Controlling Diabetes with Oral Agents


Release Date:

August 2016

Expiration Date:

August 15, 2019

Goal Statement:
With rates of diabetes rising and expected to continue rising, optometrists find themselves on the front lines of controlling diabetic eye diseases, such as diabetic macular edema and diabetic retinopathy. To successfully control these conditions, they should have an in-depth understanding of the mechanisms, contraindications and side effects of oral medications. This article provides an overview of the many agents available for these patients.

Faculty/Editorial Board: 
Candice Tolud, OD, and Joy Harewood, OD. 

Credit Statement: 
COPE approval for 2 hours of CE credit is 50776-OP for this course. Check with your local state licensing board to see if this counts toward your CE requirement for relic ensure.

Disclosure Statement: 
The authors have no relationships to disclose.


Even though the Centers for Disease Control (CDC) estimates that one in three Americans are on pace to develop diabetes by 2050, only 65% of patients with the disease report receiving an annual dilated eye exam.1 The CDC approximates that 28.5% of diabetic patients will develop some level of diabetes retinopathy (DR) or diabetic macular edema (DME).1 However, 100% of them are at risk.

A 50-year-old Hispanic male with proliferative diabetic retinopathy.
A 50-year-old Hispanic male with proliferative diabetic retinopathy. Click to enlarge.

To adequately serve these patients, optometrists must develop the skills now to combat this risk by employing current treatment models. Part of that treatment includes keeping abreast of emerging oral therapies.

This article will review the basics of diabetic classifications, oral therapies, new drugs and drug targets to control diabetes and diabetic eye diseases.

Diabetes Classifications

Type 1 diabetes, previously called juvenile-onset or insulin-dependent diabetes, is characterized by cellular-mediated autoimmune destruction of the beta-cells in the pancreas and usually leads to severe insulin deficiency.2 

Type 2 diabetes, previously referred to as adult-onset or noninsulin-dependent diabetes, is characterized by insulin resistance causing a relative, rather than an absolute, insulin deficiency. Type 2 diabetes patients have lost 20% to 65% of their functioning beta cells at diagnosis.3 Between 90% and 95% of all patients with diabetes have Type 2 diabetes.2 

Other common risk factors for the development of Type 2 diabetes include: aging, family history of diabetes, a personal history of gestational diabetes, physical inactivity, hypertension, high cholesterol, race and ethnicity. Type 2 diabetes can also be drug-induced, chemical-induced or secondary to kidney or pancreatic disease. African or Hispanic ethnicities have a disproportionately high prevalence of diabetes compared with Americans of European descent (12.6%, 11.8%, 7.0%, respectively).2

Gestational diabetes is defined as any degree of glucose intolerance resulting in hyperglycemia and is diagnosed during pregnancy, usually during the second or third trimester.1 Gestational diabetes affects 14% of pregnant women.3 Gestational diabetes can lead to neonatal hypoglycemia, respiratory distress syndrome, increased rates of birth trauma and caesarean delivery.4 Adequate glycemic control decreases maternal and fetal complications and can be accomplished through diet and exercise, while some will require pharmacologic intervention.4 Due to the short and temporary course of gestational diabetes, it does not lead to the development of DR. However, women diagnosed with gestational diabetes have a 35% to 60% increased chance of developing Type 2 diabetes in the future.5

Table 1. Summary of Major Oral Antihyperglycemic Medications12,30, 31

Agent Class

Name(s)

Mechanism of Action

Fasting Plasma Glucose (mg/dl)

HbA1c

(%)

Sulfonylureas

Glyburide, Glipizide, Glimepride

Stimulates sustained insulin release.

60-70

1.0-2.0

Meglitinides

Repaglinide, Nateglinide

Stimulates insulin release.

65-75

1.0-2.0

Biguanides

 

Metformin (Glucophage)

Decreases hepatic glucose production, increases intestinal absorption of glucose.

50-70

1.0-2.0

Thiazolidinediones

Rosiglitazone (Avandia), Pioglitazone (Actos)

Increases insulin sensitivity.

60-80

0.5-1.5

DPP4 Inhibitors

Sitagliptin (Januvia), Saxagliptin (Onglyza)

Incretin Enhancers. Increase insulin secretion.

