Diabetes is a complicated beast, with a host of available medications that can make treatment decisions difficult. Every patient is different, so clinicians must treat the person, not the disease. Some basic rules apply, however, and pharmacists can use them as quick references to improve patient outcomes. 

GENERIC TYPE 2 DIABETES
Metformin is the first-line, old-faithful treatment for diabetes mellitus.1,2 In use for more than 60 years, it was the eighth-most-prescribed drug in the United States consistently between 2008 and 2012.3 Metformin lowers hemoglobin A1C (HbA1C) by 1% to 1.5% and does not cause the weight gain often seen with sulfonylureas. In fact, metformin can provide a weight loss benefit. Its drawbacks include gastrointestinal (GI) adverse effects, which can be minimized by titrating the dose up slowly, taking it after or with food, and switching to the extended-release formula- tion when necessary.2,3

For HbA1C that remains elevated with 2 or 3 medications on board, the American Diabetes Association (ADA) recommends adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) first whenever possible.1 Health care providers should consider insulin first under certain circumstances (see table 1). Although GLP-1RAs and insulin show similar effectiveness in patients with poorly controlled diabetes, recent study results show that GLP-1RAs lower the risk of hypoglycemia and may decrease body weight, albeit with increased GI adverse effects.1



DOUBLE DIABETES
Although most clinicians are familiar with type 1 diabetes (T1D) and type 2 diabetes (T2D), a third type, double diabetes, is gaining traction. Loosely defined, double diabetes is T1D with subsequent insulin resistance, as in T2D. Patients and practitioners should focus on minimizing weight gain and/or promoting weight loss.4 GLP-1RAs and sodium-glucose cotransporter 2 (SGLT2) inhibitors often promote weight loss in people with diabetes. From most to least effective, semaglutide, liraglutide, dulaglutide, exenatide, and lixisenatide are associated with weight loss through multiple mechanisms.1 GLP-1 delays gastric emptying, slows gut motility, and stimulates central and peripheral receptors responsible for satiety.5 SGLT2 inhibitors increase urinary glucose excretion and subsequently inhibit sodium reuptake. This causes a metabolic shift in the body toward lipolysis, leading to loss of body fat.6

COMORBID ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
For patients with atherosclerotic cardiovascular disease, initiation on a drug proved to reduce cardiovascular (CV) events/mortality is best. Some GLP-1RAs, including (form most to least effective) liraglutide, semaglutide, and exenatide extended release, have CV benefits in diabetes.1 In addition to metabolic benefits, GLP-1 positively affects atherosclerosis progression and inflammation, blood pressure, heart failure, myocardial ischemia, and vascular endothelium. Naturally, augmenting activity at GLP-1 receptors in the body amplifies these benefits.7

The use of any SGLT2 inhibitor has been shown to reduce the risk of CV events and hospitalization for heart failure. Of the medications in this class, empagliflozin has shown the most cardiac benefit, with canagliflozin following closely behind. Investigators have suggested many mechanisms for SGLT2 inhibitors’ CVbenefit.8

RENAL FAILURE
Treatment of patients with diabetes who have renal disease can be tricky, and prescribers should dose-adjust most antidiabetic drugs for renal impairment. Metformin continues to be the drug of choice, even with chronic kidney disease. If patients’ estimated glomerular filtration rate (eGFR) is at least 30 to 60 mL/min, clinicians can initiate metformin with a reduced dose of 500 to 1500 mg.

If patients’ HbA1C is still above the goal after 3 months of metformin treatment, symptoms drive the next steps. In patients who are symptom free, prescribers should start a dipeptidyl-peptidase-4 (DPP-4) inhibitor, repaglinide, pioglitazone, glyburide, or glipizide. Patients who are symptomatic need insulin. Those with eGFR <30 mL/min should not use metformin.2 As an alternative for these patients, prescribers should start a DPP-4 inhibitor first, then follow the latter steps of the aforementioned guidelines, paying attention to required dose reductions for renal failure.9

Adhering to the most up-to-date diabetes treatment guidelines is important, and the ADA guidelines are ever changing. Clinical inertia is the lack of treatment intensification at appropriate times in patients failing to meet treatment goals.10 To avoid this in patients with diabetes, providers should reassess patients every 3 to 6 months and modify treatment as necessary.4 The figure10 suggests ways to overcome clinical inertia.



Pharmacists should refer patients to their prescribers for reevaluation when adherence to therapy is poor. Pharmacists should watch for symptoms of hyperglycemia indicating poor glycemic control, such as blurred vision, frequent urination, headaches, and increased thirst, and/or for treatment that appears to stagnate for an extended period.
 
Kelsey Giara is a freelance writer based in New Hampshire.

Jeanette Y. Wick, RPh, MBA, FASCP, is the assistant director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

REFERENCES
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  2. Glucophage XR (prescribing information). Princeton, NJ: Bristol- Myers Squibb Co; 2017. www.accessdata.fda.gov/drugsatfda_docs/ label/2008/020357s031,021202s016lbl.pdf. Accessed September 11, 2019.
  3. Marshall SM. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia. 2017;60(9):1561-1565. doi: 10.1007/s00125-017-4343-y.
  4. Standards of medical care in diabetes. American Diabetes Association website. professional.diabetes.org/content-page/standards-medical-care-diabetes/. Accessed July 19, 2019.
  5. Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15(3):181-187. doi: 10.1007/s11154-014-9289-5.
  6. Lee PC, Ganguly S, Goh SY. Weight loss associated with sodium-glucose cotrans- porter-2 inhibition: a review of evidence and underlying mechanisms. Obes Rev. 2018;19(12):1630-1641. doi: 10.1111/obr.12755.
  7. Del Olmo-Garcia MI, Merino-Torres JF. GLP-1 receptor agonists and cardiovascular disease in patients with type 2 diabetes. J Diabetes Res. 2018;2018:4020492. doi: 10.1155/2018/4020492.
  8. Cardiovascular benefits of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. JAMA. 2019;321(17):1720-1721. doi: 10.1001/jama.2019.2702.
  9. Ioannidis I. Diabetes treatment in patients with renal disease: is the landscape clear enough? World J Diabetes. 2014;5(5):651-658. doi: 10.4239/wjd.v5.i5.651.
  10. Reach G, Pechtner V, Gentilella R, Corcos A, Ceriello A. Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus. Diabetes Metab. 2017;43(6):501-511. doi: 10.1016/j.diabet.2017.06.003.