Diabetes updates are a game changer

On The Cover

Loren Bonner

Pharmacists and other health care professionals have anxiously awaited the most recent update to the Standards of Medical Care in Diabetes from the American Diabetes Association (ADA), which is finally here with some important updates, including how health care providers can approach pharmacologic treatment for those with type 2 diabetes.

“The big news is that metformin is no longer your choice of first line therapy,” said Susan Cornell, PharmD, FAPhA, from Midwestern University College of Pharmacy. “We have better drugs with better benefits.”

The two new drug classes that are taking center stage are SGLT-2 inhibitors and glucagon-like peptide-1 (GLP-1) agonists. They are recommended as first-line treatment with or without metformin for people with type 2 diabetes who have or who are at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease (CKD).

Cornell did note the high cost for these newer glucose-lowering drugs with cardiovascular benefits, which is concerning—especially given how expensive insulin continues to be for people with diabetes.

“Metformin has seen its time. It’s time to retire metformin,” said Cornell, who spoke about the updates at APhA2022 in San Antonio.

Plus, metformin’s ability to control glucose appears unsustainable. Metformin can improve liver function, but type 2 diabetes is a result of 8 or more organ defects, which is a reason combination therapy is recommended for optimal management.

Overall, these new drug classes are a preferred treatment, said Cornell. “Not only do they help lower blood glucose, but they improve cardiovascular disease. Another benefit of these two classes of drugs is weight loss.”

Evan M. Sisson, PharmD, BCACP, said that much in this year’s ADA update recognizes the fundamental health benefit of addressing weight loss for type 2 diabetes patients. “Now we have GLP-1 antagonists as a class and they are effective at helping people lose weight, and you [can] layer that on with lifestyle modifications—that’s a game changer,” he said.

Previously, the recommended intervention was lifestyle modifications plus metformin. “It was lockstep,” said Sisson.

A detailed meta-analysis of diabetes medications can be found on page 34.

Treating obesity first

According to the 2022 National Diabetes Statistics Report, 11.3% of the U.S. population has diabetes. New cases are higher among non-Hispanic Blacks and other people of Hispanic origin. Additionally, 38% of Americans have prediabetes.

“What’s most alarming to me is the prediabetes number,” said Cornell. “We went from 88 to 96 million people with prediabetes—the question is, why?”

There has not only been an uptick in type 2 diabetes diagnoses, but also in type 1 diabetes diagnoses across the board for all people. Cornell said individuals are being diagnosed with type 2 diabetes at a younger age, and providers are seeing type 1 diabetes more in older adults. Contrary to the norm, obese individuals are being diagnosed with type 1 diabetes.

Although not all obese people will develop diabetes, more than 80% of people with diabetes are overweight or obese. Additionally, obesity is associated with coronary heart disease and end-stage kidney disease, which are common complications related to diabetes.

“With diabetes we are first looking at treating obesity,” said Cornell. “We have to look at obesity as a chronic disease state and it needs to get treated because the other chronic condition disease states that go with that will be more of a problem.”

For people with diabetes, providers need to look beyond the patient’s glycemic measures. Weight management, CVD, and CKD must be addressed and treated, along with lowering the patient’s glucose.

“There is no such thing as a person with just diabetes […] we need to look at the person as a whole. Not just their sugar, but their blood pressure, kidney function, cholesterol, smoking cessation, etc.,” Cornell said.

SGLT-2 inhibitors: Comparisons
	Canagliflozin (Invokana)	Dapagliflozin (Farxiga)	Empagliflozin (Jardiance)	Ertugliflozin (Steglatro)
Efficacy (A1C lowering)
Dose	100 mg and 300 mg taken once daily before first meal of the day	5 mg and 10 mg taken once daily before first meal of the day	10 mg and 25 mg taken once daily before first meal of the day	5 mg and 15 mg taken once daily before first meal of the day
Monotherapy	¯ 0.77–1.03%	¯ 0.8–0.9%	¯ 0.7–0.8%	¯ 0.7–0.8%
Combination	¯ 0.79–0.94%	¯ 0.7–0.8%	¯ 0.7–0.8%	¯ 0.7–0.9%
Cardiovascular benefit outcome trial	CANVAS	DECLARE-TIMI 58	EMPA-REG	VERTIS CV
Heart failure/Renal benefit outcome trial	CREDENCE	DAPA-HF; DAPA-CKD	EMPA-Kidney
Renal dose adjustment: eGFR—mL/min/1.73 m2
Reduce dose if	eGFR 45–59: 100 mg daily	Not recommended if eGFR 30–60	No recommendation	Not recommended if eGFR 30–60
Contraindicated if	eGFR < 45	eGFR < 30	eGFR < 30	eGFR < 30
Sources: Invokana package insert, Janssen Pharmaceuticals Inc., Titusville, NJ. Farxiga package insert. AstraZeneca Pharmaceuticals LP, Wilmington, DE. Jardiance package insert. Boehringer Ingelheim Pharmaceuticals, LP, Ridgefield, CT. Steglatro package insert, Merck & Co. Inc., Whitehouse Station, NJ.