12-28

0.5-0.8

SGLT Inhibitors

 

Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance)

Decreased glucose reabsorption by the kidneys.

23-29

0.5-1.0

Alpha-Glucosidase Inhibitors

Acarbose (Precose), Miglitol (Glyset)

Delays carbohydrate absorption.

25-30

0.7-1.0

Bile Acid Sequestrants

Colesevelam (Welchol)

May reduce endogenous liver glucose production.

15

0.5

Prediabetes refers to glycemic parameters above normal, but below diabetes thresholds. These patients are in a high-risk state for diabetes with an annualized conversion rate of 5% to 10% with similar proportion converting back to normal levels. Research shows prediabetes is associated with the simultaneous presence of insulin resistance and beta cell dysfunction.6 Prediabetes is also associated with early forms of nephropathy, diabetic retinopathy and increased risk of macrovascular disease.6

Oral Therapies for Diabetes

The selection and application of a glucose lowering therapy are dependent on a number of considerations including: severity of hyperglycemia, liver and kidney functions, risk of hypoglycemia, body-mass index, ability to self-monitor blood glucose and cost of medications. We will focus on the treatment options for Type 2 diabetes. 

Biguanides are generally considered first-line diabetes therapy in the United States—specifically the biguanide metformin, an insulin sensitizer. Its mechanism of action reduces production of glucose in the liver.7 It also increases liver sensitivity to insulin and decreases extraction of gluconeogenic substrates. For metformin to work, the body must be producing, or concurrently be injected with, insulin.7

Metformin is not metabolized by the body. It is absorbed and eliminated through urine. Because of this elimination pathway, it had been thought that patients required good renal function to safely use metformin.8However, recent evidence shows that metformin may be used in patients with mild renal impairment, as long as they’re under close supervision of a physician.8 Other relative contraindications include cardiac or respiratory insufficiency, a history of alcohol abuse or a history of metabolic disease.8

It is effective, reducing HbA1c by 1% to 2%, and has the added benefits of improving lipid profile and stabilizing body weight.7 Researchers postulate that metformin causes weight loss through depletion of fat mass and its effect on appetite.9 The main reason why it is often a first-line therapy may be because it has a low probability of producing hypoglycemia. Side effects include abdominal discomfort, diarrhea and, most severely, lactic acidosis. Roughly 10% of patients cannot tolerate metformin at any dosage.7 The adverse gastrointestinal effects can be reduced, or even avoided, by taking metformin with or immediately before a meal, or by slowly titrating the dosage or by using metformin XR extended release.7 It can be combined with other medications and is available in combination with the sulfonylurea glibenclamide (Glucovance) and the SGLT2 inhibitor canagliflozin (Invokamet).7

A 38-year-old Hispanic female with moderate NPDR.
A 38-year-old Hispanic female with moderate NPDR. Click to enlarge.

Sulfonylureas bind to B-cell receptors in the pancreas and stimulate insulin secretion. Similar to metformin, these drugs reduce HbA1c by 1% to 2%.10 Since they cause unregulated insulin release, they do promote some weight gain, so using them in patients of normal weight is ideal. Insulin’s main role is to help the body absorb glucose nutrients. These drugs cause the body to store more glucose-—as fat—making weight gain inevitable, unless the patient reduces calorie intake or increases exercise.11 Sulfonylureas rely on B-cell function to act, so a patient must have some level of B-cell function for them to be effective. Treatment failure with sulfonylureas is often an indicator of poor B-cell function and may signal that insulin therapy should be initiated. 

Side effects include sensitivity reactions and weight gain of about two pounds to eight pounds, but the most important risk is hypoglycemia. Sulfonylureas will release insulin regardless of the glucose level in the blood, which can push the body into a hypoglycemic state. Twenty percent of patients treated with sulfonylureas in the United Kingdom Prospective Diabetes Study (UKPDS) had suspected hypoglycemic events, with 1% having severe hypoglycemic crises.12 Investigators have also expressed some concern that these drugs contribute to adverse cardiovascular events.13,14 The links are postulated, in part, because these medications bind to the receptors SUR2A and SUR2B, which are both found in some form on cardiac and smooth muscle.15 Not all types of these medications have binding capabilities and only in high concentrations have these effects been found. 

