Michael Mansfield Consultant Leeds Teaching Hospitals

Transcription

1 Easing, fixing and avoiding diabetic hyperglycaemia: new drugs, new approaches Michael Mansfield Consultant Leeds Teaching Hospitals Declaration: no significant gifts, fees, funding from pharma

2 Topics: Metformin SGLT-2 GLP-1 related medicines New insulins Diabetes prevention Reversing diabetes What is the ideal diabetes treatment? to prevent diabetes occurring to get rid of the diabetes and stop it returning to stop the symptoms of diabetes to stop the peculiar complications of diabetes developing to abolish the increased risk of cardiovascular risk caused by diabetes to be easy to use, without side-effects and safe to be comparatively (and sustainably) affordable for the country

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4 Galega officinalis Goat s Rue, French Lilac, Italian Fitch Plant known from middle ages to improve symptoms of what we now know as diabetes. Galegine, related to guanidine, can lower blood glucose. Work related to this led to development of the biguanides in the 1950s Metformin Gastrointestinal side-effects occur in 25-30% of users Prolonged release metformin claimed to be less likely to cause side-effects: Post hoc observational studies, and seen only in patients switched standard prolonged

5 2016 GWAS to identify loci associated with response to metformin variation at rs in the gene SLC2A2 encodes GLUT2 facilitated glucose transporter C allele homozygotes 3.6mmol/mol greater HbA1c reduction than T allele homozygotes Ileal enterocyte carriers transport metformin from bowel in to portal circulation, eg Organic Cation Transporter 1 (OCT1) on the luminal cell surface. Loss of function variants of OCT1 gene associated with reduced response to metformin in healthy individuals, although no impact on HbA1c in reduction in t2dm This study: Using the GoDARTS database, examined predictors of metformin intolerance in relation to OCT1 function

6 Medications previously shown to inhibit OCT1 in vitro: Tricyclic antidepressants Diltiazem Spironolactone Clopidogrel Rosiglitazone Quinine Tramadol Proton pump inhibitors Verapamil Doxazosin Citalopram Codeine Metformin intolerant group were on average Older 68 v 58 years Lighter 83 v 92 kg Better controlled HbA 1 c 67 v 72 mmol/mol Also more likely to be female 56% v 40% Patients with two loss-of-function OCT1 alleles more than twice as likely to be intolerant and More likely to be co-prescribed an OCT1 inhibiting medicine 48% v 33% significantly these medicines

7 Tubular sodium-glucose cotransporters 180g glucose/day 160g glucose/day SGLT2 20g glucose/day SGLT1 0g glucose/day

8 Loss of function of SGLT: a sodium glucose co-transporter Mutations of SLC5A2 reduced function of SGLT2 familial renal glycosuria Inhibitors of SGLT2: Dapagliflozin Canagliflozin Empagliflozin Lower blood glucose principally by reducing glucose reabsorption by 30-70% The good: reduce blood glucose can help weight loss no risk of hypoglycaemia used alone evidence of cardiovascular risk reduction evidence of renal risk reduction The Bad: loss of effectiveness at egfr < 45 urinary infections & genital thrush increased urine volume beware euglycaemic DKA

9 Multinational placebo-controlled RCT Empagliflozin 10mg v 25mg v placebo 7020 t2dm pts, BMI < 40, GFR > 30 High cardiovascular risk ie MI, Unstable angina CAD on angiography Stroke or Peripheral arterial disease HbA1c between 53 and 86 mmol/mol Primary end-point: composite of cardiovascular death nonfatal (non-silent) MI non-fatal stroke First 12 weeks no change to background glucose-lowering therapy After 12 weeks adjust treatment according to local guidelines High use of lipid and antihypertensive medicines Median duration of treatment 2.6 years and of observation 3.1 years

10 Primary end-point: composite of cardiovascular death, nonfatal MI or Stroke At 3.1 yrs primary end-point in 12.1% on placebo 10.5% on empagliflozin 3 year NNT 63 Superiority p=0.04 HbA1c advantage of empagliflozin was about 3 to 5 mmol/mol during study Placebo group had fewer genital thrush events F: 2.6 v 10% M: 1.5 v 5% Empagliflozin lowered mean 24hour systolic BP by approx 4mmHg Diabetes Care 2015;38:

11 Reduction in incident or worsening nephropathy: 18.8 v 12.7% (3 year NNT 16) ie albuminuria, doubling creatinine, RRT Adjusted mean egfr empagliflozin years placebo schematic

12 Incretin-based treatment Insulin is secreted in response to rising serum glucose enhanced by incretin hormones inc GLP-1 and GIP GLP-1 and GIP produced in response to glucose in the intestine Incretin effect is blunted in type 2 diabetes

13 GLP-1 increases glucose-stimulated insulin secretion supresses post-prandial glucagon secretion slows gastric emptying may contribute to satiety in brain may promote beta cell health Injected GLP-1 analogs including action prolonging element exenatide and slow release (microsphere) exenatide liraglutide lixisenatide albiglutide (semaglutide) The good: reduce blood glucose can help weight loss no risk of hypoglycaemia used alone evidence of cardiovascular risk reduction The Bad: injection vomiting prior pancreatitis caution thyroid malignancy caution

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15 Plasma glucose concentration mmol/l

16 HbA1c mmol/mol 75 All on metformin plus: Glimepiride 42 =Last observation carried forward

17 All on metformin plus: Glimepiride

18 R = Number of events divided by subject years of exposure multiplied by 1000

19 LEADER trial 9340 t2dm with HbA1c > 53 mmol/mol Aged 50+ with at least one of: Coronary disease, cerebrovascular or PVD CKD 3+ NYHA II or III heart failure or Aged 60+ with at least one of microalbuminuria or albuminuria, hypertension with LVH LVSD or diastolic dysfunction or ABPI < 0.9 Randomised to: Liraglutide 1.8mg daily (or max tolerated dose) or placebo Treated to target HbAc < 53 mmol/mol Allowed diabetes meds except GLP-1 analogs, DPP-4 inhibitors or pramlintide Primary outcome: composite of cardiovascular death, non-fatal MI or stroke Follow-up 3.5 to 5 years (median 3.8 years) and powered for non-inferiority

20 LEADER trial Baseline: 64% male Mean age 64 years Mean BMI 32.5kg/m 2 HbA1c 72 mmol/mol 92% of BP lowering meds By chance, liraglutide group had marginally more frequent use of: beta blockers 56.8 v 54.1% (L v P) statins 72.9 v 71.4% aspirin 63.8 v 62.1% During the trial: The liraglutide had lower: HbA1c by about 11mmol/mol early in study, 4 mmol/mol by year 3 Weight by about 2kg from 6 months onwards BP by 1-2 mmhg and higher heart rate by about 3 bpm

21 LEADER trial Primary composite outcome: (cardiovascular death, non-fatal MI or stroke) Liraglutide 608 / % Placebo 694/ % NNT 53 for 3.8 years p=0.01 for superiority Death from any cause: Liraglutide 381/ % Placebo 447/ % Benefit apparently greater when Baseline egfr < 60ml vs > 60ml/min/1.73m 2 (p=0.01) Established CVD v only risk factors for CVD (p=0.04)

22 Primary Outcome Measures: The change in cerebral glucose metabolic rate [ Time Frame: 12 months ] The change in cerebral glucose metabolic rate from baseline to follow up (12 months) in the treatment group compared with the placebo group. Secondary Outcome Measures: The change in z-scores for the ADAS Exec, MRI changes, microglial activation and CSF markers [ Time Frame: 12 months ]

23 SUSTAIN trial 3297 t2dm randomized to weekly semaglutide 0.5 or 1mg or placebo 83% had established cardiovascular disease, CKD or both Primary outcome composite of: cardiovascular death, not fatal MI, non-fatal stroke Median observation time 2.1 years HbA1c advantage of 9mmol/mol pts on semaglutide compared to placebo Primary composite outcome: (cardiovascular death, non-fatal MI or stroke) Semaglutide 108/ % NNT 53 for 2.1 years p=0.02 for superiority Placebo 146/ %

