T2DM: We’ve Got The Meds

A1C targets 

• American Association of Clinical Endocrinology (AACE): 
  • <6.5% for patients who meet the following criteria:
    • Short duration of diabetes
    • Long life expectancy
    • No concurrent illness
    • Goal can be achieved without significant hypoglycemia or other adverse effects of treatment
  • <7.0%, a reasonable goal for many patients
  • <8.0% for patients who meet the following criteria:
    • History of severe hypoglycemia
    • Limited life expectancy
    • Advanced microvascular or macrovascular complications
    • Extensive comorbid conditions
    • Long-standing T2DM in which A1C goal has been difficult to obtain despite intensive efforts
• American Diabetes Association (ADA):
  • An A1C goal for many nonpregnant adults of <7% without significant hypoglycemia is appropriate. 
  • On the basis of provider judgment and patient preference, achievement of lower A1C levels than the goal of 7% may be acceptable, and even beneficial, if it can be achieved safely without significant hypoglycemia or other adverse effects of treatment. 
  • Less stringent A1C goals (such as <8%) may be appropriate for patients with limited life expectancy, or where the harms of treatment are greater than the benefits. 
• U.S. Department of Veterans Affairs/U.S. Department of Defense (VA/DoD): 
  • Targets depend on the presence and severity of both major comorbidities and microvascular complications: 
    • Target A1C 6-7% in patients with no major comorbidities (i.e., life expectancy >10yr) and no microvascular complications
    • Target A1C 8-9% in patients with major comorbidities (i.e. life expectancy <5yr) or advanced microvascular complications
• American College of Physicians (ACP):
  • Clinicians should aim to achieve an A1c level between 7% and 8% in most patients with T2DM.

Lifestyle Modifications Come First!

We spend a lot of time talking about pharmacotherapy in treating T2DM, but lifestyle modifications are essential. 

• The role of proper diet, physical activity and body weight should all be discussed and should be readdressed at every visit. 
• The initial diagnosis of T2DM should ideally prompt a referral to a nutritionist. 
  • Medical Nutrition Therapy (MNT) by registered dietitians reduces A1C levels by up to 2% in adherent patients after 3-6 months
• Exercise (aerobic and resistance training) may reduce reduce A1C levels by 0.5%

The Magic of Metformin

Metformin is first-line therapy for T2DM for good reason: 

• Lots of good effects (see MOA below), which reduce A1C levels by up to 1.5% (high efficacy in comparison with other diabetes medications)
• Relatively low risk and low cost

Mechanism of action:

• Decreases hepatic glucose output by reducing gluconeogenesis and glycogenolysis
• Enhances peripheral glucose uptake and enhancing insulin sensitivity (i.e., decreases insulin resistance)
• Modestly decreases glucose absorption in the GI tract (hence the common GI side effects)
• Decreases triglyceride levels, lowers LDL, and may increase HDL

Considerations:

• Metformin should be administered with the largest meal of the day, or if in divided doses, it should be administered with breakfast and dinner
• Metformin can cause vitamin B12 deficiency
• Studies have shown metformin is associated with an increased risk of lactic acidosis in renal and hepatic insufficiency, as well as CHF. Patients with a GFR <30 mL/min should not be treated with metformin

So many options…

SGLT2 inhibitors (SGLT2i)

• Rx: canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro)
• Sodium-Glucose co-Transporter 2 (SGLT2) mediates 90% of renal glucose reabsorption, so SGLT2 inhibitors increase glucose excretion via glycosuria
• A1C efficacy: intermediate

GLP1 receptor agonists (GLP1-RA)

• Rx: exenatide (Byetta), liraglutide (Victoza), dulaglutide (Trulicity), semaglutide (Ozempic)
• GLP1-RA mimics incretin, which stimulates insulin secretion, leading to decreased gastric emptying, decreased glucagon secretion, and increased satiety
• A1C efficacy: high

DPP4 inhibitors (DPP4i)

• Rx: sitagliptin (Januvia), saxagliptin (Onglyza), lanagliptin (Tradjenta)
• DPP4 enzyme degrades incretin, so DPP4 inhibitors increase endogenous GLP-1 and GIP levels, leading to decreased gastric emptying, decreased glucagon secretion, and increased satiety
• A1C efficacy: intermediate

