Diabetes: Disease-Modifying Therapies

The number of Americans with diabetes rose from 5.6 million in 1980 to 21 million in 2014, with an additional 8.1 million individuals still undiagnosed.^1,2 As of 2011 in the United States, 11.8 million patients were taking only oral medications for their diabetes, 2.9 million were using insulin only, and an additional 2.9 million were using a combination of the two.³ The Centers for Disease Control and Prevention listed diabetes as the seventh leading cause of death in the United States in 2013, with 75,578 deaths.⁴ This national epidemic resulted in a financial burden of approximately $245 billion in 2012.⁵

Coexisting conditions and complications (eg, hypoglycemia, hyperglycemic crisis, hypertension, hyperlipidemia, diabetic retinopathy, nephropathy, diabetic neuropathy, amputation) are all too common among patients who have diabetes. Other conditions associated with diabetes include nonalcoholic fatty liver disease, periodontal disease, hearing loss, depression, erectile dysfunction, and pregnancy complications.

The goal of therapy is to maintain a normal blood glucose level and reduce cardiovascular risk factors. Although patients with type 1 diabetes (T1D) require exogenous insulin provided either by inhalation, injection, or infusion through an insulin pump, patients with type 2 diabetes (T2D) can control their blood glucose levels with healthy eating habits, regular exercise, and medications. A plethora of agents are available to treat diabetes. Here is a brief summary of each class. For dosing information, please see Online Table 1.

Table 1: Dosing of Agents for Treating Diabetes

Class/Drug Name

Available Strengths

Daily Therapeutic Dose

Special Requirements

Biguanides

Metformin

Metformin ER

500 mg (also ER)

750 mg (also ER)

850 mg

1000 mg (also ER)

500 mg/5 mL

500-2000 mg/day

Max dose: 2550 mg

Divide doses

Take with food

Sulfonylureas

Glyburide

Standard: 1.25, 2.5, and 5 mg

Micronized:

1.5, 3, 4.5, and 6 mg

Standard: 2.5-20 mg

Micronized: 0.75-12 mg

Max dose:

Standard: 20 mg

Micronized: 12 mg

With breakfast

Glipizide

Standard: 2.5, 5, or 10 mg

Extended-release: 5 and 10 mg

Standard: 2.5-20 mg

Max single dose: 15 mg

Max daily dose: 40 mg

Max daily dose (ER): 20 mg

30 minutes before meals

Glimepiride

1, 2, and 4 mg

1-4 mg

Max daily dose: 8 mg

With first main meal of the day

Meglitinide Derivatives

Repaglinide

0.5, 1, and 2 mg tablets

0.5-2 mg

Within 15 minutes of every meal

Nateglinide

60 and 120 mg

180-360 mg

Before meals

Alpha-Glucosidase Inhibitors

Acarbose

25, 50, and 100 mg

75-300 mg

Max weight <60 kg: 150 mg

Max weight >60 kg: 300 mg

With first bit of each main meal (3 times per day)

Miglitol

25, 50, and 100 mg

75-300 mg

Max: 300 mg

With first bite of each main meal (3 times per day)

Thiazolidinediones

Pioglitazone

15, 30, and 45 mg

15-45 mg

Max: 45 mg

With or without food

Rosiglitazone

2, 4, and 8 mg

4-8 mg

Max: 8 mg

With or without food

Glucagon-like Peptide-1 Agonists

Exenatide

5 mcg/0.02 mL and 10 mcg/0.04 mL

10-20 mcg

Max single dose: 10 mcg

Inject subcutaneously up to 60 minutes before meals (twice a day)

Do not inject after meals

Liraglutide

18 mg/3 mL

0.6-1.8 mg

Inject subcutaneously once daily without regard to meals

Albiglutide

30 mg and 50 mg

30-50 mg

Inject subcutaneously once weekly

Dulaglutide

0.75 mg/0.5 mL

1.5 mg/0.5 mL

0.75-1.5 mg

Inject subcutaneously once weekly

Dipeptidyl Peptidase IV Inhibitors

Sitagliptin

25, 50, and 100 mg

100 mg

Swallow whole with or without food

Saxagliptin

2.5 and 5 mg

2.5-5 mg

With or without food

Linagliptin

5 mg

5 mg

With or without food

Alogliptin

6.25, 12.5, and 25 mg

25 mg

With or without food

Amylinomimetics

Pramlintide

600 and 1000 mcg/mL

45 mcg

Inject subcutaneously immediately before each major meal

Selective Sodium-Glucose Transporter-2 Inhibitors

Canagliflozin

100 mg

100-300 mg

Swallow whole before first meal of the day

Dapagliflozin

5 and 10 mg

5-10 mg

Take in morning with or without food

Empagliflozin

10 and 25 mg

10-25 mg

In the morning with or without food

Bile Acid Sequestrants

Colesevelam

625, 1875, and 3750 mg

3750 mg

Single or 2 divided doses; separate from administration of other medications

Dopamine-2 Agonists

Bromocriptine mesylate

0.8-mg tablet

0.8-4.8 mg

Within 2 hours of waking with food

^{ER = extended release.}

Insulins

Many forms of insulin are available to treat patients who have T1D or T2D. These insulins are grouped according to time to onset and duration of action.6 Physicians will prescribe based on a number of factors, including patient response, lifestyle choices, number of injections a patient can handle, blood glucose monitoring, age, and goals. See Online Table 2⁶ for a list of available agents. Dosing is done on an individual basis, often using a sliding scale based on the amount of carbohydrates consumed.

