Tre a t m e n t o f Typ e 2 D i a b e t e s

in Patients with O besity

A Review

Heidi Guzman, MD1, Leen Z. Hasan, MD

1
,
Tirissa J. Reid, MD, DABOM*

KEYWORDS
 Type 2 diabetes mellitus  Obesity  Treatment  Pharmacotherapy  Tirzepatide
 Semaglutide

KEY POINTS
 Prioritize glycemic control to minimize complications of type 2 diabetes.
 Minimize therapies for type 2 diabetes which promote weight gain.
 Prioritize type 2 diabetes therapies which promote weight loss.
 Individualize therapies to target additional comorbidities.

INTRODUCTION

Obesity, defined as body mass index (BMI) greater than or equal to 30 kg/m2, is a ma-
jor risk factor for type 2 diabetes mellitus (T2DM), the eighth leading cause of death in
the United States. Both conditions have been declared epidemics in the United States
by the World Health Organization (WHO), with a rapidly rising prevalence over the past
3 decades.1 The prevalence of T2DM among the US adults is 14.7%, highest among
older age groups, men, black, Asian, and Hispanic ethnicities.1 There is a strong inter-
relationship in the pathophysiology, genetic, and environmental risk factors for T2DM
and obesity. Understanding these intertwined relationships is crucial given the sub-
stantial burden they impose on individuals and society, and for understanding overlap-
ping pharmacologic targets.2 The role of weight management in improving glycemic
control and prevention of T2DM has been well-established.3–5 In this review, we will
discuss the overlap in pathophysiology between obesity and T2DM, highlighting the

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Columbia

University College of Physicians and Surgeons, Columbia University Irving Medical Center, New
York, NY, USA
1
Equal co-first authors: Heidi Guzman and Leen Hasan contributed equally to the article.
* Corresponding author. Columbia University Irving Medical Center, Dept of Medicine- Division
of Endocrinolgy, Metabolic and Weight Control Center, 51 Audubon Avenue, 5th Floor, New
York, NY 10032.
E-mail address: tjr2122@cumc.columbia.edu

Endocrinol Metab Clin N Am - (2024) -–-

https://doi.org/10.1016/j.ecl.2024.10.004 endo.theclinics.com
0889-8529/24/ª 2024 Elsevier Inc. All rights are reserved, including those for text and data mining,
AI training, and similar technologies.
2 Guzman et al

current treatment options, along with the challenges in management for patients with
both conditions.