Sulfonylureas (SU)

• Rx: glipizide (Glucotrol), glimepiride (Amaryl), glyburide (DiaBeta, Glynase), tolbutamide (Orinase)
  • 2nd gen SU (e.g., glipizide, glyburide, glimepiride) have lower risk of hypoglycemia
• Sulfonylureas are secretogues, which inhibits β-cell K-ATP channels, leading to increased insulin secretion (i.e., only works in patients with β-cell function)
• A1C efficacy: high

Thiazolidinediones (TZD)

• Rx: pioglitazone (Actos), rosiglitazone (Avandia)
• TZD activates transcription regulator PPAR-ɣ, leading to decreased hepatic glucose production and decreased insulin resistance
• A1C efficacy: high

Amylinomimetics

• Rx: pramlintide
• Pramlintide decreases gastric emptying, decreases glucagon secretion, and increases satiety

α-glucosidase inhibitors

• Rx: acarbose (Precose), miglitol (Glyset)
• α-glucosidase inhibitors decrease intestinal polysaccharide absorption

Meglitinides

• Rx: repaglinide (Prandin), nateglinide (Starlix)
• Meglitinides are secretogues, which inhibits β-cell K-ATP channels, leading to increased insulin secretion (i.e., only works in patients with β-cell function)

Benefits & Risks

ASCVD benefit: 

• Metformin (potential benefit)
• SGLT2i: canagliflozin and empagliflozin
• GLP1-RA: liraglutide, semaglutide, and exenatide ER

Medications that improve CHF outcomes:

• SGLT2i: canagliflozin, empagliflozin, and dapagliflozin 

Medications that may worsen CHF outcomes:

• DPP4i: saxagliptin and alogliptin
• TZD: black box warning for CHF risk

Weight loss: 

• SGLT2i
• GLP1-RA
• Metformin (modest)

Weight gain: 

• SU
• TZD
• Insulin

Potential hypoglycemia: 

• SU
• Insulin

CKD benefit:

• SGLT2i: canagliflozin, empagliflozin, and dapagliflozin
• GLP1-RA: liraglutide

In thinking about CKD benefit, consider the removed cardiorenal risk, which represents the risk of progression of cardiovascular events (i.e., MACE) and diabetes kidney disease (DKD) taken away by optimal glycemic control or the use of GLP1-RA and SGLT2i in patients with T2DM, as demonstrated by the results of intensive glucose lowering trials (IGT) and cardiovascular outcome trials (CVOT).

• IGT have shown that successful glycemic control has modest benefits, as the removed cardiorenal risk ranges from 9% for MACE to 20% for progression of DKD. The removed risk of MACE is 13% for GLP-1RA and 12% for SGLT-2i. However, SGLT-2i, as compared with GLP-1RA, removed twofold more risk (39% vs 17%) for kidney outcomes and fourfold more risk (33% vs 9%) for HF. 

Medications requiring dose adjustment in CKD patients:

• Metformin: contraindicated if GFR <30 mL/min
• SGLT2i: dose adjustment varies by agent
  • generally avoided when GFR <30
• GLP1-RA: may be associated with AKI
  • exenatide and lixisenatide require dose adjustment (exenatide is contraindicated when GFR <30
• DPP4i: adjust dose if GFR <50 (except linagliptin)
• TZD: generally avoided in CKD due to risk of fluid retention
• SU: glyburide not recommended in CKD (may accumulate, leading to hypoglycemia)
• Insulin: lower doses needed in CKD

How much $$$ did you say?

By now you’ve probably heard about the rising costs of insulin. But list prices for non-insulin diabetes medications are also increasing—GoodRx estimates that these drugs have increased 76% from 2014 to 2019. In fact, many patients don’t take their diabetes medications as prescribed in an attempt to lower costs. 

But affordable options are available. For instance, non-insulin medications on Walmart’s $4 list include metformin, three sulfonylureas (glipizide, glimepiride, glyburide), and one TZD (pioglitazone). 

Blog post based on Med-Peds Forum talk by Ruth Cadet, PGY2, and Julia Solomon, PGY3