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

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)


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)


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


Metformin

Dosing Renal Impairment

Manufacturer’s Labeling- Serum Cr >;=1.5 mg/dl (males) or >;=1.4 (females) contraindicated


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.


Sulfonylureas

Glipizide Chlorpropamide (1st Gen)

Glyburide

Gliclazide

Glimeperide


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.


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


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


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.


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.


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


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.


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.


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)


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


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


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.


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


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}


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.


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).


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


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.


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


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


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


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


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


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.


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!

tarcisio c. diaz, m.d. - uermafusa.com. diabete… · economic cost of diabetes (2012) direct...

Documents