THE PATHOPHYSIOLOGY OF GLUCOSE INTOLERANCE IN TYPE 2 DIABETES

MELLITUS AND OBESITY
Beta-Cell Dysfunction
Several theories have been proposed to explain b-cell dysfunction resulting in glucose
intolerance. Animal studies showed excessive and prolonged exposure of b cells to
hyperglycemia results in abnormal levels of oxidative stress, surpassing the capabil-
ities of antioxidant enzymes inside the cell, eventually leading to decreased insulin
gene expression.6 Oxidative stress plays a key role in the pathogenesis of T2DM;
high serum markers of oxidative stress are common in patients with diabetes, and
the treatment of hyperglycemia results in improved cellular scavenger activity.7,8
The impact of prolonged exposure of b cells to free fatty acids (FFAs) has been
investigated with in vitro and in vivo studies. Chronic exposure to elevated levels of
FFAs, seen in patients with obesity, suppresses glucose-stimulated insulin secretion.
Additionally, FFAs cause impairment in insulin gene expression9 and b-cell apoptosis
through endoplasmic reticulum stress, which activates a cascade of distinct pathways
resulting in cellular apoptosis.10
Insulin Resistance
As a major anabolic hormone, insulin plays a key role in maintaining glucose homeo-
stasis. It regulates blood glucose levels by enhancing glucose uptake in skeletal mus-
cle and adipose tissue via the glucose transporter type 4 (GLUT4). Additionally, insulin
promotes uptake of FFAs and the synthesis of triglycerides in adipose tissue while
suppressing lipolysis and hepatic gluconeogenesis.11,12 Insulin resistance (IR), char-
acterized by diminished response to insulin in target tissues (eg, skeletal muscle
and adipose tissue),13 is a fundamental contributor to glucose intolerance in patients
with obesity. The abnormal accumulation of FFAs in the liver of some patients with
obesity disrupts insulin-mediated regulation of gluconeogenesis, exacerbates hyper-
glycemia, and contributes to the development of T2DM.12,14
Incretins in Glucose Intolerance and Obesity
Incretins are endogenous gastrointestinal (GI) hormones, primarily glucagon-like pep-
tide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), playing a sig-
nificant role in glucose homeostasis by stimulating insulin secretion from pancreatic b
cells in response to an oral glucose load. Their dysfunction is implicated in glucose
intolerance and obesity-related T2DM. GLP-1, secreted by L-cells in the ileum and co-
lon, increases insulin secretion, inhibits glucagon release, slows gastric emptying, and
promotes satiety, all of which regulate postprandial glucose levels.15,16 In obesity,
GLP-1 secretion is reduced, leading to inadequate insulin response and suboptimal
glycemic control.17 Obesity can cause GLP-1 resistance, as b cells become less
responsive to GLP-1, worsening hyperglycemia.18,19 GLP-1’s role in promoting satiety
is also affected, leading to overeating and further weight gain, worsening IR, and hy-
perglycemia.20 GIP, secreted by K-cells in the duodenum and jejunum, also stimulates
insulin secretion. Unlike GLP-1, GIP levels are often elevated in patients with obesity,
as fat is a potent stimulus of GIP secretion, but its insulinotropic effect is diminished,
indicating GIP resistance.21 Also, GIP promotes lipid storage and adipogenesis, which
worsens obesity and IR, creating a feedback loop which worsens metabolic dysfunc-
tion.22 In patients with obesity and T2DM, incretin function is often impaired, with
studies showing diminished GLP-1 secretion and reduced insulin-stimulating effects
 Treatment of Type 2 Diabetes in Patients with Obesity 3

of GIP.23 These impairments in incretin function explain why incretin analogs are effi-
cacious for both the conditions.

GOALS

Glycemic control and prevention of diabetes-related complications are the goals of

treatment. Glycemic goals should be individualized to the patient’s medical history,
age, and comorbidities. For most nonpregnant adults, a hemoglobin A1c (HbAlc) of
less than 7% in the absence of recurrent hypoglycemia is the target treatment goal.
Patients over age 65 with multiple comorbidities or at higher risk for hypoglycemia
may have a less stringent HbA1c goal of less than 8%. A weight-centric management
strategy can help achieve these goals, and in some cases can lead to T2DM remission.
Weight loss of 3% to 7% can reduce HbA1c and cardiovascular risk factors. Patients
with weight loss greater than or equal to 10% have higher rates of diabetes remission
and improvements in quality of life.24

THERAPEUTIC OPTIONS

Pharmacologic therapy should be used in conjunction with lifestyle modification and

