Intensification after basal insulin in type 2 diabetes

Transcription

1 Earn 3 CPD Points online Intensification after basal insulin in type 2 diabetes Introduction Professor Martin Pfohl Chief Physician Bethesda Hospital Duisburg, Germany It is vital to advise the type 2 diabetic patient from the outset of the progressive nature of this condition, which will over time require insulin therapy and intensification of therapy, Professor Martin Pfohl, chief physician at Bethesda Hospital, Duisburg, pointed out at the start of his presentation to delegates attending the Sanofisponsored Intensification Summit held in Cape Town recently. Lowering HbA 1c in type 2 diabetes reduces the relative risk of complications (Figure 1). 1 While the current focus of diabetic discussion is the reduction of macrovascular disease, over the longer term the consequences of microvascular disease, such as nephropathy, are debilitating. Currently, two-thirds of our renal dialysis patients in Germany are type 2 diabetes patients with disease of longstanding duration in fact, achieving and maintaining glucose control in type 2 diabetes over years is much more challenging than glucose control in type 1 diabetes. Achieving and maintaining glucose control over years in type 2 diabetes is much more difficult than in type 1 diabetes. KEY MESSAGES Type 2 diabetes is a progressive disease that requires insulin intensification after several years of evolution of the condition The dose of basal insulin should be titrated for maximum efficacy before prandial insulin is introduced If, despite adequate titration, the patient is still not at target, addition of one dose of postprandial insulin at the main meal should be considered Basal plus, i.e. glargine once daily with glulisine once daily, demonstrates combined efficacy and safety As the disease progresses, a second injection of prandial insulin at the second main meal can be considered For patients with advanced type 2 diabetes who are still not at target, a basal bolus regimen should be considered This article was made possible by an unrestricted educational grant from Sanofi, which had no control over content. Basal bolus has superior efficacy to premixed insulin regimens. June

2 Efficacy of basal insulin as intensification therapy It is important to note that each individual patient has his own insulin need. A number of pivotal trials of basal insulin analogues, conducted more than 10 years ago, have shown the glucose-lowering effectiveness of these insulins when titration is optimised to deliver a fasting blood glucose (FBG) below 6mmol/l. 2-4 A variety of algorithms of intensification of basal insulin was used in these studies to reach an HbA 1c <7%, which was achieved in the majority of patients (Table 1). While the insulin dosages of glargine in randomised clinical trials were quite high, a recent real-world study showed that these can be much lower in everyday practice. This multicentre study of more than patients from the German/Austrian DPVwiss database showed that a mean daily basal insulin glargine dose of 0.29IU/kg achieved HbA 1c levels around 7%. 5 Lower daily insulin dosages in modern therapy are also as a result of continued concomitant therapy with metformin, DPP-4 inhibitors and GLP-1 receptor agonists. One of the first real-world studies with global input, involving patients from three continents, including some from South Africa, produced some interesting insights into how insulin therapy has evolved in clinical practice. This global study was of physician-selected therapy and was not randomised. The reduction in HbA 1c on insulin therapy was similar over the four years, regardless of whether patients were given basal, basal plus mealtime insulin, mealtime insulin or premixed insulin alone. 6 (HbA 1c dropped by about 2%.) Basal insulin alone resulted in less hypoglycaemia over three years of treatment than other regimens and persistence rates with insulin glargine were higher than with NPH or insulin detemir. 7 It s important to note that achieving a mean HbA 1c of 7% still means that approximately 50% of patients will be above target and will require intensification of insulin therapy with either a mealtime insulin added or a switch to premixed insulin. Reduction in relative risk (%) associated with a 1% fall in HbA 1c Any diabetesrelated endpoint 21% Diabetesrelated death 21% All-cause mortality 14% Microvascular disease Cataract extraction 19% Peripheral vascular disease Myocardial infarction 14% Stroke 12% 37% 43% p < vs. baseline; p = 0.035; Lower extremity amputation or fatal peripheral vascular disease Figure 1. Lowering HbA 1c reduces the relative risk of complications Table 1. Maximum insulin glargine efficacy is obtained following optimised titration Studies based upon commonly used glargine treatment algorithms Treat-To-Target 2 LANMET 3 INSIGHT 4 Target FBG 5.6mmol/l 5.6mmol/l 5.6mmol/l Algorithm +2 to +8 IU every week +2 IU or +4 IU every three days +1 IU every day HbA 1c reached Final insulin glargine dose (IU) June 2017

