Metformin: Its Non-Glycemic Effects and Cardiovascular Risk Reduction. J. M. Miles, MD

Transcription

1 Metformin: Its Non-Glycemic Effects and Cardiovascular Risk Reduction J. M. Miles, MD

2 Case Study 73 y. o. woman, followed closely for Type 2 DM of 25 y duration. She has NYHA class 3 CHF. Echo shows HFpEF (EF = 59%). Limited by DOE has to stop after walking 200 feet. On insulin monotherapy, N65 twice daily. No hypoglycemia. Also takes lisinopril & atorvastatin. BMI 36 kg/m 2 ; BP 131/68; 2+ pitting LE edema HbA1c 8.9%; TC 159, TG 186, HDL-C 24 and calc. LDL-C 88 mg/dl. Cr 0.8 mg/dl. Assuming lifestyle issues are fully addressed, you recommend:

3 Case Study (cont d) A. An increase in insulin B. Addition of a TZD C. Addition of metformin D. Addition of an SU

4 Learning Objectives 1. To review outcomes of clinical trials. 2. To consider the use of metformin in chronic disease of aging. 3. To discuss mechanisms of action that might explain favorable effects of metformin on cardiovascular disease.

5 Disclosures none

6 The Botanical Background of Metformin Culpeper, N. The English Physitian and a discourse on the vulgar herbs of this nation. Peter Cole, London, Galega Officinalis Metformin synthesis reported by Werner and Bell (J Chem Soc Trans 121:1790, 1922) Lowers glucose in animals (Deutschen Chemischen Gesellschaft 62:1398, 1929) First clinical trial In France by J Sterne, 1957 Introduced in U.K. 1958, Canada 1972, and USA 1995 Practical Diabetes Int 21:115, 2004

7 ADA/EASD Consensus Statement 2012 Diabetes Care 35:1364, 2012

8 Proportion of patients with events overweight patients Myocardial Infarction Conventional (411) Intensive (951) Metformin (342) M v C p= M v I p= Years from randomisation ukpds Lancet 352:837 and 352:854, 1998

9 weight change (kg) Change in Weight overweight patients 10 Conventional cohort, mean values Insulin Chlorpropamide Glibenclamide Metformin 5 0 A Years from randomisation Lancet 352:837 and 352:854, 1998

10 Effects of Metformin and Sulfonylurea/Insulin on Glycemic Control in Obese Patients in the UKPDS HbA 1c Plasma insulin Years in trial Sulfonylurea or insulin treatment n = 695 Metformin n = 251 Diabetes 44:1249, 1995

11 Hazard ratio Hazard ratio Sulfonylurea Insulin 1.4 Myocardial Infarction 1.2 P=0.052 P= N Metformin 1.4 Myocardial Infarction P=0.01 P=0.005 N a A N Engl J Med 359:1577, 2008

12 Mortality rate ratio Relationship Between Intentional Weight Loss and Mortality Rate in Type 2 Diabetes Weight loss (lbs) Diabetes Care 23:1499, 2000

13 Metformin Use and Mortality in People with T2DM and CV Disease: the REACH Study Arch Int Med 170: 1892, 2010

14 Safety of Metformin in People with CKD Swedish Diabetes Registry >50,000 people with T2DM, ~32,000 on metformin 4,454 patients with CKD3, 3763 with egfr HR 0.94 for CVD, 0.85* for infection or acidosis, 0.87* for all-cause mortality vs other agents *P<0.05 BMJ Open Access 2:e001076, 2012

15 Risk of Lactic Acidosis with Metformin Rx Lactate concentrations increase on metformin (Diabetologia 13:145, 1977) Frequency of LA is 4/10 5 and 5/10 5 in metformin treated and untreated patients, respectively (Cochrane Database of Systematic Reviews 2010:CD002967) When LA occurs in T2DM, it is Type A, not Type B (Diabetes Care 18:779, 1995) 20-40% of patients with CKD3 are taking metformin (Diabetes, Obesity & Metabolism 12:1079, 2010) Nonetheless, LA does occur in metformin overdose

