Macro- and Microvascular Outcomes in Patients with Type 2 Diabetes Treated with Rapid-Acting Insulin Analogues or Human Regular Insulin: a Retrospective Database Analysis

Abstract

Aims:

To investigate the risk of macro- and microvascular complications in patients with type 2 diabetes receiving rapid-acting insulin analogues (IA) or human regular insulin (HI).

Methods:

General practice diabetes patients with continuous prescription of any IA or HI for ≥3 years were selected from the German Disease Analyzer database (IMS Health). Logistic and Cox regression models were applied to analyze the incidence and time to onset of vascular outcomes (IA vs. HI).

Results:

2764 patients on IA (insulin lispro, glulisine, aspart) and 4193 patients on HI were included (age, mean [SD]: 61.0 [11.3] and 64.7 [10.5] years, follow-up [Q1,Q3]: 4.6 [3.7,6.1] and 4.7 [3.7,5.9] years). No significant differences were detected between IA and HI regarding the incidence of vascular complications (OR [95%CI]: macrovascular 0.92 [0.72–1.18], microvascular 0.95 [0.77–1.17]) or regarding time to their onset, after adjustment for sex, age, comorbidities and time on IA/HI, or by propensity-score-based matching. However, in an additional short-term analysis (median [Q1,Q3] follow-up (IA 2.9 [1.2,4.6], HI 2.4 [0.8,4.4] years) of a larger sample (no continuous insulin treatment required) with more comorbidities, time to onset of macrovascular complications was significantly longer for AI than HI (HR 0.88 [0.81–0.97], p=0.009; microvascular complications: no difference).

Conclusions:

After long-term continuous treatment with IA or HI under real-life conditions, there was no different risk of macro- or microvascular complications, contradicting previous short-term analyses. Further prospective studies are needed to clarify whether selection bias may have been introduced by using strict entry criteria.

Key words

diabetes - cardiovascular risk management - insulin

• References

• 1 Howey DC, Bowsher RR, Brunelle RL et al. [Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin. Diabetes 1994; 43: 396-402
• 2 Giugliano D, Ceriello A, Razzoli E et al. Defining the role of insulin lispro in the management of postprandial hyperglycaemia in patients with type 2 diabetes mellitus. Clin Drug Investig 2008; 28: 199-210
• 3 Plank J, Siebenhofer A, Berghold A et al. Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Arch Intern Med 2005; 165: 1337-1344
• 4 Institute for Quality and Efficiency in Health Care (IQWIG). Rapid-acting insulin analogues for the treatment of diabetes mellitus type 2. Final report. [Assignment No. A05-04]; 2006 Available from: https://www.iqwig.de/download/A05-04_Abschlussbericht_Kurzwirksame_Insulinanaloga_bei_Typ_2_Diabetes_mellitus.pdf
• 5 Singh SR, Ahmad F, Lal A et al. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 2009; 180: 385-397
• 6 Koivisto VA. The human insulin analogue insulin lispro. Ann Med 1998; 30: 260-266
• 7 Malone JK, Woodworth JR, Arora V et al. Improved postprandial glycemic control with Humalog Mix75/25 after a standard test meal in patients with type 2 diabetes mellitus. Clin Ther 2000; 22: 222-230
• 8 DCCT Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329: 977-986
• 9 Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103-117
• 10 Shichiri M, Kishikawa H, Ohkubo Y et al. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000; 23 (Suppl. 02) B21-B29
• 11 Adler AI, Stratton IM, Neil HA et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405-412
• 12 DECODE Study Group . Glucose tolerance and cardiovascular mortality. Comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 2001; 161: 397-405
• 13 Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-393
• 14 Nathan DM, Cleary PA, Backlund JY et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group . Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-2653
• 15 Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 2003; 26: 881-885
• 16 Coutinho M, Gerstein HC, Wang Y et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233-240
• 17 Cavalot F, Pagliarino A, Valle M et al. Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study. Diabetes Care 2011; 34: 2237-2243
• 18 Raz I, Ceriello A, Wilson PW et al. Post hoc subgroup analysis of the HEART2D trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia. Diabetes Care 2011; 34S: 1511-1513
• 19 Kress S, Kostev K, Dippel FW et al. Micro- and macrovascular outcomes in Type 2 diabetic patients treated with insulin glulisine or human regular insulin: a retrospective database analysis. Int J Clin Pharmacol Ther 2012; 50: 821-829
• 20 Rathmann W, Kostev K. Lower incidence of recorded cardiovascular outcomes in patients with type 2 diabetes using insulin aspart versus those on human regular insulin: observational evidence from general practices. Diabetes Obes Metab 2013; 15: 358-363
• 21 Rathmann W, Kostev K, Gruenberger JB et al. Treatment Persistence, Hypoglycemia, and Clinical Outcomes in Type 2 Diabetes Patients with DPP-4 Inhibitors and Sulfonylureas: A Primary Care Database Analysis. Diabetes Obes Metab 2012; 2013; 15: 55-61
• 22 Charlson ME, Pompei P, Ales KL et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987; 40: 373-383
• 23 Cammarota S, Bruzzese D, Catapano AL et al. A large-scale longitudinal population-based study of risk reduction of cardiovascular complications in patients on bolus insulin analogues. Abstract. Value in Health 2012; 15: A495
• 24 Raz I, Wilson PW, Strojek K et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 2009; 32: 381-386
• 25 Bolli GB, Di Marchi RD, Park GD et al. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia 1999; 42: 1151-1167
• 26 ORIGIN Trial Investigators . Gerstein HC, Bosch J, Dagenais GR et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-328
• 27 NAVIGATOR Study Group . Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events. N Engl J Med 2010; 362: 1463-1476
• 28 Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-1589