Table 2: Insulins⁶

Type of Insulin and Brand Names

Onset (minutes)

Peak

Duration

Typical Schedule

Rapid-Acting

Lispro (Humalog)

15-30

30-90 minutes

3-5 hours

15 minutes before meal time

Aspart (NovoLog)

10-20

40-50 minutes

3-5 hours

Glulisine (Apidra)

20-30

30-90 minutes

1-1.5 hours

Short-Acting

Regular (humulin or novolin)

30-60

2-5 hours

5-8 hours

30-60 minutes before a meal

Velosulin (for use in pump)

30-60

2-3 hours

2-3 hours

Intermediate-Acting

Neutral protamine hagedorn (NPH)

60-120

4-12 hours

18-24 hours

Up to 60 minutes before a meal

Long-Acting

Glargine (Lantus)

60-90

No peak; continual

20-24 hours

Detemir (Levemir)

60-120

6-8 hours

Up to 24 hours

Pre-Mixed: Combination Intermediate- and Short-Acting Insulins

Humulin 70/30

30

2-4 hours

14-24 hours

Two to 3 times daily before meal time

Novolin 70/30

30

2-12 hours

Up to 24 hours

NovoLog 70/30

10-20

1-4 hours

Up to 24 hours

Humulin 50/50

30

2-5 hours

18-24 hours

Humalog mix 75/25

15

30-150 minutes

16-20 hours

Inhaled

Afrezza

12-15

30 minutes

3 hours

Biguanides

The only available biguanide in the United States is metformin, which is considered first-line therapy for T2D. Although the mechanism of action is not clearly understood, biguanides primarily reduce blood glucose levels by decreasing hepatic gluconeogenesis and secondarily increasing peripheral insulin sensitivity.⁷ Metformin does not increase body weight, has a low incidence of hypoglycemia, and may reduce cardiovascular risk, cancer, and mortality.⁷ Adverse effects (AEs) include diarrhea, abdominal cramping, and vitamin B₁₂ deficiency.

Sulfonylureas

Sulfonylureas (glyburide, glipizide, glimepiride) are used as monotherapy or in combination with other hypoglycemic agents or insulin. Sulfonylurea drugs stimulate insulin secretion from the pancreatic beta-cells by closing the ATP-sensitive K+-channels in the betacell plasma membrane. This depolarization opens up Ca²+-channels, resulting in increased fusion of insulin granulae and release of pro-insulin.⁸ Some sulfonylureas are metabolized by the liver and also induce the CYP450 system; therefore, some drug interactions may be anticipated. Possible AEs include weight gain and hypoglycemia.

Meglitinide Derivatives

Meglitinides derivatives (repaglinide, nateglinide) stimulate insulin secretion from the pancreatic beta-cells by closing the ATP-sensitive K+-channels in the beta-cell plasma membrane. They seem to cause less weight gain and hypoglycemia.⁹

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors (acarbose, miglitol) inhibit intestinal alpha-glucosidase, thereby slowing intestinal carbohydrate digestion and absorption. Because these drugs do not cause the pancreas to increase insulin production, hypoglycemia is not an issue. Flatulence and diarrhea are the most common AEs.

Thiazolidinediones

Thiazolidinediones (TZDs) (pioglitazone, rosiglitazone) increase insulin sensitivity by activating the nuclear transcription factor peroxisome proliferatoractivated receptor (PPAR-gamma). This activation alters gene transcription of several components involved in glucose and lipid metabolism.¹⁰ TZDs have positive effects on high-density lipoprotein cholesterol and triglycerides, and produce no hypoglycemia. Common AEs include weight gain, edema, heart failure, bone fractures, and negative effects on low-density lipoprotein cholesterol (LDL-C).

Glucagon-like Peptide-1 Agonists

Glucagon-like peptide-1 (GLP-1), considered an incretin, is released from the gut in response to ingestion of nutrients. This peptide affects gut motility and inhibits gastric acid and glucagon secretion. In the pancreas, GLP-1 induces expansion of insulin-secreting beta-cell mass and augments glucose-stimulated insulin secretion through manipulation of ion channels—such as K+ _ATP, voltagedependent Ca²+, and K+ channels—and nonselective cation channels, as well as by the regulation of intracellular energy homeostasis and exocytosis.¹¹

GLP-1 agonists (exenatide, liraglutide, albiglutide, dulaglutide) do not cause hypoglycemia; their major benefits include weight loss and reduction of some cardiovascular risk factors. Available only as injectables, GLP-1 agents require administration training. Common AEs include nausea, vomiting, diarrhea, and increased heart rate.

