Tarcisio C. Diaz, M.D. - uermafusa.com. Diabete… · Economic Cost of Diabetes (2012) Direct...
Transcript of Tarcisio C. Diaz, M.D. - uermafusa.com. Diabete… · Economic Cost of Diabetes (2012) Direct...
Diabetes Update
Old Reliables and New Kids in the Block
Tarcisio C. Diaz, M.D.
Demographics
Number of Diabetics (Year 2014) 22.0 Million
Crude and Age Adjusted Incidence of Diabetes in the U.S. Per 1,000 Population Aged 18-79 (Year 2014)
Crude: 6.9 (Standard Error 0.4)
Age Adjusted: 6.6 (Standard Error 0.4)
Source CDC
Demographics
Riverside County
Number of Diabetics-83,280
Percent of Population-7
Economic Cost of Diabetes (2012)
Direct Medical Cost $306B
Annual Medical Expenditure
Diabetic $13,700
Non-Diabetic $5,800
Source: ADA (Diabetes Care-2013)
Overview of Medical Care in Adults with Diabetes Mellitus
Initial Evaluation:
History and Physical Examination
Nutrition and Weight
Physical Activity
Overview
Initial Evaluation
Cardiovascular Risk Factors
History of Diabetes Related Complications
Hypoglycemic Episodes
DKA frequency (for type 1 diabetes only)
Overview
Labs
HgbA1C -initially and every 3 months if >7, every 6 months
if <7
Overview
Labs
If Not Measured in the Past Year
Lipid Profile
Liver Function Test
Urine Albumin Excretion (Spot Urine) and Creatinine
Overview
Labs
In Type 1 Diabetes Only-TSH
Overview
Diabetes Related Complications
Macrovascular Disease
Coronary Artery Disease
Strokes
Peripheral Artery Disease
Overview
Diabetes Related Complication
Microvascular
Diabetic Nephropathy
Diabetic Retinopahy
Diabetic Neuropathy
Overview
Morbidity from diabetes is a consequence of macrovascular and microvascular disease.
In type 2 diabetes, the onset is insidious, and the diagnosis is often delayed. As a result, diabetes complications may already be present at the time of diagnosis.
Overview
The progression of these complications can be slowed down with aggressive intervention such as:
Glycemic Control, BP control, Lipid Lowering
ACE-I or ARB for Nephropathy
Laser Treatment for Retinopathy
Overview
Early intervention appear to reduce diabetes-related complications including MI, Strokes, L.E. amputations and ESRD.
The greatest reductions are those related to Acute MI, and stroke (95.6 and 58.9 fewer cases per 10,000 between 1990 and2010).
overview
Overview
11 Per cent of Diabetics 20 years or older had visual impairment (visual acuity <20/40) in their best eye with glasses.
The impairment was correctable prescription of glasses or contact lenses in over two-thirds of the patients
These data indicates that refractive error assessment in addition to dilated pupil and ocular pressure exam, is needed to improve quality of life and reduce visual loss
Source: NHANES study
Overview
Foot Care
Visual Inspection of the feet at each routine visit should be performed
Identify problems with nail health (onychomycosis, sharp nails, foot hygene)
Signs of ill fitting shoe, barotrauma, callus formation, etc.
Overview
Comprehensive Foot Examination- Performed Annually
The skin should be assesses for integrity especially between toes and under the metatarsal heads.
Screen for Peripheral Artery Disease (claudication, Pedal Pulses/ABI)
Test for loss of Protective Proprioception with a 10 g monofilament at specified sites
Overview
Screening for Nephropathy
Spot urine for albumin/Cr ratio is preferred and should be done yearly
At the time of diagnosis for Type 2
May be deferred for 5 years for Type 1
Establishing the diagnosis requires demonstration of 2 abnormal test
Overview
Normal <30 mg/day (20 mcg/min)
Moderately increased (Microalbuminuria) 30-300 mg/day (20-200 mcg/min)
Severely increased (Macroalbuminuria) >300 mg/day (>200 mcg/day)
The availability of effective treatment of Diabetic nephropathy with ACE-I and ARBs is the rationale for yearly screening.