3 Insulin intensification In the face of progressive deterioration of β-cell function, the basal plus approach is suitable for patients whose HbA 1c control has slipped to between 7% and 9%, despite optimal titration of the basal insulin, and whose FBG is controlled close to, or at target of, 6mmol/l (Figure 2). The excess hyperglycaemia in these patients is largely due to postprandial hyperglycaemia. 8 Cultural and personal lifestyles are different and the clinician should assess the patient s mealtime routine and add prandial insulin at the main meal. If this is not possible, select breakfast as a target of postprandial control. Tips for the introduction of basal plus are summarised in Table 2. Basal Plus: once-daily basal insulin glargine plus once daily rapid-acting insulin glulisine (before main meal) Basal Bolus Additional prandial doses as needed Basal Plus Add basal insulin at main meal I am a great believer in the self-awareness and self-responsibility of patients to monitor and control their glucose levels after appropriate education Lifestyle changes Figure 2. Type 2 diabetes: a stepwise therapeutic escalation Basal Add basal insulin and titrate Oral agents Progressive deterioration of β-cell function Table 2. Clinical tips for basal plus introduction Add one injection of prandial insulin before the selected meal Start with 4U of glulisine and adjust by 2U every three days until blood glucose is in range (target <7mmol/l, two hours after main meal) Taper and discontinue sulphonylureas over time to allow the prandial insulin to replace the insulin secretagogues smoothly Advise the patient at the outset that the basal plus approach can be sufficient for a number of years, but a second/third prandial insulin may well be needed over time. The effectiveness of the basal plus approach in patients on insulin glargine, with a regular lifestyle and the introduction of insulin glulisine at either breakfast or the main meal, was seen in the OPAL study. 9 Thirtythree percent of patients in this study reached a strict target HbA 1c of less than 6.5%, although initial HbA 1c levels were not greatly elevated (a mean of 7.3%). An interesting study of basal plus control with insulin glargine plus glulisine, the ELEONOR trial, evaluated a telecare support approach compared to standard patient blood glucose monitoring and failed to show any benefit of this more intensive at-a-distance approach. I am a great believer in the self-awareness and self-responsibility of patients to monitor and control their glucose levels after appropriate education, Professor Pfohl noted. In this study 10 more than 50% of patients achieved an HbA 1c 7% with standard blood glucose monitoring. June

4 Transitioning from basal plus to basal bolus It is important to note that early in an individual s progression of type 2 diabetes (first 10 years), the stepwise addition of prandial insulin glulisine is an effective transition to the full basal bolus regimen frequently required in late-stage type 2 diabetes (20-30 years duration). In this early stage, the study 11 and the AT.LANTUS study 12 showed that the addition of a third prandial insulin injection achieved very little further benefit in HbA 1c reduction, as compared to two prandial injections (Figure 3) over a sixmonth period. In advanced type 2 diabetes, the basal bolus regimen is the most physiological insulin regimen. These patients with advanced type 2 diabetes are becoming fragile; they have frequently had at least one or two late diabetic complications and therefore the HbA 1c target range should be between 7% and 8.5% to reduce the risk of hypoglycaemia. Patients in this category of advanced disease require more precise basal bolus approaches. However, the prescribed prandial insulin dosage should not seek to cover the glucose excursion of the whole meal, but aim to cover about 70-80% of the postprandial blood glucose in order to limit the risk of hypoglycaemia. Stepwise addition of insulin glulisine to insulin glargine improves glycaemic control over 24 weeks 0 Insulin glargine + OHAs + Insulin glargine + OHAs + Insulin glargine + OHAs + insulin glulisine 1 (n = 64) 1 insulin glulisine 2 (n = 68) 1 prandial insulin 3 (n = 68) 1 HbA 1c (%) p < from baseline to endpoint (week 24) 1 Per protocol population Figure 3. The study 4 June 2017