24 GLP-1 actions of GLP-1 increases glucose-stimulated insulin secretion supresses post-prandial glucagon secretion slows gastric emptying brain satiety promote beta cell health Oral inhibitors of dipeptidyl peptidase 4 (DPP-4) ie the gliptin sitagliptin saxagliptin linagliptin ## vildagliptin alogliptin The good: daily oral administration no risk of hypoglycaemia used alone low side effects no weight gain The bad:? increased heart failure admissions pancreatitis caution

25 Risk Risk of hospital admission for heart failure et al reported TECOS sita VIVIDD vilda Laakso lina SAVOR-TIMI 53 saxa EXAMINE alo Total hospital admission for heart failure

26 Abasaglar Biosimilar insulin glargine 100 units/ml Toujeo Insulin glargine 300 units/ml Tresiba Insulin deguldec 100 units/ml & 200 units/ml

27 Xultophy insulin degludec 100 units/ml with Liraglutide 3.6mg/ml For example: 50 units of degludec with 1.8mg liraglutide

28 Humalog insulin lispro 100 units/ml 200 units/ml Humalog mix 25 insulin lispro 25% Insulin lispro protamine 75% 100 units/ml Humalog mix 50 insulin lispro 50% Insulin lispro protamine 50% 100 units/ml

29 Diabetes prevention 3 large studies of individuals with impaired glucose tolerance Da Qing China DPS Finland consistent finding that diet and exercise reduce risk of diabetes DPP America Da Qing: 6 year lifestyle intervention of diet, exercise or diet & exercise cumulative prevalence of diabetes 6 years 43 v 66% 20 years 80 v 93% Intervention resulted in an average 3.6 fewer years with diabetes DPS: DPP: 4 year intervention At 2 years prevalence of diabetes was 6 v 14% At 4 years 11 v 23% At 6 years 23 v 38% 3 year intervention (achieved initial 7kg weight loss) At 3 years prevalence of diabetes was 14 v 29% At 15 years 55 v 62%

30 Why to reduce incidence of type 2 diabetes and its complications to reduce health inequalities associated with diabetes Who Adults with non-diabetic hyperglycaemia HbA1c mmol/l or fasting plasma glucose mmol/l 10% of the adult population aged over 18 What 13 face to face group sessions over 9 months at least 16 hours Underpinned by behavioural theory Focus on weight loss, dietary improvement and physical activity Where Across England, already in Leeds

31 Reversing type 2 diabetes Bariatric surgery 217 t2dm 5 yrs follow-up after bariatric surgery Complete remission defined as: HbA1c < 42 mmol/mol & fasting glucose < 5.6 mmol/l & off diabetes medicines Long-term complete remission rate at 5 years = 24% Recurrence of diabetes more likely where duration of diabetes longer less weight loss post-surgery more weight regain after surgery

32 Reversing type 2 diabetes Counterbalance Study 30 t2dm for <4 or >8 years years old BMI 27 to 45 kg/m 2 Intervention: Stop all anti-diabetes treatment Liquid diet formula (Optifast) plus 240g non-starchy vegetables So: 624 to 700 kcal/day 2L calorie-free liquid and no alcohol Maintain usual activity level One to one support by weekly phone, , SMS or face to face This for 8 weeks, then isocaloric diet reintroduced then 6 month weight maintenance phase: monthly reviews

33 fasting glucose on isocaloric diet < 7 mmol/l ie responder > 7 mmol/l ie non-responder

34 VLCD Responders: 41% of this cohort of motivated individuals 60% of the short duration individuals Shorter duration of diabetes Higher initial fasting insulin level Return of first phase insulin response Remission of diabetes last for at least 6 months Reduction of NAFL and pancreatic fat

35 3 other classes of glucose lowering medication I haven t discussed today Intestinal digestive/absorptive enzyme inhibitors: acarbose orlistat (unlicensed) PPAR-g activators: pioglitazone Sulfonylurea receptor 1 ligands: sulfonylureas meglitinides: repaglinide, nateglinide

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