Ada Treatment Standards
Ada Treatment Standards
Ada Treatment Standards
Insulin Therapy
Because the hallmark of type 1 diabetes is absent or near-absent b-cell function,
insulin treatment is essential for individuals with type 1 diabetes. In addition to
hyperglycemia, insulinopenia can contribute to other metabolic disturbances like
hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be
life threatening. Severe metabolic decompensation can be, and was, mostly pre-
vented with once or twice daily injections for the six or seven decades after the
discovery of insulin. However, over the past three decades, evidence has accumulated
supporting more intensive insulin replacement, using multiple daily injections of Suggested citation: American Diabetes Associa-
insulin or continuous subcutaneous administration through an insulin pump, as tion. 2. Pharmacologic approaches to glycemic
providing the best combination of effectiveness and safety for people with type 1 treatment: Standards of Medical Care inDiabetesd
diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110
intensive therapy with multiple daily injections or continuous subcutaneous insulin © 2019 by the American Diabetes Association.
infusion (CSII) reduced A1C and was associated with improved long-term outcomes Readers may use this article as long as the work
is properly cited, the use is educational and not
(1–3). The study was carried out with short-acting (regular) and intermediate-acting for profit, and the work is not altered. More infor-
(NPH) human insulins. In this landmark trial, lower A1C with intensive control (7%) mation is available at http://www.diabetesjournals
led to ;50% reductions in microvascular complications over 6 years of treatment. .org/content/license.
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99
However, intensive therapy was associ- meta-analysis concluded that pump ther- Typical multidose regimens for pa-
ated with a higher rate of severe hypo- apy has modest advantages for lowering tients with type 1 diabetes combine
glycemia than conventional treatment (62 A1C (–0.30% [95% CI –0.58 to –0.02]) and premeal use of shorter-acting insulins
compared with 19 episodes per 100 pa- for reducing severe hypoglycemia rates with a longer-acting formulation, usually
tient-years of therapy). Follow-up of sub- in children and adults (11). However, there at night. The long-acting basal dose is
jects from the DCCT more than 10 years is no consensus to guide the choice of titrated to regulate overnight, fasting
after the active treatment component of injection or pump therapy in a given glucose. Postprandial glucose excur-
the study demonstrated less macrovas- patient, and research to guide this sions are best controlled by a well-timed
cular as well as less microvascular com- decision-making is needed (12). The arrival injection of prandial insulin. The opti-
plications in the group that received of continuous glucose monitors to clinical mal time to administer prandial insulin
intensive treatment. practice has proven beneficial in specific varies, based on the pharmacokinetics
Over the last 25 years, rapid-acting and circumstances. Reduction of nocturnal of the formulation (regular, RAA, in-
*For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD benefit. ‡FDA-approved for heart failure indication; §FDA-approved for CKD
indication. CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic
steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes.
Pharmacologic Approaches to Glycemic Treatment
S101
approach to choosing appropriate phar- very high circulating levels (e.g., as a re- positive and negative effects of new drugs
macologic treatment of blood glucose sult of overdose or acute renal failure) and reduces patient risk and expense (42);
(Fig. 9.1). This includes consideration of have been associated with lactic acidosis. based on these factors, sequential addi-
efficacy and key patient factors: 1) im- However, the occurrence of this compli- tion of oral agents to metformin has been
portant comorbidities such as atheroscle- cation is now known to be very rare, and the standard of care. However, there is
rotic cardiovascular disease (ASCVD) and metformin may be safely used in patients data to support initial combination ther-
indicators of high ASCVD risk, chronic with reduced estimated glomerular filtra- apy for more rapid attainment of glycemic
kidney disease (CKD), and heart failure tion rates (eGFR); the FDA has revised the goals (43,44), and a recent clinical trial
(HF) (see Section 10 “Cardiovascular Dis- label for metformin to reflect its safety in has demonstrated that this approach is
ease and Risk Management,” https://doi patients with eGFR $30 mL/min/1.73 m2 superior to sequential addition of medica-
.org/10.2337/dc20-S010, and Section 11 (37). A recent randomized trial confirmed tions for extending primary and secondary
“Microvascular Complications and Foot previous observations that metformin use failure (45). In the VERIFY trial, partic-
Figure 9.1—Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular;
CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF,
heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies and colleagues (33,34).
Pharmacologic Approaches to Glycemic Treatment
S103
Figure 9.2—Intensifying to injectable therapies. DSMES, diabetes self-management education and support; FPG, fasting plasma glucose; FRC, fixed-ratio
combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (33).