diabetes patient education. Pharmacologic management should be tailored to the in-
dividual patient’s medical history, glycemic targets, weight management goals, and
social determinants of health.
Pharmacologic therapies which contribute to weight gain should be avoided or mini-
mized in patients with T2DM and obesity. These medications include insulin secreta-
gogues like sulfonylureas, meglitinides, and thiazolidinediones. Insulin is weight-
promoting but should be considered among patients with severe hyperglycemia.
Metformin was previously considered first-line therapy to manage T2DM. However,
the increased efficacy of incretins in treating both T2DM and obesity has made them
first-line therapy, with tirzepatide and semaglutide being the most efficacious.
Patients with a history of cardiovascular disease (CVD) or CVD risk factors, like hy-
pertension and hyperlipemia, should first be considered for the treatment with GLP-1
agonists and/or sodium-glucose cotransporter-2 inhibitors (SGLT2i), which have clin-
ical data to support CVD risk reduction.
Metformin
Metformin helps to improve insulin sensitivity, decreases glucose production in the
liver, and helps decrease absorption of glucose in the intestines. It is generally well-
tolerated, affordable, reduces CVD mortality, and studies show mixed effects on
weight, with either no difference or modest weight loss ( 3.8 kg in the Metformin
Study Group).25
Glucagon-Like Peptide-1 and Dual Glucagon-Like Peptide-1/Glucose-Dependent
Insulinotropic Polypeptide Agonists
GLP-1 and GIP agonists mimic the naturally occurring incretin hormones secreted
from the intestines described earlier. Randomized controlled studies with GLP-1 ag-
onists have shown a significant reduction in mean HbA1c from 0.61% to 2.10%,
and up to 15% total body weight loss (TBWL).26 Along with glycemic benefits, studies
have shown the dual GLP-1/GIP agonist tirzepatide causes reductions in waist
circumference and up to 20% TBWL.27 These weight loss benefits further contribute
to glycemic control and help improve other comorbidities such as hepatic steatosis. A
meta-analysis of GLP-1 agonists compared with placebo found a 12% to 14% reduc-
tion in major adverse cardiovascular event (MACE) outcomes.28
4 Guzman et al

SGLT2 Inhibitors
Sodium-glucose cotransporter-2 inhibitors are antihyperglycemic agents, reducing
glucose reabsorption in the renal tubules leading to increased glucose excretion in
the urine and a reduction in blood glucose levels. Meta-analysis has shown mean
HbA1c reductions of 0.5% to 1.4% compared with placebo.29 SGLT2i have also
been shown to provide reductions in CVD risk, nephropathy progression, and confer
modest weight loss benefits. SGLT2i can reduce weight by directly removing 60 to
100 g of glucose through the urine and, therefore, removing calories.29 In the
EMPA-REG trial with over 7000 patients with T2DM, randomized to receive empagli-
flozin versus placebo for 3.1 years, patients on empagliflozin, had reductions in MACE
with an average weight loss of 2 kg.30
Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors are not considered first-line therapy for the management
of T2DM due to modest HbA1c reductions and poor tolerability. They delay absorption
of dietary carbohydrates, slowing the postprandial glucose increase. In a meta-
analysis of alpha-glucoside inhibitor use versus placebo, alpha-glucosidase inhibitors
led to a mean HbA1c reduction of 0.68% to 0.77%.31 Some weight loss benefits
have also been noted with a systemic review reporting weight loss of 0.4 to
0.7 kg.32
Pramlintide
Pramlintide is an amylin mimetic which works to reduce postprandial hyperglycemia.
Similar to GLP-1 agonists, pramlintide helps reduce gastric emptying, reduce inappro-
priate postprandial glucagon secretion, and increase satiety. Pramlintide efficacy in
lowering HbA1c ranges from 0.2% to 0.7% above placebo. Significant weight loss
has been reported versus placebo, with reductions in body weight of 1.5 to 2.5 kg.33
Bariatric Surgery
Bariatric surgery is currently the most effective tool for treating T2DM and obesity and
should be considered for patients with a BMI of greater than or equal to 30.0 kg/m2 if
other therapies have failed among surgically appropriate candidates. Research has
shown overall remission rates of up to 68.2% after gastric bypass surgery with a me-
dian remission duration of 8.3 years.34