Dipeptidyl Peptidase IV (DPP-4) Inhibitors

DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) inhibit the degradation of the incretins such as GLP-1 and glucose-dependent insulinotropic peptide. Therefore, DPP-4 inhibitors are considered to be comparable to GLP-1 therapies in terms of mechanism of action and AEs; however, these drugs are administered orally.¹²

Amylinomimetics

Human amylin is co-located and cosecreted with insulin by the pancreas. In patients who have T1D or T2D, there is a reduction in these secretions from the pancreatic beta-cells in response to nutrient ingestion. Amylin slows gastric emptying without altering the overall absorption of nutrients and suppresses glucagon secretion, thereby suppressing endogenous glucose output from the liver. Amylinomimetics (pramlintide) have a positive effect on body weight. The most notable AEs include nausea, vomiting, and hypoglycemia. Available only as an injectable, this agent requires administration training and has a frequent dosing schedule.

Selective Sodium-Glucose Transporter-2 Inhibitors

Selective sodium-glucose transporter-2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) are located in the S1 and S2 segments of the proximal convoluted tubules of the kidneys and have a high capacity for glucose transport, reabsorbing approximately 90% of filtered glucose in healthy individuals. SGLT-2 inhibitors reduce that reabsorption, resulting in increased urinary excretion of glucose and lower blood glucose levels. SGLT-2 inhibitors work independently of insulin; therefore, they do not create hypoglycemia. The most common AEs are genital mycotic infections in males and females, as well as urinary tract issues such as frequent urination and urinary tract infections. Hypotensive episodes and acute deterioration of kidney function have also been observed.

Bile Acid Sequestrants

The exact mechanism by which bile acid sequestrants (BASs) (colesevelam) exhibit glycemic regulation remains unexplained. However, they may affect the secretion of incretin hormones such as GLP-1 and GIP, as well as reduce hepatic glucose production. Hypoglycemia is not an issue, and BASs have positive effects on LDL-C. Administration should be separate from other medications, as BASs can decrease absorption of these medications. Constipation, upset stomach, and diarrhea are common AEs. Colesevelam may increase triglyceride levels.

Dopamine-2 Agonists

The mechanism of action of dopamine-2 agonist bromocriptine mesylate has not yet been elucidated; however, it is unique in that it does not have a specific receptor mediating its action on glucose metabolism. Instead it works in the central nervous system by resetting dopaminergic and sympathetic tones. Notable AEs include nausea, fatigue, dizziness, syncope, and rhinitis.

Conclusion

Pharmacists are in a unique position to contribute to medication selection based on the combined dynamics of the patient, disease progression, medical history, comorbidities, and other factors. Understanding the mechanism of action and AE profile of each class of these medications can help determine the appropriate choice.

Dr. Kenny earned her doctoral degree from the University of Colorado Health Sciences Center. She has 20-plus years’ experience as a community pharmacist and works as a clinical medical writer based out of Colorado Springs, Colorado. Dr. Kenny is also the Colorado education director for the Rocky Mountain Chapter of the American Medical Writer’s Association.

References

• Number (in millions) of civilian, noninstitutionalized persons with diagnosed diabetes, United States, 1980-2011. Centers for Disease Control and Prevention website. www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Updated March 28, 2013. Accessed August 9, 2015.
• 2014 national diabetes statistics report. Centers for Disease Control and Prevention website. www.cdc.gov/diabetes/data/statistics/2014StatisticsReport.html. Updated May 15, 2015. Accessed August 9, 2015.
• Data and statistics. Centers for Disease Control and Prevention website. www.cdc.gov/diabetes/statistics/. Accessed August 9, 2015.
• Deaths and mortality. Centers for Disease Control and Prevention website. www.cdc.gov/nchs/fastats/deaths.htm. Updated February 6, 2015. Accessed August 9, 2015.
• National diabetes statistics report, 2014: estimates of diabetes and its burden in the United States. Centers for Disease Control and Prevention website. www.cdc.gov/diabetes/pdfs/data/2014-report-estimates-of-diabetes-and-its-burden-in-the-united-states.pdf. Accessed August 9, 2015.
• Types of insulin for diabetes treatment. WebMD website. www.webmd.com/diabetes/guide/diabetes-types-insulin. Accessed August 11, 2015.
• Type 2 diabetes mellitus medication. MedScape website. http://emedicine.medscape.com/article/117853-medication. Accessed August 1, 2015.
• Rena G, Pearson E, Sakamoto K. Molecular mechanism of action metformin: old or new insights? Diabetologia. 2013;56(9):1898-1906. doi: 10.1007/s00125-013-2991-0.
• Healthwise staff. Meglitinides for Type 2 Diabetes. WebMD website. www.webmd.com/diabetes/meglitinides-for-type-2-diabetes. Updated November 14, 2014. Accessed August 8, 2015.
• Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev. 2002;18(suppl 2):S10-S15.
• Macdonald P, El-kholy W, Riedel MJ, et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes. 2002;51(suppl 3):S434-S442.
• Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab. 2009;23(4):479-486. doi: 10.1016/j.beem.2009.03.004.