Macrovascular Disease
Diabetes is an MI equivalent
Patients with Diabetes have an increased risk for atherosclerosis due both to diabetes and to the frequent presence of other risk factors
Diabetic patients with CHD are more likely to be asymptomatic or have atypical symptoms than non diabetic patients with CHD
It has not been proven that identifying asymptomatic disease or providing early intervention will improve outcomes
Macrovascular disease
Routine performance of exercise stress testing in asymptomatic patients with diabetes is not recommended
Annual performance of risk criteria (BP, Lipid Profile, Smoking History) to identify patients at high risk for Coronary Heart Disease who might benefit from interventions such as Aspirin, ACE-I, and statin therapy is preferred
Comorbid Conditions
Hearing impairment, Sleep Apnea, Fatty Liver Disease, Periodontal Disease, Cognitive Impairment, Depression, and Fractures
May be present at diagnosis or may develop over time
For patients with signs and symptoms of these conditions, additional assessment is warranted
Annual dental assessment for dentate and non-dentate patients is recommended
Comorbid Conditions
Diabetes and Cancer
Some studies suggest an increased risk of certain cancers (liver, pancreas, endometrium, colon/rectum, breast and bladder)
Adults with Type 2 diabetes have and increased risk of cancer mortality
The increased risk of cancer mortality is associated specifically with cancers of the liver, pancreas, ovary, colon/rectum, lung, bladder and breast
Source: Diabetes mellitus and the risk of cancer; m Arch Intern Med 2006
Comorbid Conditions
Diabetes and Cancer
The relative risk was substantially reduced when HgbA1c levels were considered in a multivariate analyses, consistent with a dierect effect of hyperglycemia on cancer risk
Patients with diabetes should undergo recommended gender-specific cancer screening
Glycemic Control
DCCT, UKPDS, and the Kumamoto Study have demonstrated that intensive therapy aimed at lower levels of glycemia results in decreased rates of retinopathy, nephropathy and neuropathy.
Every 1 percent drop in HgbA1c was associated with improved outcomes and there was no threshold effect
These benefits have to be weighed against an increased risk of hypoglycemia associated with intensive therapy
Glycemic Control
HgbA1C Goals
Should be tailored to individuals
<7 percent for most
<8 percent for older patients and those with comorbidities or a limited life expectancy
<6 percent for pregnant diabetics and certain type 1 patients without complications
Treatment
Nonpharmacologic Treatment
Dietary Modification
Exercise
Weight Reduction
u
Pharmacologic Intervention
Biguanides
Metformin
Mechanism of Action-Decreased hepatic glucose production, decreased intestinal absorption of glucose and improves insulin sensitivity ( increased peripheral glucose uptake and utilization)
Pharmacologic Intervention
Metformin
Onset of action: Within days; maximum effects up to 2 weeks
Distribution: partitions into erythrocytes; concentrates in the liver, kidney, and G.I. tract
Excretion: urine (90% as unchanged drug)
Pharmacologic Intervention
Metformin
Dosing: Adults (DM-2)
Immediate Release- 500 mg. BID or 850 mg. once daily titrate in increments of 500 mg weekly or 850 bi-weekly
Clinically significant response not seen in doses <1500 daily, but gradual increase in dosage is recommended to minimize G.I. symptoms
Maximum recommended dose: 2550 mg daily
Pharmacologic Intervention
Metformin
Dosing Renal Impairment
Manufacturer’s Labeling- Serum Cr >;=1.5 mg/dl (males) or >;=1.4 (females) contraindicated
Pharmacologic Intervention
Metformin
Dosing Adjustments in Renal Impairment ADA Proposed Recommendation
eGFR > 60 mL/mim/1.73 m2- No contraindication, monitor renal function yearly
eGFR> 45 <60 mL/min/1.73 m2 ; continue use, monitor renal function every 3-6 months
eGFR < 30 mL/min/1.73 m2 Discontinue use.
Pharmacologic Intervention
Sulfonylureas
Glipizide Chlorpropamide (1st Gen)
Glyburide
Gliclazide
Glimeperide
Pharmacologic Intervention
Sulfonylureas
Mechanism of Action: Lowers blood sugar by activating SU receptors in the beta cells of the Pancreas
Effective as monotherapy or in combination with other OHGA and insulin
Lowers blood glucose concentration by 20% and HgbA1C by 1-2 %
Most likely effective in normal or slightly overweigt patients.