Cost concerns

Sisson said he was pleased with ADA’s approach in the update, which considers the whole picture of the individual patient. “ADA has done a nice job this time around [in] recommending that it’s not a one-size-fits-all for patients and that social determinants of health need to be considered as well as juggling complex regimens—we need to think about those things,” he said.

Pharmacists are keenly aware of the cost issues for patients in obtaining insulin and other medications, noted Sisson. However, most providers in clinics are immune to pricing issues because they are not dealing with a patient’s health insurance or medication copays like pharmacists normally are.

“I’m excited about how [ADA] is starting to talk about the cost of medications and how that can affect medication taking behaviors,” Cornell said.

Included in the ADA update is a table with expectations of diabetes drug costs.

Experts all agree that lowering the costs of these newer type 2 diabetes drugs and reversing the trend toward more expensive analog insulin is needed.

A recent study in the Journal of Managed Care + Specialty Pharmacy found that patients with type 2 diabetes were more likely to have a 60-day gap in insulin supply when the out-of-pocket cost was more than $35 per 30-day supply. For patients with type 1 diabetes, they were more likely to experience a 6-day gap in insulin supply when their out-of-pocket costs were more than $50 for a 30-day supply.

The cost of insulin has skyrocketed in the United States and remains high. According to 2020 data from HHS, the United States pays “dramatically” higher prices for insulin compared to other countries in the Organization for Economic Co-operation and Development.

“There was time when insulin prices were steady and then they just ballooned,” said Sisson.

Sisson sees patients in a free clinic and in a traditional university clinic where most patients are insured. Regardless of insurance status, he said patients struggle to afford insulin.

“Even with good insurance, the copay prices can add up,” Sisson said. “Consider that most patients with diabetes are on 5 to 8 medications off the bat, so even a $10 or $20 copay for each really adds up.”

Earlier this year, lawmakers passed a U.S. House of Representatives bill that would require Medicare and private insurance plans to limit the cost of insulin for patients to $35 a month for a 30-day supply or 25% of the price negotiated between manufacturers and plans, whichever is lower. The legislation is supposed to target PBMs.

Injectable GLP-1 RA comparison
	Exenatide BID	Lixisenatide	Liraglutide	Exenatide QW	Dulaglutide	Semaglutide
	Short-acting twice daily	Short-acting once daily	Long-acting once daily	Long-acting once weekly	Long-acting once weekly	Long-acting once weekly
Dose	5 mcg and 10 mcg	10 mcg and 20 mcg	0.6 mg, 1.2 mg, and 1.8 mg	2 mg	0.75 mg, 1.5 mg, 3 mg, and 4.5 mg	0.25 mg, 0.5 mg, 1.0 mg, and 2.0 mg
	within 30–60 min of am/pm meal	within 60 min of same meal	0.6 mg initially then ­ to 1.2 mg			0.25 mg initially then ­ to 0.5 mg
			Can ­ to 1.8 mg if needed			Can ­ to 1.0 mg or 2.0 mg if needed
Max dose	10 mcg BID	20 mcg daily	1.8 mg daily	2 mg weekly	4.5 mg weekly	2.0 mg weekly
Half-life	2–4 hours	2–4 hours	13 hours	5 days	5 days	7 days
Homology to GLP-1	53%	50%	97%	53%	90%	94%
Antibodies	44%	69.8%	8.6%	44%	2%	1%
CV benefit Outcome trial	Neutral?? -----	Neutral ELIXA	Yes LEADER	Neutral EXSCEL	Yes REWIND AWARD 7	Yes SUSTAIN-6
Renal dosing:	< 30 not recommended	< 15 avoid	No adjustment	< 30 not recommended	No adjustment	No adjustment
(eGFR— mL/min/1.73 m2)		15–59 use caution and monitor
Sources: Byetta package insert, AstraZeneca Pharmaceuticals Inc., Wilmington, DE. Adlyxin package insert, Sanofi, Inc., Bridgewater, NJ. Victoza package insert, Novo Nordisk, Inc., Princeton, NJ. Bydureon package insert, Bristol-Myers Squibb Co., Princeton, NJ. Trulicity package insert, Eli Lilly & Co., Indianapolis, IN. Ozempic package insert, Novo Nordisk, Inc., Princeton, NJ.						2.0 mg = coming in 2022

Other important ADA updates

Pharmacists should also be aware that the COVID-19 vaccine has been added to the immunization recommendations in the Comprehensive Medical Evaluation & Assessment of Comorbidities section of ADA’s 2022 Standards of Medical Care in Diabetes.

ADA includes an important change in the section on glycemic targets, too: time in range is now fully incorporated into the glycemic assessment.

To monitor glucose, the use of personal continuous glucose monitoring (CGM) devices is becoming more convenient and affordable for patients. They also provide data that can help patients and providers better manage diabetes.

“Pharmacists need to get familiar with diabetes technology—it’s the future, and to me personally it’s a game changer,” said Cornell.

