Endocrinologist faculty of Mazandaran university Dr.Ozra.Akha Endocrinologist faculty of Mazandaran university 2

Natural History of Type 2 Diabetes Progression Years from diagnosis -10 -5 5 10 15 Insulin resistance Insulin secretion Microvascular complications Macrovascular complications Pre-diabetes Type 2 diabetes (T2DM) Onset Diagnosis 3

T2DM is a progressive disease with β-cell function decrease over time Insulin secretion (%) in T2DM patients 100 Diagnosis IGT 75 Insulin initiation 50 PPBG 25 OADs* Basal initiation / titration Basal + prandial -8 -2 +2 +8 +14 Years Insulin-naive Insulin intensification Lebovitz. Diab Rev 1999;7:139. 4

Lessons from UKPDS: Better control in T2DM means fewer complications 1% reduction in HbA1c Risk reduction* -21% 1% Deaths from diabetes The UKPDS has proven that intensive glycemic control is strongly associated with significant clinical benefits for patients with T2DM. In an epidemiological analysis of the UKPDS cohort (n=3,642) every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of:1 Diabetes-related death (-21%) Myocardial infarction (-14%) Microvascular complications (-37%) Peripheral vascular disease (-43%). Reference Stratton IM, Adler AI, Neil AW et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412. -14% Myocardial Infarction -37% Microvascular complications -43% Peripheral vascular disorders *p<0.0001 n=3,642 type 2 diabetes patients 1. Stratton IM et al. BMJ 2000;321:405–412 5

Risk of Microvascular Complications vs. A1C in Type 1 Diabetes Results From the DCCT 20 Retinopathy progression Neuropathy progression 15 Relative risk Microalbuminuria progression 10 5 1 5 6 7 8 9 10 11 12 A1C (%) Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

The benefits of early tight control: UKPDS 10-year post-trial follow-up

Early Insulinization Prevents the Progressive β-cell Dysfunction Early intensive insulin therapy has favorable outcomes on recovery and maintenance of β-cell function compared with oral hypoglycemic agents Insulin provides a type of β-cell rest and reduce excessive secretory demands on damaged β-cell recovery and maintenance of β-cell function Weng JP et al. Lancet, 2008, 301:1753-1780

HbA1c targets in current guidelines ADA/EASD <7 IDF NICE <6.5 AACE ≤6.5 France Canada ≤7 Australia Latin America 9

Only around one-third of patients Only around one-third of patients* in developing countries achieve HbA1c <7% The International Diabetes Management Practice Study (IDMPS) Patients* with HbA1c <7% (%) *Patients with HbA1c test (36% of overall population) Chan JC, et al. Diabetes Care 2009;32:227–33. 10 10

Fewer than 5% of patients in developing countries achieve glycaemic and CV goals The International Diabetes Management Practice Study (IDMPS) Patients achieving goals (%)* *HbA1c <7%, blood pressure 130/80 mmHg, LDL-C <100 mg/dL Chan JC, et al. Diabetes Care 2009;32:227–33. 11 11

Clinical inertia: ‘Failure to advance therapy when recommended’ 10 9.6% Combination oral agents 8.9% 9 8.6% Mean HbA1c at last visit (%) SU or metformin Diet & exercise 8 ADA goal 7 2.5 years 2.9 years 2.8 years Years since initial diagnosis 8.2 years Initiation of insulin therapy Brown JB, et al. Diabetes Care 2004;27:1535–40. 12

Delaying insulinization results in increased A1C 10 Combination therapy Sulfonylurea or metformin monotherapy Insulin Diet/exercise 9 Mean A1C at last visit (%) 8 ADA/ EASD goal <7% 7 6 2 3 4 5 6 7 8 9 10 Diagnosis Years Brown JB, et al. Diabetes Care 2004;27:1535−40

Perceived burden of treating diabetes in experienced and inexperienced patients Lower Greater burden burden 0 1 2 3 4 5 6 Moderate diet Self-monitoring of blood glucose once a day Insulin once a day Combination bedtime insulin and daytime oral agents Self-monitoring of blood glucose three times a day Insulin twice a day Insulin twice a day+ self-monitoring of blood glucose three times a day Insulin 3- 4 times a day n=1653 Rating with experience Rating without experience Inexperienced patients perceived a greater burden of treating diabetes than experienced patients 2.0 1.8 2.6 2.4 3.5 3.1 3.7 4.7 4.3 4.9 4.1 5.1 5.2 Vijan et al. J Gen Intern Med 2005;20:479–82.

