Diabetes Treatment Update

Transcription

1 Diabetes Treatment Update Timothy C. Evans, MD PhD FACP University of Washington Department of Medicine Disclosure: Dr. Evans has no significant financial interest in any of the products or manufacturers mentioned.

2 Topics Why go to all this trouble and what should the blood sugar be? Drugs and insulin Surgery Lifestyle

3 How Low Should the Glucose Be? DCCT, UKPDS, and long-term benefits Steno-2 and long-term followup ACCORD NEJM. 2008;358: ADVANCE NEJM. 2008;358: VADT NEJM. 2009;360:

4 DCCT Type 1 DM Intensive vs conventional control, 6.5 yrs Retinopathy: Primary 76% Secondary 54% Nephropathy: Microalbuminuria 39% Macroalbuminuria 54% Neuropathy 60% Risk: hypoglycemia HbA 1c 7.4% vs 9.1% NEJM. 1993;329:

5 Epidemiology of Diabetes Interventions and Complications (EDIC) 11-yr DCCT F/U. HbA 1c 7.9% vs 7.8% at yr 11 All offered intensive Rx Initial intensive type 1 DM Rx Any CV dis 42% Non-fatal MI, CVA, CV death 57% HbA 1c and alb ur assoc with CV risk but benefit remained after correction Benefits persist for yrs after initial intensive control in the intervention group. NEJM. 2005;353:

6 UKPDS Type 2 DM For each 1% in HbA 1c : 14% all-cause mortality and MI 21% diabetes-related death 37% microvascular disease HbA 1c s in upper 7% to mid-upper 8%

7 UKPDS 10 Years Later HbA 1c differences gone after 1 year RR decrease in SU/insulin aggressive Rx 9% any DM endpoint 24% microvascular disease 15% MI 13% any cause death RR decrease in metformin aggressive Rx 21% any DM endpoint 33% MI 27% any cause death NEJM. 2008;359:

8 Steno-2 Study and Follow-Up 160 pts with DM2, microalbuminuria Rx glucose, lipids, BP, lifestyle vs std Microvasc (ret, neph, neur), 3.8 yrs Lancet. 1999;353: Also CV disease, 7.8 yrs NEJM. 2003;348: Then, Rx arms stopped. Also any cause and CV death, 13.3 yrs NEJM. 2008;358: Almost no patients on TZDs.

9 ACCORD 10,251 pts; HbA 1c goal 6% vs 7-7.9% At 1 year, HbA 1c 6.4% vs 7.5% At 3.5 years, study terminated CV events, HR 0.90 ( ) Death, HR 1.22 ( ) serious hypogly and 10 kg+ wt gain Rapid HbA 1c decline, 1.4% in 4 months TZD use 91.7% vs 58.3% Rosiglitazone use 91.2% vs 57.5% Insulin use 77.3% vs 55.4%

10 ADVANCE 11,140 pts; HbA 1c goal < 6.5% At 5 years intensive 6.5%, std 7.3% Results Micro/macrovasc; HR 0.90 ( ), 1 renal Major microvasc; HR 0.86 ( ) 1 renal (HR 0.79; ), no effect retinopathy No effect on major macrovasc, CV death, or any cause death Gliclazide 90.5% vs 1.6%, TZD 16.8% vs 10.9% Insulin 40.5% vs 24.1%

11 Veterans Affairs Diabetes Trial 1791 pts, intensive HbA 1c 1.5% less than std Rx met/rosi vs glimep/rosi based on BMI Result HbA 1c 6.9% vs 8.4% No effect on major CV, death, or microvasc dis except albuminuria (9.1% vs 13.8%) Pts male, older, longer hx DM Rosiglitazone use 72% vs 62% Insulin use 90% vs 74%

12 Glucose Control Commentary NEJM. 2009;360: Ann Int Med. 2009;150: Ann Int Med. 2009;150: NEJM. 2010;362: JAMA. 2010;303:

13 Recommendations for Now HbA 1c 7% remains standard of care Probably more to be gained from getting uncontrolled pts down to 7% than from lowering tightly controlled pts further Attention to healthy lifestyle Diet, exercise, weight control Aggressive BP control Aggressive dyslipidemia control Discontinue smoking

14 Drugs and Insulin

15 Biguanide Metformin HbA 1c 1 2% First choice agent, lots of experience, hypoglycemia rare, improved lipids, CV events, wt loss GI intol, lactic acidosis, B 12 def Inexpensive

16 Sulfonylureas Glimepiride, glipizide, glyburide HbA 1c 1 1.5% Lots of experience Hypoglycemia, less durability, wt gain Inexpensive

17 Meglitinides Nateglinide, repaglinide HbA 1c 0.5 1% Short duration, hepatic clearance, glucosedependent postprandial action Low efficacy, hypoglycemia in some, wt gain Expensive

18 Thiazolidindiones Pioglitazone, rosiglitazone HbA 1c % Hypoglycemia rare, durable effect, improved lipid profile Edema, CHF, wt gain, risk of long-bone Fx, CV events (rosiglitazone) Expensive

19 DPP-IV Inhibitors Linagliptin, saxagliptin, sitagliptin HbA 1c % Hypoglycemia rare, infreq side effects Less efficacy than GLP-1 agonists angioedema, risk of pancreatitis, relatively new with unknown long-term safety Expensive

20 α-glucosidase Inhibitors Acarbose, miglitol HbA 1c % postprandial glucose, hypoglycemia rare Flatulence, diarrhea Moderate price

21 Bile Acid Sequestrant Colesevalam HbA 1c 0.5% Lowers LDL, hypoglycemia rare GI side effects, low efficacy, only approved agent in class Expensive

22 D2 Dopamine Receptor Agonist Rapid release bromocriptine HbA 1c 0.5% Hypoglycemia rare Low efficacy, GI side effects, dizziness, rhinitis, only the rapid-release form approved Expensive

23 GLP-1 Receptor Agonist Exenatide, exenatide once weekly, liraglutide HbA1c % Hypoglycemia rare, wt loss Nausea and vomiting, risk of pancreatits, thyroid C-cell hyperplasia and tumors, unknown long-term safety, injectable Expensive

24 Amylin Analog Pramlintide HbA 1c % Wt loss, control of postprandial glycemia Nausea and vomiting, modest efficacy, hypoglycemia with insulin use, unknown longterm safety, injectable Expensive

25 Insulins Fastest (aspart, glulisine, lispro), short (regular), intermediate (NPH), longest acting (detemir, glargine) HbA 1c 1 2.5% Large effect in all patients Hypoglycemia, wt gain Moderate to expensive

26 Glucose Control in the ICU Early studies showed benefit of tight control. More recent multicenter studies, in both medical and surgical ICUs, show risk. Ideal is probably a compromise between risk of out-of-control DM and hypoglycemia. Ann Int Med. 2009;150:

27 ACP Guidelines for Intensive Insulin Therapy (IIT) in Hospitalized Patients No evidence of benefit, hypoglycemia Recommends not to use IIT in non-icu pts for tight glucose control with or without DM Recommends not to use IIT in ICU pts to normalize glucose with or without DM Recommends target blood glucose of mg/dl if insulin therapy is used in ICU pts Ann Int Med. 2011;154:

28 Surgery

29 Gastric Banding JAMA. 2008;299: obese pts, BMI 30 40, recent Dx DM-2 Lifestyle change vs. adjustable gastric banding 2 year F/U, 92% completed Wt loss (% of starting wt) 20.7% surgery; 1.7% std care DM remission 73% surgery; 13% std care 10% wt loss required for remission

30 Swedish Obesity Subjects Study 2010 bariatric surgery (non-randomized, prospective controlled) Age 37-60, F/U 14.7 yrs BMI men > 34, women > 38 Surgery: gast bypass (13.2%), banding (18.7%), vertical banded gastroplasty (68.1%) CV deaths (HR 0.47 [95% CI, , P<.002]) CV events (HR 0.67 [95% CI, , P<.001]) JAMA. 2012;307:56-65.

