels are approximately 10 μU/ml),” A very recent study evaluated three strate- Professor Bolli noted. gies8 – twice-daily premix, basal plus one before diagnosis rapid-acting prandial insulin and thirdly, compels us to Initiation: Premixed insulins basal-bolus with up to three prandial injec- 1-3 Several studies have highlighted the limi- tions added. The HbA1c achieved with the act quickly in tations of premixed insulins, despite their premix and the basal-plus (glargine plus 1) treating these universal use. “The premixes are rigid, non- was identical, but incident hypoglycaemia flexible treatments; there is a greater risk of was very different after one year (Table 2). patients.” hypoglycaemia at the same HbA1c levels, “There was a doubling of episodes/ with increased variability in dose-delivery patient-year with premix as compared to due to the need to re-suspend NPH prior to basal insulin plus three prandial injections injection,” Professor Bolli pointed out. – a rather unexpected finding.”

Table 1. Hypoglycaemic events over 12 weeks in type 2 diabetic patients

BIAsp 30 BHI 30 (85 patients) (102 patients) Major episodes Total number of episodes in type 2 6 12 patients

Minor episodes Total number of episodes in type 2 184 170 patients

Table 2.

Incidence of hypoglycaemia <3.9mmol & (%) symptoms

Premix 72 (3.8) Basal plus 1 62.5 (4.2) Basal plus 3 60.1 (4.2)

Earn 3 CPD points at Overall hypoglycaemic event rate (event/ patient year) www.denovomedica.com Premix 12.2 (1.7) Click on Accredited Education Basal plus 1 7.1 (0.9) Programmes Basal plus 3 7.2 (1.0)

2 MAY 2014 INSULINS: INSULIN THERAPY IN TYPE 2 DIABETES

“In the now classic, 10-year-old study9 useful as basal insulins, but increased comparing insulin glargine to NPH insulin detemir doses are required in obese

mean HbA1c levels on treatment were simi- type 2 diabetes patients. “An excellent lar, but hypoglycaemic events were signifi- • NPH insulin is associated with more cantly reduced with glargine, particularly hypoglycaemic events than the ana- new study nocturnal hypoglycaemia,” Professor Bolli logue basal insulins provides pointed out. Hypoglycaemia is serious and has seri- “The new longer-acting basal insulins will evidence- ous consequences (Table 3). provide opportunities for better compli- based data With regard to basal insulins, Professor ance from patients, but clinicians will need Bolli summarised his evidence-based to assess their place in type 2 diabetes man- on initiating views as: agement as more data emerges from inter- and advancing • Insulin glargine and detemir are equally national trials,” Professor Bolli concluded. insulin Table 3. Harmful effects of hypoglycaemia strategies • Brain dysfunction • Seizures and associated injuries, e.g. fractures • Probable cause of long-term cognitive impairment in children for type 2 • In adults may provoke vascular events diabetes.”8 • Possible mechanism for ‘dead in bed’ syndrome

Conflict of interest (Over past 2 years) – Declared as receiving grants from Sanofi, Eli Lilly, Novartis, Roche Pharma, BMS, Menairini, Lifescan.

References: 1. Dimitriadis G, Gerich J. Effect of twice daily subcutaneous 6. Ciofetta M, Lalli C, Del Sindaco P, et al. Contribution administration of a long-acting somatostatin analog of postprandial versus interprandial blood glucose

on 24-hour plasma glucose profiles in patients with to HbA1c in type 1 diabetes on physiologic intensive insulin-dependent diabetes mellitus. Horm Metab Res therapy with lispro insulin at mealtime. Diabetes Care 1985; 17(10): 510-511. 1999; 22: 795-800. 2. Luzio S, Dunseath G, Peter R, et al. Comparison of the 7. Raskin P, Allen E, Hollander P, Lewin A, et al. Initiating and pharmacodynamics of biphasic insulin therapy in type 2 diabetes: a comparison of and insulin glargine in people with type 2 biphasic and basal insulin analogs. Diabetes Care 2005; diabetes. Diabetologia 2006; 49(6): 1163-1168. 28(2): 260-265. 3. Boehm BO, Home PD, Behrend C, et al. Premixed 8. Riddle MC, Rosenstock J, Vlajnic A, Gao L. Randomised insulin Aspart 30 vs. premixed human insulin 30/70 1-year comparison of three ways to initiate and advance twice daily: a randomized trial in type 1 and type 2 insulin for type 2 diabetes: twice-daily premixed insulin diabetic patients. Diabetic Med 2002; 19(5): 393-399. versus basal insulin with either basal-plus one prandial 4. UK Prospective Diabetes Study (UKPDS) Group. Effect insulin or basal-bolus up to three prandial injection. of intensive blood-glucose control with metformin Diabetes Obes Metab 2014; 16(5): 396-402. on complications in overweight patients with type 2 9. Fonseca V, Bell DS, Berger S, Thomson S, Mecca TE. A diabetes (UKPDS 34). Lancet 1998; 352(9131):854-65 comparison of bedtime insulin glargine with bedtime 5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management neutral Hagedorn insulin in patients with of hyperglycaemia in type 2 diabetes: A patient- type 2 diabetes: subgroup analysis of patients taking centered approach. Diabetes Care 2012; 35(6): 1364- once-daily insulin in a multicenter, randomized, parallel 1379. group study. Am J Med Sci 2004; 328(5): 274-280.

How to earn CPD points: Visit www.denovomedica.com, click on Accredited Educational Programmes, click on registration, then answer the relevant questionnaire. Your CPD certificate will be e-mailed to you CPD within a week.

Published by Disclaimer

The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medi- 70 Arlington Street, cal practitioners are referred to the product insert docu- Everglen, Cape Town, 7550 mentation as approved by relevant control authorities. Tel: (021) 976 0485 I [email protected]

MAY 2014 3