Meglitinides, or glinides, also stimulate insulin release. These drugs bind to a receptor on the plasma membrane of the B-cell with a similar action as sulfonylureas. They are preferred by some, since they’re short acting, lowering the risk of hypoglycemia. Glinides are metabolized rapidly and removed from the body by the liver. They can cause a small weight gain, and can be used in combination with other drug classes.7 The overall reduction A1c is 1% to 2%, which is comparable to the previously mentioned drugs.7

A 52-year-old Hispanic male with moderate NPDR.
A 52-year-old Hispanic male with moderate NPDR. Click to enlarge.

Patients with predictable eating patterns may not need this drug, but it is a boon to those with irregular eating patterns. It is to be taken orally at least 15 minutes before a meal and works for three hours. It can be combined with metformin for even tighter control of blood sugar.

Thiazolidinediones stimulate receptors that lead to enhanced effects of endogenous insulin. Because of this mechanism of action, there needs to be functional insulin for there to be an effect. These medications are quickly absorbed and metabolized by the liver.7 They can be used in monotherapy or in combination with sulfonylureas or biguanides. They lower hemoglobin A1c by 0.5% to 1.5% but have side effects of fluid retention, reduced hemoglobin and reduced hematocrit. This can put a patient at risk of peripheral edema and anemia. Thiazolidinediones can also increase the risk of macular edema, particularly in patients on concurrent or high dose insulin therapy.16 They can be associated with an increase in total cholesterol and in mild weight gain. Hypoglycemia is possible with these medications but usually only when they are used in combination. 

Dipeptidyl peptidase 4 (DPP-4) inhibitors improve glycemic control by preventing the inactivation of the incretin hormone GLP-1, which thereby stimulates insulin secretion, and reduces glucagon and glucose levels after meals.17

As a class, DPP4 inhibitors have been shown to decrease fasting glucose by 12mg/dL to 28mg/dL and HbA1c by 0.5% to 0.8%.17 There was no shown effect on body weight or lipid levels. DPP-4 Inhibitors are often used in combination with sulfonylureas as an add-on therapy.17

Table 2. Retinopathy Staging

Degree of Retinopathy

Findings

Mild NPDR

At least 1 MA

Moderate NPDR

Hemorrhages and/or MAs (2A), CWS, or VB(<6B) or IRMA (<8A)

Severe NPDR

4/2/1 (Hemorrhages, VB, IRMA)

Very severe NPDR

2 of severe findings

PDR

Definite NVD or NVE and/or VH/PRH

Note: CWS=cotton-wool spots; IRMA=intraretinal microvascular abnormalities; MAs=microaneurysms; NPDR=nonproliferative diabetic retinopathy; NVD=neovascularization of the optic disc; NVE=neovascularization elsewhere; PDR=proliferative diabetic retinopathy; VB=venous beading; VH/PRH=vitreous hemorrhage/preretinal hemorrhage.

Reports show increased risk of pancreatitis with the use of DPP-4 inhibitors; gastrointestinal events can occur, but are rare. Headaches, nasopharyngitis and upper respiratory tract infections have also been reported.17

Sodium-glucose transport protein-2 (SGLT2) inhibitors are naturally occurring proteins that aid in the reabsorption of glucose in the kidneys. SGLT2 inhibitors work to block the reabsorption of glucose and increase its excretion in the urine, thereby lowering blood glucose levels.17

SGLT inhibitors are shown to decrease HbA1c 0.7% to 1.5% and lower weight one to three pounds; and this was attributed to its diuretic effect.17 The most common side effects seen are urinary tract infections, postural hypotension, vaginal yeast infections and increased urination.17

In 2015, at the European Association for the study of Diabetes Meeting, the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) trial were released.18 This study looked at 7020 patients over a median of three years and showed that those patients treated with either 10mg or 25mg of empagliflozin (Jardiance) had a statistically significant reduced rate of mortality from cardiovascular causes, decreased rates of hospitalization for heart failure, as well as decreased rate of death from any cause, as compared with placebo in patients already receiving standard of care treatment with Type 2 diabetes.18

