IMPROVED DIAGNOSIS OF TYPE 2 DIABETES AND TAILORING MEDICATIONS

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1 IMPROVED DIAGNOSIS OF TYPE 2 DIABETES AND TAILORING MEDICATIONS Dr Bidhu Mohapatra, MBBS, MD, FRACP Consultant Physician Endocrinology and General Medicine

2 Introduction 382 million people affected by diabetes worldwide 592 millions by 2035 Recent Australian survey: 5.4% adults over the age of 18 Type 2 diabetes is the fasted growing non-communicable disease Fourth largest disease burden Obesity is the strongest risk factor for type 2 diabetes Annual cost $14 billion

3 Jenny 46 year old female Abnormal FBG 6.4 mmol/l No past medical history Several vitamins but no prescription medications Father type 2 diabetes BMI 27.9 BP 121/80 mmhg

4 Jenny 75 gm OGTT FBG 6.5 2Hr Glu 8.5 HBA1C 6.4% Lipid profile: TC 7.2,HDL 5.6, HDL 1.0, TG 1.1 What next?

5 Diagnostic criteria of type 2 DM (ADS and RACGP) FBG > 7.0 mmol/l ( on two separate occasions ) 2 hr post prandial > 11.0 mmol/l ( on two separate occasions ) HBA1C > 6.5% (48 mmol/mol) ( on two separate occasions )

6 Screening and diagnosis of type 2 diagnosis RACGP guidelines 2014 FBG or RBG < 5.5 Diabetes unlikely Retest every 3 years

7 FBG > 7 or RBG > 11.1 Confirm with FBG or HBA1C FBG > 7 FBG HBA1C < 6.5 HBA1C > 6.5 Diabetes OGTT Life style and diet

8 HBA1C > 6.5 % Repeat FBG or HBA1C HBA1C > 6.5% FBG HBA1C < 6.5 FBG > 7.0 Diabetes OGTT life style changes

9 FBG mmol/l or RBG mmol/l OGTT

10 OGTT FBG < 6.1 FBG FBG < 7 FBG > 7.0 2h < 7.8 2h < 7.8 2h h > 11.1 No diabetes IFG IGT Diabetes excess macro vascular risk excess macro- and micro

11 Case -Jenny FBG 6.4 OGTT FBG 6.5, BG2h 8.5, HBA1C 6.4% Intensive life style modification weight loss increase physical activity Good compliance with recommendations Lost 6kg FBG Annual OGTT isolated IFG HBA1C Dyslipidemia improved

12 Prediabetes: stage between normal glucose level and clinical type 2 diabetes Diabetes is defined by the threshold level above which there is significant increase incident of retinopathy But cardiovascular events increases linearly at level way below the diabetes diagnosis level It suggest the disease before the official diagnosis of diabetes

13 Prediabetes Annual risk of progression to diabetes Normoglycemia: 0.7% per year Prediabetes: 5-10% per year Increase risk for macrovascular disease and retinopathy Finnish study and DPP : Lifestyle intervention - 58% reduction in the progression Metformin 31% reduction in the progression Metformin + Life style =no additional benefit

14 OGTT- what to tell the patient? More validated but less reproducible Affected bycarbohydrate intake 150gm carb per day for 3 days duration of fasting preceding the test- fasting after 2200 hour except water, no caffeine or smoking time of the day the test performed hour Activity during the test seated for 2 hours

15 What if OGTT is unreliable? Repeating the test at least in two circumstances: Marginally abnormal results and potential for incorrect preparation and administration of the test Marginally abnormal results and major implications in life (eg. Loss of job; difficulty obtaining insurance

16 Case - Jenny By age 54 Less diligence with life style changes Gained weight OGTT : FBG 6.8, BG2h 14, HBA1C 6.9% Repeat: FBG 8.2, BG2h 12.4 Lipids: TC 7.4, LDL 5.3, HDL 1.1, TG 2.1

17 Case- Jenny By age 54 Less diligence with life style changes Gained weight OGTT : FBG 6.8, BG2h 14, HBA1C 6.9% Repeat: BFG 8.2, BG2h 12.4 Lipids: TC 7.4, LDL 5.3, HDL 1.1, TG 2.1 Metformin, Statin and Aspirin BP in target, no microalbuminuria and retinopathy

