Starting Insulin Sooner Than Later

Transcription

1 Starting Insulin Sooner Than Later Rotorua GP Insulin Seminar 13 June 2014 Kingsley Nirmalaraj MBBS, FRACP, FACE Consultant Endocrinologist and Physician Tauranga Hospital/ Bay Endocrinology Ltd

2 Declaration Sanofi sponsored workshop- am receiving speaking fee

3 Agenda Global problem What is T2 DM? Diagnosis Natural History of Type 2 diabetes Does management of glycaemia matter? Self-monitoring of blood glucose (SMBG) ADA/EASD Guidelines for the treatment of hyperglycaemia in type 2 diabetes (DM 2) Treatment targets

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6 Global projections for the diabetes epidemic: (millions) World 2003 = 189 million 2025 = 324 million Increase 72% % % % % % % % Amos et al. Diabet Med 1997;14:S1 S85; Zimmet et al. Nature 2001;414:

7 NZ Statistics Estimated number of people diagnosed with diabetes now > 200,000 (predominantly T2). Further 100,000 with diabetes undiagnosed. Prevalence of diabetes in Māori and Pacific populations is 3x higher than among other NZ ers. T2D is increasingly being diagnosed in children and is related to obesity, but T1D is also increasing.

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9 Undiagnosed rate ratios Auckland Heart and Health Survey (2007) 1:2 1:3 1: Diabetes by ethicnity (%) new known 10.0 Age European Maori Pacific

10 People with diabetes are over represented as hospital inpatients

11 Diabetes Management Remains Suboptimal Over 40% of individuals with Type 2 had an HbA1c over 53(7%) NZ Get Checked data Over 90% of individuals with Type 1 had an HbA1c over 53 11

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14 Diagnosis HbA1c is the NZSSD-recommended diagnostic screening test for diagnosing diabetes. If it is not possible to measure HbA1c or there are concerns about its validity, then a fasting plasma glucose is recommended. HbA1c can be misleading in some circumstances. An oral glucose tolerance test (OGTT) should be used where there is uncertainty about the validity of HbA1c measures. NZ Primary Care Handbook 2012

15 Symptomatic Diagnostic Criteria HbA1c 50 mmol/mol and, if measured, fasting plasma glucose 7.0 mmol/l or random plasma glucose 11.1 mmol/l No further tests required Diabetes confirmed Asymptomatic HbA1c 50 mmol/mol and, if measured, fasting plasma glucose 7.0 mmol/l or random plasma glucose 11.1 mmol/l Repeat HbA1c or a fasting plasma glucose 2 results above the diagnostic cut-offs, on separate occasions, are required for the diagnosis of diabetes

16 Asymptomatic Diagnostic Criteria HbA1c mmol/mol and, if measured, fasting plasma glucose mmol/l Advise on diet and lifestyle modification. If over 35 years a full cardiovascular risk assessment and appropriate management is indicated. Repeat the test after 6-12 months. Results indicate prediabetes or impaired fasting glucose. HbA1c 40 mmol/mol and, if measured, fasting plasma glucose 6.0 mmol/l Retest at the next cardiovascular reassessment interval. This result is normal.

17 Discordant Results When HbA1c and fasting plasma glucose are discordant with regard to dx of diabetes, repeat test in 3-6 months. Repeat test that is above the diagnostic cut-point. If 2 nd test remains above diagnostic threshold then diabetes is confirmed. If 2 nd result is discordant with the first, then subsequent repeat testing at 3-6 months intervals. NZ Primary Care Handbook 2012

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19 Insulin secretion Age, weight, sedentary Insulin resistance Age, genes, glucose

20 HOMA (%) -Cell Function & Glycaemic Control in DM2 A1C 100 As -cell function declines 10 hyperglycemia increases over time Diet/conv Rx (n=376) Metformin (n=159) SU/intensive (n=511) Years 7 6 Diet/conv Rx (n=297) Metformin (n=251) SU/intensive (n=695) Years UKPDS=United Kingdom Prospective Diabetes Study; SU=sulfonylurea. Reprinted UK Prospective Diabetes Study Group 16. Diabetes. 1995;44:

21 ADOPT study- Monotherapy failure at 5 years

22 But, does glucose control prevent CVD? How long does the investment take to pay the dividend?

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25 Cumulative Incidence DCCT-EDIC: Long-term Risk of Macrovascular Complications 12% Conventional Any Cardiovascular Outcome Hemoglobin A 1C 10% 8% Intensive 42% risk reduction P = 0.02 Conventional 6% P < P < P = 0.61 Intensive DCCT End of Randomized Treatment EDIC Year 1 EDIC Year Years Since Entry* *Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years. **There is a metabolic memory of good glucose control. Nathan DM, et al. N Engl J Med. 2005;353: Copyright 2005 Massachusetts Medical Society. All rights reserved.