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S105
failure, an SGLT-2 inhibitor or GLP-1 RA with preferred option for patients requiring Insulin Therapy
demonstrated CVD benefit (Table 9.1, the potency of an injectable therapy for Many patients with type 2 diabetes even-
Table 10.3B, Table 10.3C) is recommended glucose control (Fig. 9.2). However, high tually require and benefit from insulin
as part of the glucose-lowering regimen costs and tolerability issues are impor- therapy (Fig. 9.2). See the section INSULIN
independent of A1C and in consideration of tant barriers to the use of GLP-1 RAs. INJECTION TECHNIQUE above, for guidance on
patient-specific factors (Figure 9.1). For Cost for diabetes medicine has in- how to administer insulin safely and
patients without established ASCVD, indi- creased dramatically over the past two effectively. The progressive nature of
cators of high ASCVD risk, HF, or CKD, the decades, and an increasing proportion is type 2 diabetes should be regularly
choice of a second agent to add to met- now passed on to patients and their families and objectively explained to patients,
formin is not yet guided by empiric evi- (53). Table 9.2 provides cost information for and providers should avoid using insulin
dence. Rather, drug choice is based on currently approved noninsulin therapies. Of as a threat or describing it as a sign of
avoidance of side effects, particularly hy- note, prices listed are average wholesale personal failure or punishment. Rather,
Table 9.2—Median monthly (30-day) cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.
Dosage strength/product Median AWP Median NADAC Maximum approved
Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose*
Biguanides c Metformin 500 mg (IR) $84 ($4, $85) $2 2,000 mg
850 mg (IR) $108 ($6, $109) $3 2,550 mg
1,000 mg (IR) $87 ($4, $88) $2 2,000 mg
500 mg (ER) $89 ($87, $7,412) $5 ($5, $988) 2,000 mg
750 mg (ER) $74 ($65, $74) $4 1,500 mg
1,000 mg (ER) $242 ($242, $7,214) $224 ($224, $910) 2,000 mg
Sulfonylureas (2nd c Glimepiride 4 mg $74 ($71, $198) $4 8 mg
generation) c Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR)
10 mg (XL) $48 $15 20 mg (XL)
c Glyburide 6 mg (micronized) $50 ($48, $71) $4 12 mg (micronized)
a pace several fold that of other medical familiar with its use (75). Human regular patient needs (see Figure 9.2). People
expenditures (76). This expense contrib- insulin, NPH, and 70/30 NPH/regular prod- with type 2 diabetes are generally more
utes significant burden to patients as ucts can be purchased for considerably insulin resistant than those with type 1
insulin has become a growing “out-of- less than the AWP and NADAC prices listed diabetes, require higher daily doses (;1
pocket” cost for people with diabetes, in Table 9.3 at select pharmacies. unit/kg), and have lower rates of hypo-
and direct patient costs contribute to glycemia (77). Titration can be based
treatment nonadherence (76). Therefore, Prandial Insulin on home glucose monitoring or A1C.
consideration of cost is an important com- Many individuals with type 2 diabetes With significant additions to the prandial
ponent of effective management. For require doses of insulin before meals, in insulin dose, particularly with the evening
many patients with type 2 diabetes addition to basal insulin, to reach glyce- meal, consideration should be given to
(e.g., individuals with relaxed A1C goals, mic targets. A dose of 4 units or 10% of decreasing basal insulin. Meta-analyses
low rates of hypoglycemia, and prominent the amount of basal insulin at the largest of trials comparing rapid-acting insulin
insulin resistance, as well as those with meal or the meal with the greatest post- analogs with human regular insulin in
cost concerns), human insulin (NPH and prandial excursion is a safe estimate for patients with type 2 diabetes have not
regular) may be the appropriate choice initiating therapy. The prandial insulin reported important differences in A1C
of therapy, and clinicians should be regimen can then be intensified based on or hypoglycemia (78,79).
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S107
Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (54) and NADAC (55) per 1,000 units of specified dosage
form/product
Insulins Compounds Dosage form/product Median AWP (min, max)* Median NADAC (min, max)*
Rapid-acting c Lispro follow-on U-100 vial $157 $126
product U-100 prefilled pen $202 $162
c Lispro U-100 vial $330 $264
U-100 3 mL cartridges $408 $327
U-100 prefilled pen; U-200 $424 $340
prefilled pen
c Glulisine U-100 vial $341 $273
U-100 prefilled pen $439 $353
c Aspart U-100 vial $347† $278†
U-100 3 mL cartridges $430 $345
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