Alpha-glucosidase inhibitors are saccharides that decrease the digestion of carbohydrates, such as starches and table sugar, by competitively inhibiting the binding sites in the small intestine, thereby resulting in a smaller rise in blood glucose concentration following meals.17

Alpha-glucosidase inhibitors lower fasting plasma glucose 25mg/dl to 30mg/dl and lower HbA1c 0.7% to 1.0% with no effect on lipid levels or body weight.16 This class of drug is used in combination with sulfonylureas and is known to cause gastrointestinal disturbances in up to 30% of patients and is contraindicated in patients with inflammatory bowel disease, cirrhosis or elevated plasma creatinine levels.17 

Bile acid sequestrants (BAS) were initially developed as lipid lowering agents for hypercholesterolemia and were also found to improve the glycemic index. The exact mechanism for its anti-hyperglycemic effect is unknown; however, one proposed mechanism is its effect on the farnesoid X receptor within the liver reduces endogenous glucose production.17,19 

BAS has been shown to decreased fasting glucose 15mg/dl and decrease HbA1c 0.5%. Gastrointestinal side effects are common with BAS treatment, since these agents bind to bile acids within the intestine.17,19

Oral Therapies for DR

Many ocular complications accompany diabetes, including, but not limited to, dry eye, premature cataract formation, increased risk of glaucoma, retinal vein and artery occlusions and most commonly DR. Researchers estimate that up to 93 million people worldwide are affected by diabetic eye disease and, in developed countries, DR is the leading cause of vision loss in adults of working age.20

Key factors in the pathogenesis of DR include microangiopathy and capillary occlusion, which cause a breakdown of the blood-retinal barrier and result in hemorrhage, exudates and edema.21 Microvascular occlusion and ischemia contribute to the formation of cotton-wool spots, arteriovenous shunting and neovascularization.21 Additionally, research shows an increase in vascular endothelial growth factor (VEGF) contributes to the progression of DR.21 

A 57-year-old white male with severe PDR.
A 57-year-old white male with severe PDR. Click to enlarge.

Oral diabetes medications discussed above, as well as insulin, act to control diabetes and that control ultimately reduces the likelihood of diabetic retinal changes.22 The Diabetes Control Complications Trial demonstrated that tight control of blood sugar lowers the risk of these complications by roughly 60%.23 For each 10% reduction in hemoglobin A1c (i.e., 8% to 7.2%), there was a 42% reduction in the risk for retinopathy.23 

For moderate to severe forms of retinopathy, therapies such as intravitreal VEGF medications and laser photocoagulation help to treat vascular proliferation. 

There are, however, other targets in the retina that move beyond the vascular tree. These novel targets may be the future of treatment of diabetic retinopathy, especially in its early stages. As the understanding of the pathophysiological pathways of diabetes expands, more novel therapies and therapeutic targets will be discovered. We will touch on a few such therapies and targets, but this list is not exhaustive.

Tetracyclines. The upregulation of immune modulators in the retina has shown to be associated with diabetic retinopathy. Microglia are the primary immune cells in the retina and are part of the inflammatory cascade that leads to diabetic retinopathy. These cells have been shown to grow in the diabetic retina, causing increased inflammation and damage. The tetracycline class of antibiotics has showed promise in attacking this pathway. Minocycline is a second generation tetracycline with known anti-inflammatory properties.24 Microglia happen to be targeted by minocycline, thus it has been investigated as a therapy for diabetic retinal changes.

A few small studies have demonstrated improvement in diabetic macular edema and visual acuity in patients that took minocycline more than six months. One such study shows mean improvement in retinal thickness and no increase in edema in four out of five patients who had taken 200mg of oral minocycline after six months.24 Almost all patients in the intervention group had mean improvement in best corrected visual acuities.

Doxycycline is another tetracycline shown to have a positive effect on retinal function in patients with diabetes. One study used the change in mean foveal sensitivity, measured by frequency-doubling perimetry, as the primary measure of retinal function.25 Study participants with severe nonproliferative diabetic retinopathy and non-high risk proliferative diabetic retinopathy were randomized to placebo or 50mg of oral doxycycline per day. The mean foveal sensitivity improved the treatment group as opposed to the placebo group after six months.25 This outcome, however, was not replicated in an identical study that enrolled patients with mild or moderate nonproliferative diabetic retinopathy.25

Limitations of all studies on oral tetracyclines are the small sample size and the lack of repeatable results. More work is needed to show the practical use of these drugs, as well as uncovering other targets. 