Pharmacologic Intervention
Sulfonylureas
Side Effect and Precautions: Usually well tolerated, the most common side effect is hypoglycemia especially with the long acting SU (chlorpropamide and glyburide)
Association with coronary disease outcomes- Some studies suggest that sulfonylureas may be associated with poorer outcomes in patients with myocardial infarction
Pharmacologic Intervention
Meglitinides
Repaglinide
Natiglinide
Mechanism of Action: Structurally different from SU, but their actions are similar.
Shorter acting therefore may have less hypoglycemia incidence
Similar Efficacy to SU in terms of glucose and HgbA1C lowering
Pharmacologic Intervention
Thiozolidinediones (TZD/Glitazone)
Pioglitazone
Mechanism of Action: Increase insulin sensitivity by acting on adipose, muscle, and liver to increase glucose utilization (periphery) and decrease glucose production (liver). They bind to PPARs which regulate gene expression in response to ligand binding.
Pharmacologic Intervention
TZD
studies have shown that TZDs improve glucose levels by preserving beta cell function
Efficacy - Similar Metformin as monotherapy. More effective when used in combination with other OHGA.
Pharmacologic Intervention
TZD- Safety Concerns
CHF/Fluid Retention- Peripheral edema occurs in 4 to 6 percent of patients on TZDs and in a higher percentage of patients with CHF. This fluid retention may lead to the precipitation or worsening of CHF
Skeletal- Increased Fracture Risk in women
Bladder Cancer- There were more cases of bladder cancer (14 vs 5) in the PROACTIVE Trial
Pharmacologic Intervention
TZD-Safety Concerns
Hepatotoxicity- Mostly seen in Troglitaone, none in Rosiglitazone, 2 cases in Pioglitazone.
Macular Edema- Has been reported in patients on TZDs but frequency of occurence is unknown.
Weight Gain - May be fluid retention, but mostly the effect of PPAR activation in the brain causing increased caloric intake.
Pharmacologic Intervention
Glucagon Like Peptide -1 Agonist
Mechanism of Action- GLP-1 is produced from the proglucagon gene from the L-cells of the small intestines and is secreted in response to nutrients (incretin effect). GLP-1 binds to specific receptors in pancreatic beta cells, pancreatic ducts, gastric mucosa, kidneys, lung, heart, skin, immune cells and hypothalamus.
Pharmacologic Intervention
GPL-1 Agonist
Exenatide Albiglutide Taspoglutide
Liraglutide Lixinatide
Binds to -receptors but are resistant to DPP-4 enzyme degradation and stimulates glucose dependent insulin release
Plarmacologic Intervention
GLP-1 Agonist
Glycemic Efficacy- Reduces HgbA1C by 1 percent
Cardiovascular Effects- There are only a few studies assessing cardiovascular outcomes. In 1 study, after a median follow-up of 25 months, the primary nd point (a composite endpoint of cardiovascular death, nonfatal MI, nonfatal strokes or hospitalization for unstable angina), there was no significant difference between GLP-1 (Lixisenatode) and comparator agents (SU, Metformin, Insulin)
Pharmacologic Intervention
GLP-1 Agonist
Weight Loss- Reduction of approximately 1.5 to 2.5 kg over a 30 week period
May be due to the effect of slowed gastric emptying, and their well recognized side effect of nausea and vomiting.
Not recommended as initial therapy
Pharmacologic Intervention
Dipeptidyl Peptidase 4 (DPP-4) Inhibitors
Sitagliptin Saxagliptin Vildagliptin
Linagliptin Alogliptin
Mechanism of Action: DPP-4 is a ubiquitous enzyme expressed in the surface of most cells that deactivates bioactive peptides including glucose-dependent insulinotropic (GIP )and GLP-1; therefore its glucose lowering effect is related to its effect on these peptides
Pharmacologic Intervention
DPP-4 Inhibitors
Glycemic Effect- HgbA1C reduction of -0.52 to -0.63 percent
Cardiovascular Effects- In short term studies so far, no adverse events hve been reported.
Pharmacologic Intervention
DPP-4 Inhibitors
Adverse Effect
Immune Function- Increased incidence of Nasopharyngitis, UTIs and headache
Pancreatitis-Acute pancreatitis has been reported in patients taking DPP-4 inhibitors
Skin- Have been associated with serious skin reactions in pre-clinical studies
Pharmacologic Intervention
Glucose Cotransporter 2 (SGLT-2) Inhibitors
Mechanism of Action - SGLT-2 is expressed in the proximal tubules and mediates the resorption of 90% of the filtered glucose load. SGLT-2 inhibitors promote the renal excretion of glucose thus providing a modest lowering of blood glucose.