CURRENT EVIDENCE

Clinical trials have shown significant weight loss benefits of GLP-1 agonists and dual
GLP-1/GIP agonists leading to independent Food and Drug Adminstration (FDA)
approval for obesity management. The first GLP-1 agonist approved to treat obesity
was liraglutide. Multiple studies have documented the weight loss potential of liraglu-
tide, including the LEADER trial. In the LEADER trial, over 9000 patients with T2DM
were randomized to liraglutide versus placebo and followed over 3.8 years. Patients
on liraglutide achieved a lower HbA1c, a reduction in MACE, and an average weight
loss of 2.3 kg.35 Semaglutide was the second antihyperglycemic agent the FDA
approved to treat obesity. Similar to liraglutide, the SUSTAIN-6 trial found that the
semaglutide was associated with a significant reduction in MACE outcomes and
HbA1c reduction, with a greater weight loss benefit, an average weight loss of
4.3 kg.36 See Table 1 for a summary of GLP-1 agonist clinical trials examining
CVD risk reduction. Tirzepatide is the dual incretin therapy most recently the FDA
approved to treat obesity. The SURPASS-1 trial was a randomized clinical trial
 Treatment of Type 2 Diabetes in Patients with Obesity 5

Table 1
Glucagon-like peptide-1 agonist clinical trials examining cardiovascular disease and
nephropathy reduction versus placebo

LEADER35 SUSTAIN-636 REWIND38

(Liraglutide) (Semaglutide) (Dulaglutide)
Study population 9340 3297 9901
Median follow-up 3.8 y 2.1 y 5.4 y
3-point MACE (CV mortality, 13% vs 14.9% 6.6% vs 8.9% 12% vs 13.4%
nonfatal MI, or nonfatal NNT 52.6, P 5 .01 NNT 43.5, P 5 .02 NNT 71.4, P 5 .026
stroke)
New or worsening 5.7% vs 7.2% 3.8% vs 6.1% 17.1% vs 19.6%
nephropathy NNT 66.6, P 5 .003 NNT 43.5, P 5 .005 NNT 40, P 5 .0004
Weight change 2.3 kg 4.3 kg (1 mg dose) 1.46 kg

Data comparisons presented as % with outcome in active drug group versus placebo group.
NNT refers to the number of patients who need to be treated with the active drug to prevent one
additional adverse outcome (MACE or new/worsening nephropathy).
NNT 5 1/Absolute Risk Reduction (event rate in placebo group – event rate in active therapy
group).
Abbreviations: CV, cardiovascular; MACE, major adverse cardiovascular event; MI, myocardial
infarction; NNT, number needed to treat.

evaluating the efficacy of tirzepatide in HbA1c lowering over 40 weeks. The trial
demonstrated that tirzepatide lowered HbA1c at various doses with most participants
achieving an HbA1c goal of less than 7%. The study also showed a dose-dependent
weight loss benefit ranging from 7 to 9.5 kg.37

PATIENT MONITORING, SIDE EFFECTS AND ADVERSE EVENTS

Metformin
Metformin is renally cleared and contraindicated in patients with GFR less than 30 mL/
min. Patients with a glomerular filtration rate (GFR) between 30 and 45 mL/min should
not exceed a dose of 1000 mg/d. The most common side effects of metformin are
gastrointestinal, including bloating and diarrhea. Metformin extended-release tends
to be better tolerated. Metformin is associated with vitamin B12 deficiency and should
be monitored periodically. Metformin-associated lactic acidosis is a rare side effect
which can occur in patients with impaired renal, cardiovascular, or hepatic function.

Glucagon-Like Peptide-1 and Dual Glucagon-Like Peptide-1/Glucose-Dependent

Insulinotropic Polypeptide Agonists
GLP-1 agonists and dual GLP-1/GIP agonists are most associated with GI intolerance.
Due to the delay in gastric emptying, patients can develop nausea, vomiting, and con-
stipation. Less commonly, gallstone and biliary disease or more serious conditions like
bowel obstruction, may rarely occur. Dehydration with cases of acute kidney injury has
been reported; renal function should be monitored routinely. Exenatide is the only
GLP-1 agonist contraindicated in patients with a creatinine clearance less than
30 mL/min. GLP-1 and dual GLP-1/GIP agonists should not be used in patients with
a family or personal history of multiple endocrine neoplasia syndrome type 2
(MEN2) or medullary thyroid cancer. Pancreatitis has also been reported in postmar-
keting surveillance and clinical trials.39,40 However, a recent meta-analysis of 43 trials
examining GLP-1 agonist use and pancreatitis risk found no significant association.41
Patients should be informed of this potential risk and be educated on symptoms of
pancreatitis. Patients with documented GLP-1 agonist-induced pancreatitis should
6 Guzman et al