Vitamin and Mineral Therapy 

Patients with poorly controlled diabetes are susceptible to multiple micronutrient deficiencies.26 While we’ve seen anecdotal evidence of the benefits of supplementation of minerals—including chromium, zinc and calcium; and vitamins A, C and E—diabetes patients should be educated about the importance of acquiring daily vitamin and mineral requirements from natural food sources, including a plant-based diet.26 At the present time there are no placebo-controlled trials demonstrating benefits from vitamin or mineral supplementation in patients with diabetes who do not have underlying deficiencies, above the recommended dietary intake.26

Microbiome Therapy

Researchers have referred to intestinal microbiota itself as a “new organ” which affects many biological systems throughout the body, including the immune and nervous systems and metabolic functions.27 Type 2 diabetes is associated with abnormal energy metabolism and low-level chronic inflammation, and the resident microbiota associated with chronic inflammation is shown to contribute to the disease’s onset.28 

A 74-year-old black female with severe nonproliferative diabetic retinopathy.
A 74-year-old black female with severe nonproliferative diabetic retinopathy. Click to enlarge.

Intestinal bacteria are in an essential symbiotic relationship with their human host, aiding in the regulation of intestinal permeability and immune system function. Growing evidence shows an altered composition of gut microbiota, in particular a higher Firmicutes/Bacteriodetes ratio in patients with insulin resistance compared with healthy patients.27-29 Researchers propose that the altered microbiota negatively affect intestinal permeability, and can lead to an increase in various opportunistic pathogens, particularly endotoxin producing gram-negative bacteria. An accumulation of gut-derived bacterial inflammatory molecules in the intestine is thought to accelerate the inflammation, considered a deterioration factor in Type 2 diabetes.28

Some probiotic strains are able to modulate blood glucose homeostasis, and improve Type 2 diabetes and its related complications.28 While the exact mechanism for the improvement seen with the use of probiotics is not yet clear, researchers propose its favorable effects are due to immune system modulation through antioxidative properties.28

Current approaches that are being investigated are: probiotic supplementation with live strains of Bifidobacteria and Lactobacilli and prebiotics, which are nondigestible fermentable fibers that shift the composition of gut microbiota by stimulating the growth or activity of beneficial species—such as inulin and lactulose.29

However, further research is needed to identify the specific therapeutic types of bacterial strains that will elucidate beneficial patterns in gut microbiota composition. 

Fenofibrate 

One drug has received major attention as novel medical treatment for DR and has shown promise in the prevention of diabetic microvascular complications. Fenofibrate is an orally administered fibric acid derivative that is conventionally used to treat hypertriglyceridemia, low HDL-C levels or as adjunct to statin therapy in dyslipidemia.29 Fenofibrate is also shown to have beneficial effects on inflammation, angiogenesis and cell apoptosis.29 

Two prospective randomized controlled trials were conducted to evaluate its effect on cardiovascular outcomes and included the assessment of fenofibrate as a possible systemic treatment for DR in substudies:

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

The FIELD study looked at 9,795 patients for more than five years and found patients with existing DR who were treated with 200mg/day of fenofibrate required treatment with laser photocoagulation less frequently than those who had not received fenofibrate.31

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study.

Researchers from the ACCORD Eye Study followed 2,856 subjects for four years and found that those treated with 160mg/day of fenofibrate along with simvastatin had a 40% decrease in DR progression compared with simvastatin alone.32 

Micro-nutritional Supplements 

The effect diabetes plays on visual function is more apparent than ever—specifically, its impact on contrast and visual field sensitivity, color vision, macular pigment density and multifocal ERG prior to the development of DR. New attention is being given to the use of nutritional supplementation.