Glycemic Efficacy- Similar to DPP-4 inhibitors (-0.7to -0.9}
Pharmacologic Intervention
SGLT-2 Inhibitors
Cardiovascular Effects -
In a trial designed specifically to evaluate cardiovascular mortality and morbidity in patients with DM-2, and established cardiovascular disease, the primary outcome (a composite of death from cardiovascular causes, non-fatal MI, or non-fatal stroke) occurred in fewer patients assigned to SGLT2 inhibitor (empagliflozin) than to placebo. The findings were driven by a significant reduction in risk of death from cardiovascular causes.
Pharmacologic Intervention
SGLT-2 Inhibitors
Cardiovascular Effects- There are several ongoing trials evaluating the effects of SGLT-2 I on cardiovascular outcomes
In a trial designed specifically to evaluate cardiovascular Mortality and Morbidity in patients with DM-2 and established CVD (mean HgbA1C 8%) randomized between empagliflozin and placebo (majority were taking Metformin, antihypertensives, and lipid lowering agents).
Pharmacologic Intervention
SGLT-2 Inhibitors
After 3 years, the primary outcome (a composite of death from CV causes, non-fatal MI, non-fatal stroke) occurred in fewer patients assigned to empagliflozin than to placebo.
The findings were driven primarily by a significant reduction in risk of death from CV causes.
The rate of hospitalization from CHF was lower in the SGLT-2 group vs. placebo
Pharmacologic Intervention
SGLT-2 Inhibitors
Weight Loss- SGLT-2 Inhibitors decrease weight. Loss of 2 to 3 kgs were reported in 3 12-week trials of dapagloflozin, canagliflozin, and empagliflozin.
The weight loss appears to be sustained over time.
Parmacologic Intervention
SGLT-2 Inhibitor
Adverse Effects-
Vulvovaginitis
UTI/Cystitis
Bone Fractures
Euglycemic DKA- in patients with DM-2.
Pharmacologic Intervention
New Insulins
Inhaled Insulin- Insulin, Rapid acting
Causes rapid rise in serum insulin concentration (similar to rapid acting analogs, faster than sub Q regular insulin
Intended to control post-prandial glucose, or rapid correction of a high glucose
Needs pulmunary function test before use
Pharmacologic Intervention
New Insulins
Medical Safety Issues: High alert medication due to the number insulin medications being used, it is essential to identify/clarify the type of insulin being used.
High Risk of Acute bronchospasm in COPD patients (need for spirometry to identify high risk patients.
As with other injectable insulin
Pharmacologic Intervention
New Insulins
Insulin Degludec
Modified insulin to achieve a long half life (48 hours)
True once a day dosing with stable flat levels
Can be combined with rapid acting insulin Aspart
Pharmacologic Intervention
New Insulins
Insulin Degludec
Safety concerns: High alert medication as with other insulins
Hypersensitivity
Hypoglycemia
Non-Pharmacologic Intervention
Diet
Plant based diet (Mostly Vegetable Diet)
$ 2.2B spent on fresh vegetables last year
$ 10B spent on sugared drinks
Non-Pharmacologic Intervention
Exercise
Short Term Effect- Utilizes muscle glycogen to convert glucose to energy. Also utilizes glucose from circulation-a process that requires insulin
If the process continues, counter regulatory hormones kick in (epinephrine, norepinephrine, growth hormone and cortisol)
Increase in glucose production by the liver
Non-Pharmacologic Intervention
Exercise
Long Term effect-Moderate aerobic exercise on a regular long term basis improves the energy efficiency of the muscle by several mechanisms
Increases the population of the mitochondrial enzyme
Increased Translocation of glucose transporter (GLUT 4), from the intracellular stores to the cell surface. GLUT 4 promotes glucose uptake, which is probably responsible for increased insulin sensitivity.
Non-Pharmacologic Intervention
Weight Reduction
By Diet and Exercise
Pharmacologic
Conclusions
Diabetes is a growing problem worldwide
It is growing at an unsustainable rate that will bankrupt most countries as the incidence of diabetes increases (at the current trajectory).
There are more affordable ways to treat the disease that needs a change in the way we look at the disease (from treatment to prevention)
Questions
Thank You!