not resume the medication. Postmarketing surveillance also noted reports of mental
health distress and suicidal ideation, but an FDA preliminary evaluation did not find ev-
idence of a direct association.42 Also, a retrospective study found a decreased risk for
suicidality in patients taking semaglutide.43 Hypoglycemia has been reported when
medications in this class are combined with insulin or insulin secretagogues.

SGLT2 Inhibitors
Given their mechanism of action, osmotic diuresis through glucosuria, patients should
have baseline renal function and volume status assessments before and after initiating
SGLT2i. There is a potential for dehydration and intravascular volume depletion result-
ing in acute kidney injury and a decrease in blood pressure. Hyperkalemia has also
been reported, especially among patients on angiotensin-converting enzyme inhibi-
tors or angiotensin receptor blockers after starting SGLT2i therapy.44 SGLT2i should
be renally dosed and are contraindicated in patients on dialysis. Patients on diuretic
therapy should be monitored closely when adding SGLT2i or doses may need to be
reduced prior to commencement.
Patients should be advised of an increased risk for mycotic infections with this class
of medication. Studies show mixed findings regarding an increased risk of urinary tract
infections (UTIs) and SGLT2i use,45,46 but patients can be monitored for signs of UTI
and a urinalysis can be obtained for patients with dysuria. Euglycemic diabetic ketoa-
cidosis can be precipitated by SGLT2i use. Patients present with an anion gap meta-
bolic acidosis with serum glucose of less than 250 mg/dL. This risk is further increased
in patients predisposed to a ketogenic state such as an infection, missed insulin
doses, or during a prolonged fast for a procedure or surgery.47 It is now recommended
that SGLT2i are held 3 to 4 days prior to medical procedures to reduce this risk. Four-
nier’s gangrene, a necrotizing fasciitis of the perineum, is a rare complication of
SGLT2i.
The CANVAS trial noted a higher risk of limb ischemia among patients with diabetes
taking canagliflozin; however, further clinical trials have not found this association.48
Given this mixed finding, SGLT2i can be used in patients with stable peripheral arterial
disease but used with caution or avoid in patients with critical limb-threatening
ischemia.
Hypoglycemia can also occur when SGLT2i are combined with insulin and/or insulin
secretagogues. Doses of insulin or other oral antihyperglycemic agents may need to
be adjusted when adding SGLT2i.

Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors can cause GI discomfort, including bloating, diarrhea
and flatulence. This class has notable drug interactions, including digoxin and valproic
acid, and has rarely been associated with pneumatosis cystoides intestinalis, a con-
dition characterized by gas-filled cysts within the walls of the intestines.49

Pramlintide
Pramlintide can increase the risk for severe insulin-induced hypoglycemia. Patients on
insulin should be monitored closely and their pramlintide doses gradually titrated.
Pramlintide is also associated with GI side effects including nausea and vomiting.50