5 The role of premixed insulin in intensification strategies Premixed insulin also provides an effective strategy for both insulin initiation and intensification. The use of premixed insulin in intensification strategies does, however, suffer from poor flexibility with an increased risk of hypoglycaemia when planned meal times are not adhered to. A recent open-label multicentre trial of patients with inadequately controlled type 2 diabetes (HbA 1c %) on premixed insulins requiring intensification were randomised to insulin glargine and three daily doses of insulin glulisine (basal bolus) or twice-daily premixed insulin. 13 These intensification regimens achieved similar glucose control and the difference was not very significant, Professor Pfohl noted. Symptomatic hypoglycaemia was, however, lower on the basal bolus regimen. The choice of which of these regimens is most suitable rests with the individual patient and the clinician. In my experience, younger patients want the flexibility of changing mealtimes that basal bolus insulin regimens offer, while older patients with a more settled daily routine are happy with the premixed insulins. Carbohydrate counting is not essential to basal bolus therapy in type 2 diabetes. 14 The key findings of these basal bolus studies are summarised below: Basal bolus is the gold standard regimen for patients with advanced type 2 diabetes Compared with premixed insulin, basal bolus therapy with glargine plus glulisine, three times daily, brings significantly more patients to target HbA 1c (47% vs 28%) with no increased risk of hypoglycaemia When both insulin glargine and glulisine are titrated optimally, basal bolus enables ~70% of patients to achieve an HbA 1c <7%. Switching from a premix-based insulin regimen to basal bolus The effect of switching from premixed insulin to basal bolus has been evaluated in the everyday clinical situation in primary care in the United Kingdom. 15 The HbA 1c of these patients was above 9% at the switch and after one year of insulin glargine and postprandial insulin glulisine, in the patients whose HbA 1c was above 10%, a reduction of 1.2% had been achieved with little change in body weight. A real-life clinical study in the USA looked at the efficacy and cost-effectiveness of the basal bolus approach relative to that of premixed insulin in type 2 diabetes patients requiring intensification therapy. 16 While the basal bolus approach resulted in better HbA 1c reduction, there was little difference in hypoglycaemia in these patients who were not too strictly controlled (i.e. who achieved an HbA 1c between 7% and 8%). It is important for the clinician to accept that insulin regimens can be switched and that this does not imply initial poor clinical judgement, but rather that patients needs change over time, Professor Pfohl concluded. June

6 References 1. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321(7258): Riddle MC, Rosenstock J, Gerich J, et al. The treat-totarget trial: randomised addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26(11): Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 2006; 49(3): Gerstein HC, Yale JF, Harris SB, et al. A randomised trial of adding insulin glargine vs avoidance of insulin in people with type 2 diabetes on either no oral glucoselowering agents or submaximal doses of metformin and/ or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) study. Diabet Med 2006; 23(7): Laubner K, Molz K, Kerner W, et al. Daily insulin doses and injection frequencies of neutral protamine Hagedorn (NPH) insulin, insulin detemir and insulin glargine in type 1 and type 2 diabetes: a multicenter analysis of patients from the German/Austrian DPV-wiss database. Diab Metab Res Rev 2014; 30(5): Home PD, Dain MP, Freemantle N, et al. Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents. Diabetes Res Clin Pract 2015; 108(2): Gordon J, Pockett RD, Tetlow AP, et al. A comparison of intermediate and long-acting insulins in people with type 2 diabetes starting isulin: an observational database study. Int J Clin Pract 2010; 64(12): Riddle M, Umpierrez G, DiGenio A, et al. Contributions of basal and postprandial hyperglycaemia over a wide range of A1G levels before and after treatment intensification in type 2 diabetes. Diabetes Care 2011; 34(12): Lankisch MR, Ferlinz KC, Leahy JL, et al. Introducing a simplified approach to insulin therapy in type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs. Diabetes Obes Metab 2008; 10(12): Del Prato S, Nicolucci A, Vespasiani G. Optimising basal plus insulin therapy in type 2 diabetes by telecare assistance for self-monitoring of blood glucose - the ELEONOR study. Diabetologia 2008; 51: S452-S Davidson MB, Raskin P, Tanenberg RJ, et al. A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. Endocrinol Pract 2011; 17(3): Davies M, Sinnassamy P, Storms F, et al. Insulin glarginebased therapy improves glycaemic control in patients with type 2 diabetes sub-optimally controlled on premixed insulin therapies. Diabetes Res Clin Pract 2008; 79(2): Fritsche A, Larbig M, Owens D, Häring HU. GINGER study group. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes-results of the GINGER study. Diabetes Obes Metab 2010; 12: Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes. Comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care 2008; 31(7): McEwan P, Gordon JP, Sharplin P, et al. PDB3 switching from premixed insulin to insulin glargine-based regimen improves glycaemic control in patients with type 1 or type 2 diabetes: a retrospective primary care-based analysis. Value in Health 2008; 11(6): A Lee F, Zhang Q, Mersey J, et al. Glycaemic control and costs with insulin glargine plus glulisine versus premix a randomized, prospective, observational study. Diabetologia 2008; 51(Suppl 1): S406. Earn CPD points online Visit Log in or register and start earning CPD points today. Certificates will be ed to you. 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, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com 6 June 2017