With the increased use of personal and professional CGM, pharmacists need to understand the concept of time in range, said Cornell. Time in range is the amount of time a person with diabetes is within the target glucose range within a 24-hour period. The specific criteria are based on whether the individual has type 1 or type 2 diabetes, as well as their age. In general, most people should be within the range of 70–180 mg/dL for at least 70% of the day, or about 16 hours, if not more.

“As CGM gets more affordable and popular, this time in range may tighten,” said Cornell. She noted that patients experience less complications and ED visits when they have better time in range.

ADA also updated some terminology: “Self-monitoring of blood glucose” is being replaced with “blood glucose monitoring,” and “smart pens” are now referred to as “connected insulin pens.”

In the new Standards of Care, there are also updates to the management of type 1 diabetes for adults.

“Everything has always been type 2 diabetes, [type 1 diabetes] has kind of been neglected,” said Cornell. “We are also seeing an uptick in misdiagnosis. We see people who are older and because of their age they are diagnosed with having type 2 diabetes, but they have type 1. We need to diagnose appropriately to get the person the right treatment.” ■

Comparative effectiveness meta-analysis of diabetes medications
Therapy	Efficacy	Hypoglycemia	Weight change	CV effects: ASCVD	CV effects: HF	Cost	Oral/SQ	Renal effects: progression of DKD	Renal effects: dosing/use considerations*	Additional considerations
Metformin	High	No	Neutral (potential for modest loss)	Potential benefit	Neutral	Low	Oral	Neutral	Contraindicated with eGFR < 30 mL/min/1.73 m2	GI adverse effects common (diarrhea, nausea) Potential for B12 deficiency
SGLT-2 inhibitors	Intermediate	No	Loss	Benefit: empagliflozin†, canagliflozin†	Benefit: empagliflozin†, canagliflozin, dapagliflozin‡, ertugliflozin	High	Oral	Benefit: empagliflozin, canagliflozin§, dapagliflozin§	See labels for renal dose considerations of individual agents Glucose-lowering effect is lower for SGLT-2 inhibitors at lower eGFR	Should be discontinued before any scheduled surgery to avoid potential risk for DKA DKA risk (all agents, rare in T2D) Risk of bone fractures (canagliflozin) Genitourinary infections Risk of volume depletion, hypotension Higher LDL cholesterol Risk of Fournier’s gangrene
GLP-1 Ras	High	No	Loss	Benefit: dulaglutide†, liragludtide†, semaglutide (SQ)† Neutral: exenatide once weekly, lixisenatide	Neutral	High	SQ; oral (semaglutide)	Benefit on renal end points in CVOTs, driven by albuminuria outcomes: liraglutide, semaglutide (SQ), dulaglutide	See labels for renal dose considerations of individual agents No dose adjustment for dulaglutide, liraglutide, semaglutid Caution when initiating or increasing dose due to potential risk of nausea, vomiting, diarrhea, or dehydration. Monitor renal function in patients reporting severe adverse GI reactions when initiating or increasing does of therapy.	FDA black box: risk of thyroid C-cell tumors in rodents; human relevance not determined (liraglutide, dulaglutide, exenatide extended release, semaglutide) GI adverse effects common (diarrhea, nausea, vomiting) Injection site reactions Pancreatitis has been reported in clinical trials, but causality has not been established. Discontinue if pancreatitis is suspected.
DPP-4 inhibitors	Intermediate	No	Neutral	Neutral	Potential risk: saxagliptin	High	Oral	Neutral	Renal dose adjustment required (sitagliptin, saxagliptin, alogliptin); ca be used in renal impairment No dose adjustment required for linagliptin	Pancreatitis has been reported in clinical trials, but causality has not beenestablished. Discontinue if pancreatitis is suspected. Joint pain
Thiazolidinediones	High	No	Gain	Potential benefit: pioglitazone	Increased risk	Low	Oral	Neutral	No dose adjustment required Generally not recommended in renal impairment due to potential for fluid retention	FDA black box: congestive HF (pioglitazone, rosiglitazone) Fluid retention (edema; heart failure) Benefit in NASH Risk of bone fractures Bladder cancer (pioglitazone) Higher LDL cholesterol (rosiglitazone)
Sulfonylureas (second generation)	High	Yes	Gain	Neutral	Neutral	Low	Oral	Neutral	Glyburide: generally not recommended in chronic kidney disease Glipizide and glimepiride: initiate conservatively to avoid hypoglycemia	FDA special warning on increased risk of cardiovascular mortality based on studies of an older sulfonylurea (tolbutamide)
Insulin	High	Yes	Gain	Neutral	Neutral			Neutral	Lower insulin doses required with a decrease in eGFR; titrate per clinical response	Injection site reactions Higher risk of hypoglycemia with human insulin (NPH or premixed formulations) vs. analogs
Human						Low (SQ)	SQ; inhaled
Analogs						High	SQ
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic steatohepatitis; SGLT-2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2D, type 2 diabetes. *For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information; †FDA-approved for CV disease benefit; ‡FDA-approved for HF indication; §FDA-approved for chronic kidney disease indication. Source: American Diabetes Association Professional Practice Committee. Diabetes Care. 2022;45(Supplement_1):S125–S143.