26 Cumulative incidence of CVD events (%) Steno-2 Post Trial: Any CVD events Cumulative incidence of patients with a major CVD event during follow-up HR 0.41, P= Years of follow-up Numbers at risk Conventional Intensive Gaede et al. NEJM 2008

27 ACCORD & ADVANCE Decreased microvascular complications in intensive Rx. Lower rates of CV event than predicted studies. (Secondary to high levels of statins use, BP control, ASA usage, smoking cessation? No statistical difference in composite CV outcome Trend towards decreased CV events in intensive arm But, increased mortality in intensive arm of ACCORD only-why? ACCORD vs. ADVANCE patients Longer duration of diabetes (by 2 yrs) in ACCORD Worse DM (more patients already on insulin & with higher baseline) More obese with greater weight gain through the study Higher usage of TZDs and insulin HBA1c was lowered more rapidly in ACCORD vs. ADVANCE (<1yr vs >1 yr) Much higher rate of severe hypoglycaemia**

28 Intensive N (%) Standard N (%) HR (95% CI) P Primary 352 (6.86) 371 (7.23) 0.90 ( ) 0.16 Secondary Mortality 257 (5.01) 203 (3.96) 1.22 ( ) 0.04 Nonfatal MI 186 (3.63) 235 (4.59) 0.76 ( ) Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 ( ) 0.74 CVD Death 135 (2.63) 94 (1.83) 1.35 ( ) 0.02 CHF 152 (2.96) 124 (2.42) 1.18 ( ) 0.17

29 Subset Analysis Significant decrease in CV events in those with: Shorter duration of DM Absence of known CV disease Higher risk of mortality in those with: Severe hypoglycaemia (& higher HBA1c?) (Hypoglycaemia unawareness is associated with cardiovascular autonomic neuropahty which is a strong risk factor for sudden death)

30 Intracellular hyperglycemia induces overproduction of superoxide, a ROS, at the mitochondrial level as a possible cause of the metabolic memory of hyperglycemic stress after glucose normalization by Endocrine Society Ceriello A et al. JCEM 2009;94:

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33 Glycaemic control: Targets FPG 4.5-6mmol/L Reach individual HbA target WITH SAFETY i.e. with reduced risk hypos PPG 6-8, upto 10mmol/L Individual Treatment GOAL Normoglycaemia HbA 1c <7% (53mmol/mol) New Zealand Guidelines Group December European Diabetes Policy Group International Diabetes Federation (Europe). A desktop guide to Type 2 diabetes mellitus. Diabetic Medicine 16 ( ). RACGP. Diabetes Management in General Practice 2005/6.

34 Most of Our Lives are Spent in the Postprandial State Postprandial state; Postabsorptive state; Fasting state Breakfast Lunch Dinner 0.00am 4.00am Breakfast Reference: Monnier L. Is postprandial glucose a neglected cardiovascular risk factor in type 2 diabetes? Eur J Clin Invest 2000;30(Suppl 2): 3-11.

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36 To normalise BG both FPG & PPG need to be controlled Most insulin is initiated when HbA 1c >8.5% % contribution to HbA 1c % 50% 45% 40% 70% 70% 50% 55% 60% 30% < >10.2 HbA 1c range (%) PPG FPG Adapted from Monnier L et al. Diabetes Care 2003;26:881 5

37 Self Monitoring of Blood Glucose (SMBG) HBA1c only provides information on average blood sugar. It will not tell you the range of blood sugars. SMBG is essential in treatment of DM. Analogy: It is hard to drive safely if you can t see where you are going.

38 HbA1c s are not created equal mmol/l HbA1c = 7.8% Breakfast Lunch Supper Over Night 68

39 HbA1c s are not created equal mmol/l HbA1c = 7.8% Breakfast Lunch Supper Over Night Example of someone on too much long/intermediate acting insulin & not enough prandial insulin who will need to snack in between meals & at bedtime to avoid hypoglycaemia. 69

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41 ADA & EASD Consensus Statement (2006 & revised in 2009) Management of hyperglycaemia in DM2 Algorithm. Goal HBA1c is < 53, 7.0% (IDF rec. < 48, 6.5%) Basis for anti-hyperglycaemic agent choice: Effectiveness in lowering glucose Effectiveness in decreasing complications Safety profile Ease of use & expense.

42 Diabetalogia :17-30

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44 Treatment Targets HBA1c < 53, 7.0 (< 48, 6.5 if it can be done safely) Pre-meal BS< hr pp BS < LDL < 2.5 < 2.0 (current NZ CV guidelines) < 1.8 for those with pre-existing CVD BP < 130/80 (if no renal impairment) < 125/75-80 (with proteinuria)

45 Clinical inertia is due to at least three problems: 1. overestimation of care provided 2. use of soft reasons to avoid intensification of therapy 3. lack of education, training, and practice organization aimed at achieving therapeutic goals Physicians will need to build into their practice a system of reminders and performance feedback to ensure necessary care. Work to meet Targets Phillips et al, Annals of Internal Medicine, 2001

46 Reach non-glycaemic targets BP & Lipids ASA & Smoking Cessation Key Points Diabetes is a major health problem with multiple complications (esp. Maori/Pacific and Asian populations) Set the patient up realistically for the future DM is a disease of insulin deficiency (& resistance in DM2) that naturally progresses with time Education on lifestyle/meds & their effects on BSLs so that glucose readings are interpretable to the patient. Don t delay in advancing treatment to reach glucose targets (to get rid of highs & lows) Metformin SU or Insulin

47 Early insulin can never be too early! EARLY INSULIN SAVES HEALTH; SAVES WEALTH Fight clinical inertia