The Diabetes Visual Function Supplement Study (DiVFuSS), a randomized controlled clinical trial performed in 2015, looked at supplementation as an additional way to improve visual function in diabetes patients.41 

The DiVFuSS formula consists of: vitamins C, D3 and E (d-a tocopherol), zinc oxide, eicosapentaenoic acid, docosahexaenoic acid, a-lipoic acid (racemic mixture), coenzyme Q10, mixed tocotrienols/tocopherols, zeaxanthin, lutein, benfotiamine, N-acetyl cysteine, grape seed extract, resveratrol, turmeric root extract, green tea leaf and Pycnogenol.41

At the end of the six-month trial, the study showed statistically significant improvement in visual function in those patients taking the multi component nutritional supplement compared with placebo among subjects with established diabetes early DR or both, and without significantly affecting blood glucose control.41

Based on both the FIELD and the ACCORD studies, new recommendations are being considered to include the use of fenofibrate in Type 2 diabetes patients with pre-proliferative DR or DME or both, requiring laser along with statin therapy to reduce the progression of DR and reduce the need for laser intervention.33,34

Hypertensive Therapy

Systemic hypertension is a known risk factor for the progression of DR.2,35-37 In the UKPDS, tight blood pressure control (defined as target blood pressure <150/85mm Hg) in patients with Type 2 diabetes reduced the risk of both microvascular disease and deterioration of visual acuity; it also decreased the rate of progression of DR.13,35,36 

Certain medications that affect the diabetic microvascular complication of diabetic nephropathy have also been studied for their effects in treating DR. The Diabetic Retinopathy Candesartan Trials (DIRECT) shows that candesartan reduces the incidence of retinopathy in patients with Type 1 diabetes, and increased regression of retinopathy in patients with Type 2 diabetes.38,39 However, regression was only seen in cases of mild retinopathy, and candesartan was not shown to have any effect on incidence or progression of DME.35,38,39

The Renin-Angiotensin System Study (RASS) study shows enalapril and losartan both reduce the risk of retinopathy progression.35 However, this effect was independent of blood pressure changes and it was proposed that risk reduction of diabetic retinopathy seen during the study was not mediated by the effect on hypertension.35,38,39

Intensive blood pressure control for the sole purpose of slowing the progression of DR is not recommended; rather, hypertensive control in diabetes patients should be targeted on reducing other vascular complications, such as nephropathy and decreasing mortality.35,40

Optometric Considerations

The control of blood sugar is a tight balance. The diagnosis of diabetes is characterized by the inability of the body to process glucose properly, leading to elevated blood glucose, or hyperglycemia. While we often worry about blood glucose being too high for these patients, hypoglycemia can also be dangerous. Measured blood glucose of less than 70mg/dl is considered hypoglycemic.42 Symptoms include shakiness, increased anxiety, increased sweating, clammy hands and skin, confusion and headache. If severe, a hypoglycemic event can lead to seizures, loss of consciousness and death.

If a diabetes patient shows any of these signs and has not eaten recently, the patient should take in roughly 15g to 20g of simple carbohydrates. This equates to two tablespoons of raisins, four ounces of juice or regular soda, one tablespoon of a sweetener (honey, corn syrup, sugar) or eight ounces of nonfat milk.42 There are commercially available glucose tablets or gels that provide this glucose as well. Having some or all of these simple carbohydrates in the office can save your diabetes patient’s life someday.

After ingesting simple sugars, the patient’s blood sugar should be measured in 15 minutes. If it continues to be low, more of the simple carbohydrate should be taken. If severe cases of hypoglycemia glucagon must be injected. Glucagon is a hormone that stimulates the release of stored glucose into the blood stream. It is to be injected intramuscularly into the buttock, arm or thigh. 

With the rate of diabetes only projected to increase, optometrists stand to be an integral part of the comanagement of diabetes and prediabetes patients. Understanding the role of oral medications in the treatment of diabetes both systemically and from an ocular standpoint will enhance overall patient care and improve treatment outcomes. 

Dr. Tolud is in practice at South Jersey Eye Physicians, Columbus, NJ. 

Dr. Harewood is in practice at Staten Island University Hospital, Retina Center, Staten Island, NY.

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25. Scott I, Jackson G, Quillen D, et al. Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol. 2014 May;132(5):535-43.

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