31 Bariatric Surgery vs Intensive Medical DM Therapy Randomized, non-blinded, single center 150 DM2 pts, ave age 49+8 yrs, 66% women, BMI 27 43, baseline HbA 1c 9.2%, primary outcome HbA 1c < 6.0% 1/3 each group: 1 medical, 2 surgery, 12 mo F/U Roux-en-Y gastric bypass or sleeve gastrectomy 1 outcome: 12%, 42% (P<.002), 37% (P<.008) HbA 1c : 7.5%, 6.4% (P<.001), 6.6% (P<.003) Wt loss: 5.4 kg, 29.4 kg, 25.1 kg (P<.001 both) NEJM. 2012;366:

32 Life Style

33 Metabolic Syndrome NCEP (revised 2005, Circulation. 2005;112: ) Any three of five of the following Glucose intolerance/insulin resistance: FBS 110 mg/dl ( 100 mg/dl, or on drug Rx) Hypertension: BP 130/85 (or on drug Rx) Dyslipidemia TG 150 mg/dl (or on drug Rx) HDL < 40 mg/dl in men, < 50 mg/dl in women (or on drug Rx) Central adiposity: waist circ > 40 men, > 35 in women

34 Metabolic Syndrome Prevalence Third NHANES, Af-Amer, 3477 Mex-Amer, 5581 Caucas Met Synd in 22.8% men, 22.6% women Highest in Mex-Amer, lowest in Af-Amer 4.6% in nl wt, 22.4% in over wt, 59.6% in obese Increased odds in: Older age, postmenopause, Mex-Amer, BMI, smoking, low income, high carbohydrate intake, no alcohol, physical inactivity Arch Int Med. 2003:

35 Metabolic Syndrome and Cardiovascular Mortality JAMA. 2002;288:

36 Cumulative Hazard, % Metabolic Syndrome and Cardiovascular Mortality JAMA. 2002;288:

37 Cumulative Hazard, % Metabolic Syndrome and Cardiovascular Mortality JAMA. 2002;288:

38 Finnish Diabetes Prevention Study Design 522 middle-aged overweight (BMI 31) 172 men and 350 women Mean duration 3.2 years Intervention Group: Individualized counseling Reducing weight, total intake of fat and saturated fat Increasing uptake of fiber, physical activity Tuomilehto J et al. N Engl J Med 2001;344:

39 Treating the Metabolic Syndrome Goals Intervention Controls % of subjects P value Wt reduction >5% Fat intake < 30% energy Sat fat <10% energy Fiber >15 g/1000 kcal Exercise > 4 hr/wk Tuomilehto J et al. N Engl J Med 2001;344:

40 Incidence of Diabetes (%) Incidence of Diabetes during Follow-up Control Intervention No. with Diabetes/Total no. Success Score Intervention 5/13 10/66 9/69 2/38 0/25 0/24 Control 15/48 25/107 14/48 2/15 0/11 0/4

41 Diabetes Prevention Program 3234 at risk for DM average BMI 34, IGT Gp 1 diet and exercise to wt 7% Gp 2 metformin 850 mg bid + lifestyle info Gp 3 placebo + lifestyle info Terminated at 2.8 yrs (DM per 100 pt-yrs) Gp cases (58% less than placebo) Gp cases (31% less than placebo) Gp cases NEJM. 2002;346:

42 ADA Recommendations For patients with IGT or IFG Lifestyle intervention is primary Modest wt loss 5 10% Moderate exercise, 30 min daily Smoking cessation For patients with both IGT and IFG consider adding metformin Consider OGTT in pts with IFG less than 60 y/o and with BMI > 35

43 Metabolic Syndrome Summary Common constellation of metabolic risk factors Key features: visceral obesity, insulin resistance, glucose intolerance, HBP, TG, HDL, small dense LDL High risk of CVD, especially as blood sugar increases Treatment is healthy lifestyle: diet, weight loss, exercise Statins, fibrates, metformin, ACE/ARB