CHALLENGES

Cost is a prime consideration when choosing medication therapy for both T2DM and
obesity, particularly with incretin-based therapies. While tirzepatide and semaglutide
 Treatment of Type 2 Diabetes in Patients with Obesity 7

are typically covered by insurers for patients with T2DM, prior authorization is
frequently required, and some insurers require patients use and fail less expensive
medications prior to using GLP-1 or GLP-1/GIP R agonists.
As knowledge of the varied benefits of incretin-based therapies continues to
expand, including efficacy for T2DM, obesity, heart failure, and prevention of cardio-
vascular events, demand is overwhelming, and these medications frequently appear
on the FDA-shortage list. Limited availability has resulted in disruptions to therapy
for patients on stable maintenance doses. Missing multiple consecutive doses in-
creases the risk for adverse effects with resumption of the medication and may neces-
sitate a lower dose with titration back to their maintenance dose if the length of
disruption is significant. Aside from inconvenience, which may lessen patient interest
in these medications, interruptions in therapy may lead to inadequate glycemic con-
trol. While weekly incretin-based injections are highly effective therapies for T2DM
and obesity, there are patients who remain reticent about using an injectable medica-
tion therapy, and thus far oral therapies are currently unable to match their efficacy.

DISCUSSION

When approaching the task of glycemic control in patients with T2DM, glycemic con-
trol to prevent the related comorbidities remains the top priority; however, the prom-
inent comorbidity of obesity should be top of mind when considering therapeutic
options. T2DM and obesity share common pathophysiologic features,51 and both
are major risk factors for CVD, which ranks highly as a cause of death in both condi-
tions.52 Therapy which effectively targets both disease states is preferred. We know
insulin in sufficient doses can improve glycemic control; however, given its anabolic
effects causing weight gain, it is not preferred in patients affected by T2DM and
obesity. However, in patients with severe hyperglycemia, HbA1c greater than 10%, in-
sulin may initially be required. This weight-promoting effect is also shared by sulfonyl-
ureas and thiazolidinediones, which should be avoided in treating patients with T2DM
and obesity. Outside of insulin therapy, dual agonist GLP-1/GIP therapy followed by
GLP-1 agonist therapy, currently exhibit the greatest potency for treating T2DM, while
GLP-1 therapy has additional cardiovascular benefits as well. These considerations
should be top of mind when choosing a medication, with contraindications included
in the calculus.

SUMMARY

The more recent development of potent subcutaneous incretin-based therapies with

greater efficacy in treating T2DM and obesity make these the preferred agents in pa-
tients with both conditions. Cost and supply limitations are prevalent and must be
considered, along with individualizing therapy based on therapeutic goals and treat-
ment/prevention of additional comorbidities. This means other, less potent therapies
for T2DM, such as metformin and SGLT2i continue to play a key role in treating T2DM
in patients with obesity. Combination treatment strategies targeting different patho-
physiologic mechanisms may also be necessary to reach glycemic targets.

CLINICS CARE POINTS

 Minimize the use of medications for T2DM therapy which cause weight gain, including
insulin, sulfonylureas, meglitinides, and thiazolidinediones.53 For patients with severe
8 Guzman et al

hyperglycemia (HbA1c > 10), insulin therapy may be the most prudent initial therapy, with
down-titration at a later time while adding a weight loss-promoting medication.
 In patients with T2DM and obesity, without additional comorbidities, the dual GIP/GLP-1 R
agonist tirzepatide and GLP-1 R agonist semaglutide are currently preferred therapies
given their greater glycemic reduction and mean weight loss over other agents. If these are
unavailable, other subcutaneous GLP-1 R agonists should be considered, followed by SGLT2i,
metformin, and finally the weight neutral dipeptidyl peptidase-4 (DPP-4) inhibitors.
 For those with T2DM and obesity, the presence of additional comorbid conditions should
further guide the choice of agent; semaglutide, dulaglutide, and liraglutide have proven
ability to reduce MACE,35,36,38,54,55 while SGLT2i have proven benefits in patients with CVD,
heart failure, and chronic kidney disease.
 Metabolic and bariatric surgery remains the most effective and durable therapy for patients
with T2DM and obesity and should be considered for patients who have difficulty achieving
glycemic control with medication therapy, prefer to avoid chronic medication therapy, or do
not have reliable access to the most effective medication therapies.56–58

DISCLOSURE

None of the authors have any commercial or financial conflicts of interest or funding
sources to disclose.

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