18 Australian diabetes society treatment algorithm

19 Metformin- first line of treatment Well tolerated and effective HBA1C reduction 1.5% UKPDS Myocardial infarction risk reduction 39% Mortality reduction 36% Mechanism: reduction of hepatic glucose output Start low dose and then increase

20 Case - jenny 56 year of age Metformin 2gm daily Life style changes HBA1C 7.9 % FBG 8-9

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22 sulfonylureas Stimulates insulin secretion from pancreatic beta cells Risk of hypoglycemia, severe hypoglycemia rare Weight gain around 2-3 kg First generation sulfonylurea- tolbutamide increases mortality JAMA 1971

23 sulfonylureas Metaanalysis in type 2 diabetes on sulfonylurea use: - Increase risk of cardiovascular events but no major events Diabetes Obes Metab 2013 ADVANCE trial : - no increase CVD risk with the use of gliclazide-modified release NEJM 2008

24 Thiazolidinediones: PPAAR gamma agonist Insulin sensitizers Preserve beta cell function Durability of action Concerns: - Fractures - Weight gain - Fluid retention/heart failure - Bladder cancer

25 Rosiglitazone Metaanalysis of 42 studies Increase cardiovascular death : OR 1.64 ( ) NEJM 2007

26 PROactive trial: pioglitazone Secondary prevention of CVD 16% reduction of death, stroke and MI Lancet 2005

27 GLP-1 analogue- Mechanism of action

28 GLP 1 analogue Subcutaneous injections ( exenatide and liraglutide) Benefit: HBA1C reduction Post prandial hyperglycemia control Weight loss No hypoglycemia Neuroprotective effect and beneficial effect on BP, LVEF, HR Lancet 2014

29 GLP 1 analogue Concern: GI side effects pancreatitis

30 DPP-4 inhibitors

31 DPP-4 inhibitors: Gliptines Benefit: No hypoglycemia Weight neutral CRF safe with dose adjustment HBA1C reduction 1% Recent metaanalysis of RCTs: Trend towards increase risk of heart failure but no increase mortality

32 Pancreatic safety GLP1 agonist/dpp-4 inhibitors Trend towards increase acute pancreatitis But statistically non-significant Pancreatic cancer

33 SGLT-2 inhibitors: Dapagliflozin, canagliflozin, empagliflozine Increase renal glucose loss Type 2 diabetes SGLT-2 upregulated Benefit: Significant reduction of HBA1C Weight loss Improve lipid profile Systolic BP reduction by 10mmHg

34 SGLT-2 inhibitors May 2015 FDA warning Association between SGLT-2 inhibitors and DKA Euglycemic DKA Mechanism: fall of both plasma glucose and insulin increase endogenous glucose production Diabetes Care 2015

35 Empa-Reg outcome study Empagliflozin ( 10-25mg) Significant reduction in cardiovascular events/deaths and heart failure admissions NEJM 2015

36 Case Jenny HBA1C 7.9 Gliclazide slow release 120mg daily Metformin 2gm daily After 1 year HBA1C 7.8% She was advised for additional medication But she was reluctant and opted to try with diet Lost follow up

37 Case - jenny Represented 2 years later HBA1C 9.2 FBG 12.1 Lipid: TG1.2, TC 4.4, HDL 1.0,LDL 2.8 No urine microalbumin

38 Insulin therapy KISS principle It is the only therapy like to reduce HBA1C < 7 in patients with HBA1C > 8.5 Diabetes Care 2012 Safe and effective Single dose 0.2 units/kg, usually 10-20units to start with, then self titration Risk of hypoglycemia is lower compared to type 1 DM Weight gain 2-4 kg, likely if symptoms and glycosuria Oral agents insulin secretogogues can be discontinued

39 conclusion Progressive beta cell dysfunction has inevitable resulted in the need to add insulin to standard therapy in type 2 diabetes SGLT-2 inhibitors are effective adjunct to metformin/insulin with associated weight reduction Individualized approach using dietary weight loss strategy and the sequential addition of AHA remains the best practice for glycemic control of type 2 diabetes.

40 Thank you