§Usually a basal insulin (NPH, glargine, detemir, degludec)

Combination Injectable Therapy

Stepwise management of T2DM + Diet & exercise Oral monotherapy Oral combination Oral plus insulin Insulin Biggest clinical hurdle??? Adapted from Williams G. Lancet 1994;343:95–100. 19 19 19

When is insulin initiated in T2DM Data from retrospective or longitudinal surveys (initiation of insulin not protocol driven) Before insulin initiation After insulin initiation (1–4 yrs) n = 272 n = 31 n = 735 n = 52 n = 883 Mean HbA1c (%HB) These data show the level of control at which insulin is initiated in type 2 diabetes. They are taken from either retrospective or prospective longitudinal surveys of various cohorts i.e. where the decision to start insulin was not determined by study protocols but rather reflected the decision-making of the patients’ carers. Typically, HbA1c was above 9% before insulin was started. Interestingly, many of the data are from the Netherlands where such surveys have been made to assess quality of life and treatment satisfaction changes. Also of interest, though speculative, is the observation that there is no evidence of improvement between the earliest and most recent surveys in terms of point of intervention. 20 20

Multinational, observational study of T2DM (66,726) ACHIEVE study: Insulin therapy started in routine clinical care when HbA1c 9.3–9.8%: China S. Asia E. Asia N. Africa Mid East Lat. Am. Russia n 9,493 21,107 9,062 3,623 11,971 1,032 2,954 Age (yrs) 55.7 51.7 56.5 58.3 52.8 59.6 59.2 T2DM (yrs) 7.9 6.7 12.5 11.4 10.2 15.5 9.6 Complications (%) 86.1 94.0 90.3 89.7 79.9 90.7 96.1 CV disease (%) 22.9 32.5 29.4 28.5 30.5 35.3 74.6 Renal disease (%) 26.1 28.7 34.6 36.5 43.6 41.8 41.7 Eye problems (%) 25.6 22.0 29.9 41.2 36.8 71.0 Foot ulcer (%) 2.5 6.5 5.8 3.5 8.7 7.7 5.1 Neuropathy (%) 33.7 40.1 38.9 56.0 47.6 84.4 Adjusted for age at diagnosis; Complications (%) predicted from a logistic model Complications already present in people with T2DM when initiating insulin therapy Zilov AV, et al. Diabetes 2011;60(Suppl.1):2485.

Clinical inertia: patient and physician barriers Peyrot et al. Diabetes Care 2005;28:2673–9; Elgrably et al. Diabet Med 1991;8:773–7; Wallace & Matthews. QJM 2000;93:369–74; Kunt & Snoek. Int J Clin Pract 2009;63(Suppl. 164):6–10

Barriers to insulin initiation Nakar et al. J Diabetes Complications 2007;21:220–6

Do not forget! The beneficial effects of early insulin therapy in T2DM on beta-cell function, micro/macrovascular morbidity and mortality, and total mortality.

Conclusions Achievement and maintenance of tight glycaemic control is of paramount importance The ‘reality’ is that this is not being achieved in daily clinical practice Regular monitoring of HbA1c and frequent assessment of treatment regimens are needed For most patients on a 3-monthly basis Failure to advance therapy when required, particularly insulin therapy, needs to be urgently addressed

Start Insulin At The Right Time! So, why not to do! Start Insulin At The Right Time! Adjust & Follow!

Thank You!