16 Serum Creatinine in People with CKD3 ~20% of people with T2DM have CKD3 ¼ of people with CKD3 have abnormal creatinine Therefore, ~1,250,000 people with T2DM & CKD3 are ineligible for metformin Rx. Am J Kidney Dis 41:1, 2003, C Koro, personal communication

17 Metformin Use is Associated with Reduced Mortality in Patients with Diabetes and Heart Failure Diabetes Care 28:2345, 2005

18 Relative risk Effect of Diabetes Rx on HF Incidence 2.5 * 2 *P<0.001 v continuing initial therapy * 0 SU met insulin Diabetes Metab Res Rev 21: 51, 2005

19 Does Insulin Therapy Have a Hypertensive Effect in Type 2 Diabetes? JCEM 82:4037, 1997; J Cardiovasc Pharmacol 32:39, 1998

20 J Clin Invest 55:845, 1975

21 percent Metformin Use and HF Mortality in T2DM and CV Disease: the REACH Study 20 No metformin 15 Metformin *P = v no metformin 10 * 5 0 a Arch Int Med 170: 1892, 2010

22 How Would Metformin Benefit HF? Weight loss is associated with bad outcomes in HF (Eur Heart J 29:2641, 2008) RYGB improves systolic and diastolic function, in the presence and absence of HF (Am J Cardiol 80:736, 1997) A 6m lifestyle intervention produced a ~5% intentional weight loss in 34 people with HF (30% of whom had diabetes) accompanied by significant improvement in NYHA functional class, left ventricular EF, and perceived quality of life (J Cardiovasc Med 9:576, 2008)

23 mm Hg, min -1, g or ml Metformin Effects on Hemodynamics & Cardiac Function Circulation 119:2069, P<0.05 * P=0.06 baseline 24 weeks P=0.07 P=0.09 P<0.05 * P<0.01 * 6 4 L min -1 m -2 or mm Hg L -1 min systolic BP diastolic heart rate BP LV end mass stroke vol. E cardiac peak filling cardiac E - dec BP diast.vol. index work peak 2

24 Effect of Metformin on Changes in Weight and Energy Intake at One Year in Patients on Insulin 10 Weight (kg) metformin no metformin 1.0 Intake(MJ/d) * p < 0.05 * p < Diabetologia 42: 406, 1999

25 Effect of Metformin on Changes in Weight and HbA1c at 4 Months in Insulin-Treated Patients HbA1c (%) Weight (kg) 9 baseline 4 months 8 * p < v placebo 1.0 * p < 0.01 v placebo metformin no metformin 7 * 0 6 placebo metformin -1.0 * Diabetes Care 25:2133, 2002

26 Metformin: Mechanism of Action C 1 Intestine glucose absorption 2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization Blood glucose Insulin resistance 4 Liver: hepatic glucose output Metformin HGO Insulin resistance 3 Pancreas: insulin secretion DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:

27 Metformin: Mechanisms of Action Why do people who take metformin lose weight? Why do people who take metformin get diarrhea? How does metformin reduce CV risk?

28 Metformin Mechanism(s) of Action a Blood stream?bile acid malabsorption? (Serum 7αC4) Inhibition of gluconeogenesis? Clin Pharmacokinetics 30: 359, 1996

29 Metformin s Effects on the Gastrointestinal Tract?

30 Case Study (cont d) A. An increase in insulin B. Addition of a TZD C. Addition of metformin D. Addition of an SU

31 Conclusions The mechanism by which metformin reduces cardiovascular events is unclear, but suppression of appetite and promotion of weight loss may play a role. Metformin is substantially safe in people with moderately reduced renal function. However, an algorithm is needed for giving reduced doses. Metformin may actually benefit HF, perhaps via a reduction in SNS activity